Preguntas de Cardiology 2016

z.
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PSAP 2016 BOOK 1 CARDIOLOGY
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Pharmacotherapy
Self-Assessment
Program
Table of Contents
Cardiology I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Faculty Panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cardiology II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Faculty Panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Blood Pressure Management
85
87
Valvular Heart Disease
By Karen J. McConnell, Pharm.D., FCCP, BCPS-AQ Cardiology;

and William L. Baker, Pharm.D., FCCP, FACC, BCPS, AQ-Cardiology
By Douglas L. Jennings, Pharm.D., FCCP, FAHA, AACC, BCPS,

AQ-Cardiology
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
HTN Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Mitral Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
99
Uncomplicated HTN
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
HTN with Concomitant Disease States . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
Antithrombotic Potpourri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
101
Resistant HTN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
104
Ambulatory and Home Blood Pressure Monitoring . . . . . . . . . . . . .
19
References
Hypertensive Urgency and Emergency . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
HTN and Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
References
Infective Endocarditis
By Laura A. Siemianowski, Pharm.D., BCPS, BCCCP;
and Lucia Ros, Pharm.D., AAHIVP
Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Evaluation of Therapeutic Outcomes

Management of Antibiotic Allergies
New Dyslipidemia Management Guidelines . . . . . . . . . . . . . . . . . . . . .

Comparison of Previous and Current Dyslipidemia Treatment
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
36
. . . . . . . . . . . . . . . . . . . . . . . . . . 123
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Conclusion
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Cardiovascular Risk Assessment
. . . . . . . . . . . . . . . . . . . . 40
Application of Recommendations to Patient Care

Nonstatin Therapies
Oral Anticoagulants for VTE and

Stroke Prevention in Atrial Fibrillation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Traditional and Nontraditional Risk Factors
. . . . . . . . . . . . . . 43
By Nancy L. Shapiro, Pharm.D., FCCP, BCPS;

and Shubha Bhat, Pharm.D., BCACP
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
New Evidence for Use of Nonstatin Agents
Introduction
. . . . . . . . . . . . . . . . . . . . . . 48
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
49
Anticoagulant Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
135
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Treatment of VTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
136
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Stroke Prevention in Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . .
141
Treatment Controversies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
144
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
149
Emerging Therapies for Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References
Antimicrobial Prophylaxis
. . . . . . . . . . . . . . . . 34
. . . . . . . 112
. . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Role of Outpatient Antibiotic Therapy
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Historical Approach to Dyslipidemia Treatment
Conclusion
. . . . . . . . . . . . . . . . . . . . . . . . 112
Pharmacologic Management of Causative Organisms
By Laura H. Waite, Pharm.D., BCPS, CLS, BC-ADM;

and Yvonne L. Phan, Pharm.D., BCPS
Approaches
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Diagnosis and Role of Empiric Therapy
Dyslipidemia
Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Pulmonary Arterial Hypertension
References
By Kristen T. Pogue, Pharm.D., BCPS, AQ-Cardiology;

and Claire P. Walter, Pharm.D., BCPS
Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Therapeutic Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
Combination Therapy
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Treatment Guidelines
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Practical Considerations
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Conclusion
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
PSAP 2016 Book 1 Cardiology
iii
Table of Contents
A Message from the Editors

are just some of the features added to PSAP in response to
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John E. Murphy and Mary W. Lee, series editors
iv
Table of Contents
Cardiology I
Cardiology I
Series Editors:
Reviewers
John E. Murphy, Pharm.D., FCCP, FASHP

Professor of Pharmacy Practice and Science
Interim Dean for Academic Affairs and Assessment
University of Arizona College of Pharmacy
Tucson, Arizona
Tyan F. Thomas, Pharm.D., BCPS

Associate Professor of Clinical Pharmacy
Pharmacy Practice and Administration
Philadelphia College of Pharmacy,
University of the Sciences
Clinical Pharmacy Specialist
Department of Pharmacy
Corporal Michael J Crescenz VA Medical Center
Philadelphia, Pennsylvania
Mary Wun-Len Lee, Pharm.D., FCCP, BCPS

Vice President and Chief Academic Officer
Pharmacy and Optometry Education
Midwestern University
Professor of Pharmacy Practice
Chicago College of Pharmacy
Downers Grove, Illinois
Faculty Panel Chair
Sarah A. Spinler, Pharm.D., FCCP, BCPS
Professor of Clinical Pharmacy
Hypertension
Authors
Karen J. McConnell, Pharm.D., FCCP, BCPS, AQ-Cardiology
Clinical Director and Cardiology Subject Matter Expert
Innovative Delivery Solutions
Cardinal Health
Denver, Colorado
Clinical Associate Professor
Department of Clinical Pharmacy
University of Colorado Skaggs School of
Pharmacy and Pharmaceutical Sciences
Aurora, Colorado
William L. Baker, Pharm.D., FCCP,
FACC, BCPS, AQ-Cardiology
Assistant Professor
Department of Pharmacy Practice
University of Connecticut School of Pharmacy
Storrs, Connecticut
Stacy L. Elder, Pharm.D., BCPS

The Johns Hopkins Hospital
Baltimore, Maryland
Dyslipidemia
Authors
Laura Waite, Pharm.D., BCPS, CLS, BC-ADM
Assistant Professor of Clinical Pharmacy
Department of Pharmacy Practice and
Pharmacy Administration
Adult Internal Medicine Clinical Pharmacy Specialist
Hospital of the University of Pennsylvania
Yvonne L. Phan, Pharm.D., BCPS
Assistant Professor of Clinical Pharmacy
Department of Pharmacy Practice and
Pharmacy Administration
Cardiology Pharmacy Specialist
Hospital of the University of Pennsylvania
Reviewers
Mark J. Cziraky, Pharm.D., CLS, FAHA, FNLA
Vice President of Research
HealthCore Inc.
Wilmington, Delaware
Cassandra D. Benge, Pharm.D., BCPS, AQ-Cardiology, AACC

Clinical Pharmacy Specialist, Cardiology
Director, PGY2 Cardiology Residency
VA Tennessee Valley Healthcare System-Nashville Campus
Nashville, Tennessee
Sossity A. Riordan, Pharm.D., BCPS, BC-ADM
Diabetes Education and Prevention
Programs (Acting) Supervisor
Department of Diabetes Education and Prevention
Advanced Practice Pharmacist I: Clinical Pharmacy Specialist
Department of Family Medicine and
Internal Medicine Clinics
USPHS Indian Health Service: Lawton Indian Hospital
Lawton, Oklahoma

Authors
Kristen T. Pogue, Pharm.D., BCPS (AQ Cardiology)
Clinical Pharmacist Specialist, Cardiology
Adjunct Clinical Assistant Professor
Department of Pharmacy Services
University of Michigan Health System
and College of Pharmacy
Ann Arbor, Michigan
Claire P. Walter, Pharm.D., BCPS
Allegheny General Hospital
Allegheny Health Network
Pittsburgh, Pennsylvania
Reviewers
Christina Rose, Pharm.D., BCPS
Clinical Associate Professor in Pharmacy Practice
Clinical Pharmacist in Critical Care
Temple University School of Pharmacy
Ashlee Sommer, Pharm.D., BCPS
Clinical Pharmacy Specialist Internal Medicine
Sentara Virginia Beach General Hospital
Virginia Beach, Virginia
The American College of Clinical Pharmacy and the authors

thank the following individuals for their careful review of the
Cardiology I chapters:
Emilie L. Karpiuk, Pharm.D., BCPS
Oncology Pharmacist
Froedtert Hospital
Milwaukee, Wisconsin
Shannon W. Finks, Pharm.D., FCCP, BCPS (AQ Cardiology)
Associate Professor
Department of Clinical Pharmacy
University of Tennessee College of Pharmacy
VA Medical Center
Memphis, Tennessee
Lisa C. Hutchison, Pharm.D., MPH, FCCP, BCPS
Professor
Pharmacy Practice
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Disclosure of Potential Conflicts of Interest
Consultancies: William L. Baker (Boehringer Ingelheim Pharmaceuticals); Stacy L. Elder (ASHP New Practitioner Forum); Karen J.
McConnell (ACCP, ASHP); Kristen T. Pogue (Visante, Inc., Postgraduate Healthcare Education/Power-Pak C.E.)
Stock Ownership: Karen J. McConnell (Cardinal Health)
Royalties:
Grants: William L. Baker (Pfizer)
Honoraria: Tyan F. Thomas (Horizon CME)
Other:
Nothing to disclose: Cassandra D. Benge, Mark J. Cziraky, Yvonne L. Phan, Sossity A. Riordan, Christina Rose, Ashlee Sommer,
Laura Waite, Claire P. Walter,
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Cardiology II 0217-0000-16-002-H01-P, 6.0 contact hours. You may complete one or all available modules for credit. Tests may
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By Karen J. McConnell, Pharm.D., FCCP, BCPS-AQ Cardiology; and William
L. Baker, Pharm.D., FCCP, FACC, BCPS, AQ-Cardiology
Reviewed by Tyan F. Thomas, Pharm.D., BCPS; and Stacy L. Elder, Pharm.D., BCPS
LEARNING OBJECTIVES
1. Distinguish key differences between various national and international hypertension (HTN) guidelines.
2. Demonstrate appropriate drug selection and blood pressure goals for the treatment of HTN according to the presence of
concomitant conditions.
3. Devise an evidence-based treatment strategy for resistant HTN to achieve blood pressure goals.
4. Justify the use of ambulatory blood pressure monitoring.
5. Develop treatment strategies for hypertensive urgency and emergency.
6. Construct appropriate drug therapy plans for the treatment of hypotension.
7. Assess the potential effect of pharmacogenomics on blood pressure.
ABBREVIATIONS IN THIS CHAPTER
ABPM
Ambulatory blood pressure

monitoring
ACE
Angiotensin-converting enzyme
AGT
Angiotensinogen
Angiotensin receptor blocker
ARB
ASCVD
Atherosclerotic cardiovascular
disease
Coronary artery disease
CAD
Calcium channel blocker
CCB
CKD
Chronic kidney disease
CV
Cardiovascular
CVD
Cardiovascular disease
DBP
Diastolic blood pressure
HF
Heart failure
HTN
Hypertension
JNC
Joint National Committee
Left ventricular ejection fraction
LVEF
MI
Myocardial infarction
OH
Orthostatic hypotension
RAAS Renin-angiotensin-aldosterone
system
Systolic blood pressure
SBP
SNP
Single nucleotide polymorphism
Table of other common abbreviations.
EPIDEMIOLOGY
Hypertension (HTN) is a persistent, nonphysiologic elevation in blood
pressure; it is defined as (1) having a systolic blood pressure (SBP)
of 140 mm Hg or greater; (2) having a diastolic blood pressure (DBP)
of 90 mm Hg or greater; (3) taking antihypertensive medication; or
(4) having been told at least twice by a physician or other health
professional that one has HTN. According to WHO, almost 1 billion
people had uncontrolled HTN worldwide in 2008. The American Heart
Association (AHA) estimates that 41% of the U.S. population will have
a diagnosis of HTN by 2030, an increase of 8.4% from 2012 estimates.
The prevalence of HTN increases from 7.3% in people aged 1839
to 32.4% in people aged 4059 and 65.0% in those older than 59
years. Data from the National Health and Nutrition Examination
Survey (NHANES) show a higher prevalence of HTN in men than in
women until age 45 years and similar rates thereafter.
The sobering reality for those who treat patients with HTN is that
more than one-half of patients (53.5%) are inadequately controlled,
and more than one-third (39.4%) are unaware that they have HTN
(CDC 2012). A review of NHANES data shows that the percentage
of hypertensive adults with optimal blood pressure increased from
13% to 19% from 2003 to 2012, whereas mean SBP decreased during
the same time (Yoon 2015). However, with recent changes made to
HTN guidelines (see the next section), the prevalence of uncontrolled
HTN may be lower than these estimates (Sakhuja 2015). The improvements in HTN control among the U.S. population have correlated with
the increased use of antihypertensive drugs, particularly combination
therapy (Gu 2012).
7
HTN GUIDELINES
A thorough knowledge of contemporary HTN management

strategies is imperative for pharmacists participating in direct
Since the inception of the Joint National Committee guidelines

on HTN, the National Heart, Lung, and Blood Institute (NHLBI)
has sanctioned these publications. However, the last-sanctioned HTN guideline by the NHLBI was the Seventh Report
of the Joint National Committee (JNC 7), published in 2003.
The writing panel for the JNC 8 guideline was appointed in
2008; however, in 2013 the NHLBI transferred the HTN guideline development to the American Heart Association and the
American College of Cardiology (AHA/ACC) (Gibbons 2013).
The original JNC 8 writing panel published its recommendations in December 2013, acknowledging that it was not
sanctioned or endorsed by the NHLBI (James 2014). In addition,
the American Society of Hypertension/International Society of
Hypertension (ASH/ISH) published guidelines in December
2013; some of these recommendations differ from those of the
JNC 8 writing panel (Weber 2014). The official ACC/AHA guidelines for HTN management, which are intended to replace the
last NHLBI guidelines, are expected in 2016.
The JNC 7 guidelines classified blood pressure as follows: normal (SBP less than 120 mm Hg and DBP less than 80 mm Hg),
pre-HTN (SBP 120139 mm Hg or DBP 8089 mm Hg), stage 1
HTN (SBP 140159 mm Hg or DBP 9099 mm Hg), or stage 2
HTN (SBP 160 mm Hg or higher or DBP 100 mm Hg or higher)
(Chobanian 2003). Table 1-1 compares blood pressure goals for
different populations among various international guidelines,
including several U.S. guidelines, the Canadian Hypertension
Education Program, and the European Society of Hypertension/
European Society of Cardiology (ESH/ESC) guidelines.
patient care, given the increased rates of atherosclerotic and

atherothrombotic cardiovascular disease (CVD) in those with
elevated blood pressure. Data analyses show that the risk of
CVD is increased 2- to 3-fold in patients with HTN versus normotensive controls. It is estimated that 69% of individuals
who have a first myocardial infarction (MI), 77% of those who
have a first stroke, and 74% of those who have heart failure
(HF) have HTN.
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar

with the following:
White-coat hypertension (HTN)
Antihypertensive medications and their monitoring
values
Lifestyle recommendations for HTN
Pharmacogenomics describes all genes within a
genome that may relate to drug response, whereas
pharmacogenetics focuses on single genetic
polymorphisms
Table of common laboratory reference values
ADDITIONAL READINGS
The following free resources have additional background information on this topic:
Chobanian AV, Bakris GL, Black HR, et al. Seventh
report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure. Hypertension
2003;42:1206-52.
HTN Guideline Controversy
Although the various HTN guidelines differ, one controversial

issue in these guidelines is the age that the blood pressure goal
should be increased to less than 150/90 mm Hg for older adult
patients. Published data are limited on the benefits of achieving
a target blood pressure of less than 140/90 mm Hg in older adult
patients. For patients 60 years and older, the JNC 8 panel recommends initiating treatment to achieve a goal blood pressure
of less than 150/90 mm Hg (James 2014). The age chosen by
the JNC 8 writing panel for a less aggressive blood pressure target is 20 years younger than the age defined as older adults, 80
years and older, in the 2013 ASH/ISH, Canadian Hypertension
Education Program, ESH/ESC, and ACC/AHA/ASH guidelines,
which target a blood pressure goal of less than 150/90 mm Hg
(Rosendorff 2015; Weber 2014; Hackman 2013; Mancia 2013).
The JNC 8 panel authors cited the VALISH and JATOS studies as evidence for setting a goal SBP of higher than 140 mm
Hg in patients older than 60 years. Neither the VALISH nor the
JATOS study showed any difference between strict control
(SBP of less than 140 mm Hg) and more modest control (SBP
less than 150 mm Hg for VALISH; SBP less than 160 mm Hg for
JATOS) (Ogihara 2010; JATOS 2008). However, both trials were
underpowered to determine whether strict control was superior
American Diabetes Association (ADA). Standards

of medical care in diabetes 2015. Diabetes Care
2015;38(suppl 1):S1-94.
KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease.
Kidney Int 2013;5:337-414.
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high
blood pressure in adults. JAMA 2014;311:507-20.
Weber MA, Schiffrin EL, White WB, et al. Clinical
practice guidelines for the management of
hypertension in the community. J Clin Hypertens
2014;16:14-26.
Rosendorff C, Lackland DT, Allison M, et al.
Treatment of hypertension in patients with coronary artery disease: a scientific statement from the
American Heart Association, American College of
Cardiology, and American Society of Hypertension.
Circulation 2015;131:e435-70
Table 1-1. Comparison of International Guidelines on HTN Goals (mm Hg)

Uncomplicated
HTN
Diabetes
Cardiovascular
Disease
Chronic Kidney
Disease
Older Adults
JNC 7 (2003)a
< 140/90
< 130/80
< 140/90
< 130/80
Not specified
JNC 8
(2014)b
< 140/90
< 140/90
< 140/90
< 150/90, age 60 yr
ASH/ISH
(2013)c
< 140/90
< 140/90
< 140/90
< 140/90
< 150/90, age 80 yr
CHEP (2013)d
< 140/90
< 130/80
< 140/90
< 140/90
< 150/90, age 80 yr
ESH/ESC (2013)e
< 140/90
< 140/85
< 140/90
< 140/90
< 150/90, age 80 yr
Disease-specific
guidelines
Not applicable
< 140/90;
ADA (2015)f
< 140/90; unless 80 yr,

then < 150/90
ACC/AHA (2015)g
< 130/80 with

proteinuria;
otherwise, < 140/90;
KDIGO (2012)h
Not specified;
ACC/AHA (2011)i
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults. JAMA
2014;311:507-20.
Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community. J Clin
Hypertens 2014;16:14-26.
Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian Hypertension Education Program recommendations for blood pressure
measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2013;29:528-42.
Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension. J Hypertens
2013;31:1281-357.
American Diabetes Association (ADA). Standards of medical care in diabetes 2015. Diabetes Care 2015;38(suppl 1):S1-S94.
Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific
statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension.
Circulation 2015;131:e435-70.
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the
management of blood pressure in chronic kidney disease. Kidney Int Suppl 2012;2:337-414.
Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the
American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2011;123:2434-506.
CHEP = Canadian Hypertension Education Program; HTN = hypertension.
CI, 162; p=0.05), and a 21% reduction in the rate of death
to less stringent targets. Of interest, the authors of the JATOS

trial noted that strict treatment may decrease CVD risk in
from any cause (95% CI, 435; p=0.02) compared with the pla-
patients younger than 75 (JATOS 2008). A minority of the JNC 8
cebo group (Beckett 2008). This study supports increasing
writing panel published a report stating that there was no con-
the blood pressure goal for patients older than 80 to less than
sensus on the age at which to increase the blood pressure goal
150/90 mm Hg because lowering blood pressure below this
in older adults. This report stated that the evidence supporting
level decreased both death and stroke.
raising the target from 140 mm Hg to 150 mm Hg in people 60 or
New HTN Landmark Trial
older was insufficient and inconsistent (Wright 2014).

The HYVET trial assessed various CV end points in 3845
In September 2015, the National Institutes of Health issued a
patients 80 years and older (mean age 83) with an SBP of
press release about the SPRINT study, which it funded. The
160 mm Hg or greater treated with indapamide versus pla-
study was terminated early after a median of 3.26 years, and
cebo. Perindopril or matching placebo was added to achieve
data were published in November 2015 (NIH 2015). More than
a target blood pressure of 150/80 mm Hg. After 1.8 years, the
9300 patients 50 years or older with at least one CV risk fac-
mean SBP was 143.5 mm Hg in the treatment group and 158.5
tor or with renal disease (but no diabetes) were enrolled, and
mm Hg in the placebo group. The treated group had a 30%
about 25% were 75 years or older. Patients were randomized
reduction in the rate of fatal or nonfatal stroke (95% CI, -1 to 51;
to the intensive blood pressure arm (target SBP less than 120
p=0.06), a 39% reduction in the rate of death from stroke (95%
mm Hg) or the conventional arm (target SBP less than 140
mm Hg). The primary composite outcome was MI, other ACS,

stroke, HF, or death from CV causes.
In the intensive treatment group, the mean SBP was 121.4
mm Hg and in the standard treatment group, the mean SPB
was 136.2 mm Hg at 1 year. During follow-up (3.26 years),
the intensive group maintained a mean SBP of 121.5 mm Hg
and the standard treatment group had a mean SPB of 134.6
mm Hg. The mean number of BP drugs was 2.8 and 1.8,
respectively. The primary composite outcome in the intensive-treatment group was significantly lower than in the
standard-treatment group (1.65% per year vs. 2.19% per year;
HR 0.75; 95% CI, 0.640.89; p<0.001). Compared with the conventional arm, the intensive arm had a 38% reduction in HF,
a 30% reduction in CV events, a 43% reduction in death from
CV causes, and a 27% reduction in all-cause mortality. During
the 3.26 years, the numbers needed to treat to prevent a primary outcome event, death from any cause, and death from
CV causes were 61, 90, and 172, respectively. These benefits
(primary outcome and death) were consistent across all subgroups, including participants aged 75 years or older.
Serious adverse events occurred in 38.3% of the intensive-treatment group and 37.1% of the standard-treatment
group (HR 1.04; p=0.25). Rates of serious adverse events
(hypotension, syncope, electrolyte abnormalities, and acute
kidney injury or failure) were higher in the intensive-treatment
group (4.7%) than in the standard-treatment group (2.5%) (HR
1.88; p<0.001). However, bradycardia and injurious falls were
not seen more often in the intensive group, and orthostatic
hypotension was seen significantly less in the intensive group.
Among participants 75 years of age or older, adverse events
were similar to those in the overall cohort (SPRINT 2015).
Given the novelty of this information, the impact on guidelines
is yet to be seen.
Therefore, although current national and international
guidelines agree that the blood pressure goal should be
increased to less than 150/90 mm Hg for older adult patients,
the age at which this should be done is not universally agreed
on. New evidence from the SPRINT trial may influence these
recommendations in the future.
prevention were examined in two recent meta-analyses with

conflicting conclusions. A Cochrane review examined four
randomized controlled trials with more than 8900 patients,
concluding that treatment with antihypertensive drugs for 45
years compared with placebo did not reduce total mortality
(RR 0.85, 95% CI, 0.631.15), CAD (RR 1.12; 95% CI, 0.801.57),
stroke (RR 0.51; 95% CI, 0.241.08), or total cardiovascular
(CV) events (RR 0.97; 95% CI, 0.721.32). In addition, 9% of
patients discontinued antihypertensive therapy because of
adverse effects (Diao 2012).
However, a recent systematic review and meta-analysis updated this review with data from the Blood Pressure
Lowering Treatment Trialists Collaboration. This group completed a series of reviews of trials studying blood pressure
lowering, with access to individual study participant data.
This added 6361 eligible patients (96% had diabetes) for a
study sample of more than 15,000 patients. After 5 years,
patients in the treatment arms had a reduction in stroke (OR
0.72; 95% CI, 0.550.94), CV death (OR 0.75; 95% CI, 0.57
0.98), and total death (OR 0.78; 95% CI, 0.670.92). However,
reductions in total CV events, coronary events, and HF were
not statistically significant. Treatment withdrawal for adverse
events was more common in the treatment groups; however,
data were limited (Sundstrom 2015). Additional randomized
controlled trials are needed in these patients to help clarify the
benefits of treating stage 1 HTN in primary prevention.
Antihypertensive Therapy
Thiazide diuretics decrease the incidence of mortality and

CAD and have supporting evidence as first-line therapy for the
treatment of HTN (Wright 2009). Control of blood pressure is
more important than the drug class used in the primary prevention of complications from HTN (Staessen 2003; Wang
2003). Other recommended first-line options for uncomplicated HTN include angiotensin-converting enzyme (ACE)
inhibitors, angiotensin receptor blockers (ARBs), and calcium
channel blockers (CCBs). In women of childbearing potential,
ACE inhibitor and ARB therapy should be avoided because of
possible teratogenic effects. If ACE inhibitor or ARB therapy
must be used in young women, they should be counseled on
the importance of using highly effective birth control methods.
-Blockers are no longer recommended as a first-line
option for uncomplicated HTN. A meta-analysis of 13 randomized trials comparing -blockers with other antihypertensive
therapy in 105,951 patients reported an RR of stroke that was
16% higher for -blockers (95% CI, 4%30%; p=0.009) than for
other drugs; there was no difference for MI (Lindholm 2005).
-Blockers may be useful in patients with uncomplicated HTN
requiring antihypertensive drug therapy who also have atrial
fibrillation, migraine, or essential tremor, but they should be
avoided in patients with second- or third-degree heart block.
Table 1-2 compares U.S. guidelines on antihypertensive therapy recommendations, highlighting the variability
among them. The JNC 8 panel guidelines and 2013 ASH/ISH
UNCOMPLICATED HTN
Blood Pressure Goals
The term uncomplicated HTN refers to HTN in the absence of

diabetes, HF, chronic kidney disease (CKD), or known coronary
artery disease (CAD). According to the guidelines, the blood
pressure goal for uncomplicated HTN is less than 140/90 mm
Hg. Lifestyle changes should be encouraged for patients with
elevated blood pressure, including increased consumption of
fruits and vegetables, moderation in alcohol and salt intake,
participation in regular exercise, weight reduction to a healthy
body mass (if needed), and tobacco cessation.
The benefits and risks of pharmacotherapy for stage 1 HTN
(SBP 140159 mm Hg and/or DBP 9099 mm Hg) in primary
10
11
JNC 7
ACE inhibitor or
ARB
CCB or thiazide
diuretic
(combine if
necessary)
Thiazide-type
diuretic or CCB
Thiazide diuretic,
-blockers, and
DHP CCB
ACE inhibitor or
ARB
Urine albumin
excretion > 30
mg/24 hr: ACE
inhibitor or ARB
No proteinuria:
no preferred
antihypertensive
drugs
ADAe
CCB or thiazide
diuretic (combine
if necessary)
ACE inhibitor or
ARB
KDIGOd
CCB or thiazide
diuretic (combine if
necessary)
ACE inhibitor or ARB
Diuretic, -blocker,
ACE inhibitor or
ARB, CCB
Other
antihypertensive
drugs as needed to
achieve BP goal
-Blocker and/or
ACE inhibitor and/or
diuretics
ACC/AHA CVDf
CCB or thiazide
diuretic (combine if
necessary)
-Blocker PLUS ACE

inhibitor or ARB
-Blocker, ACE
inhibitor, aldosterone
antagonist
Coronary
Disease
CCB or thiazide
diuretic (combine
if necessary)
ACE inhibitor or
ARB
Diuretic, ACE
inhibitor
Stroke
Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of
Hypertension. Circulation 2015;131:e435-70.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CKD = chronic kidney disease; CVD = cardiovascular disease; DHP = dihydropyridine; HF = heart failure; HTN = hypertension.
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl 2012;2:337-414.
American Diabetes Association (ADA). Standards of medical care in diabetes 2015. Diabetes Care 2015;38(suppl 1):S1-S94.
Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community. J Clin Hypertens 2014;16:14-26.
DHP CCB
Regardless of
BP, ACE inhibitor
or ARB PLUS
-blocker, diuretic,
and spironolactone
Diuretic, -blocker,
ACE inhibitor or
ARB, aldosterone
antagonist
Symptomatic
HF
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults. JAMA 2014;311:507-20.
Three-drug
therapy: CCB
PLUS thiazide
diuretic PLUS ACE
inhibitor or ARB
Two-drug therapy:
--------------CCB or thiazide
diuretic PLUS ACE
inhibitor or ARB
Diabetes
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.
ACE inhibitor or
ARB
CCB or thiazide
diuretic (combine
if necessary)
Two-drug therapy:
thiazide diuretic
PLUS CCB, ACE
inhibitor or ARB,
-blocker
Chronic
Kidney
Disease
Subsequent
therapy
CCB or thiazide diuretic

(combine if necessary)
Thiazide-type diuretic, CCB, ACE inhibitor

or ARB
60 yr
Stage 2 HTN
Initial therapy
Disease-Specific Guidelines
Subsequent
therapy
Initial therapy
ASH/ISHc
Initial therapy
JNC 8b
Thiazide diuretic
CCB, ACE inhibitor or ARB, -blocker
Initial therapy
< 60 yr
NonAfrican American
Subsequent
therapy
African
American
Stage 1 HTN
Table 1-2. Comparison of U.S. Guidelines on Antihypertensive Therapy
guidelines both base antihypertensive therapy recommendations on race (African American vs. nonAfrican American).
For example, they advise a thiazide diuretic or CCB as initial
therapy for African American patients (James 2014; Weber
2014). However, the ASH/ISH guidelines also factor in age
(younger than 60 years and 60 years or older) for antihypertensive recommendations. For stage 2 HTN (i.e., greater than
160/100 mm Hg), guidelines recommend that patients be initiated on combination therapy (Weber 2014; Chobanian 2003).
Finally, disease-specific guidelines (CKD, diabetes, and CVD)
provide their own set of treatment recommendations.
the blood pressure goal from less than 130/80 mm Hg to

less than 140/90 mm Hg (Smith 2011). The 2012 ACC/AHA
guidelines for patients with stable ischemic heart disease
again recommend a goal of less than 140/90 mm Hg (Fihn
2012). The 2015 ACC/AHA/ASH blood pressure guidelines for
patients with CAD also support the goal of less than 140/90
mm Hg (class I, level of evidence A), with caveats: a goal blood
pressure of less than 130/80 mm Hg may be appropriate in
some individuals with CAD, previous MI, stroke or transient
ischemic attack, or CAD risk equivalents (carotid artery disease, peripheral artery disease, abdominal aortic aneurysm)
according to some epidemiologic data and several post hoc
analyses of clinical trials (class IIb, level of evidence C).
Caution is advised in causing DBP to drop below 60 mm Hg in
any patient with diabetes mellitus or who is older than 60. In
older hypertensive individuals with wide pulse pressures, lowering SBP may cause very low DBP values (less than 60 mm
Hg) (class IIa, level of evidence C). Despite a lack of data to
support a specific blood pressure goal, a blood pressure target of less than 150/80 mm Hg may be seen as reasonable for
patients with CAD who are older than 80 (Rosendorff 2015).
HTN WITH CONCOMITANT DISEASE

STATES
Coronary or Other Atherosclerotic Vascular
Disease
Hypertension has long been recognized as an independent risk

factor for CVD. In a large meta-analysis (almost 1 million primary prevention adults) there was a linear increase in vascular
death from a blood pressure of 115/75 mm Hg to 185/115 mm
Hg; the risk of CVD doubled for each 20-mm Hg increase in SBP
(Lewington 2002). The mechanisms of blood pressure elevation
and end-organ damage involving the heart include increased
sympathetic nervous system and renin-angiotensin-aldosterone
system (RAAS) activity; decreased release or activity of vasodilators; changes in natriuretic peptides, growth factors, and
inflammatory cytokines; increased vascular stiffness and endothelial dysfunction; and modifications in hemodynamic effects.
Cardiac structure and function are primarily influenced by the
physical forces on them (blood pressure and flow), which contribute to remodeling and atherosclerosis (Rosendorff 2015).
Box 1-1 highlights first- and second-line treatment options for

patients with ischemic heart disease (Rosendorff 2015). The
benefits of -blockers in these patients are likely caused by a
decrease in oxygen demand resulting from a lower heart rate
and blood pressure, decreased risk of ventricular arrhythmias,
and prolonged diastole leading to improved diastolic perfusion.
However, recommendations for -blocker therapy have been
updated to reflect evidence that their efficacy is greatest among
patients experiencing an MI (or acute coronary syndrome) within
the previous 3 years and/or left ventricular systolic dysfunction
(left ventricular ejection fraction [LVEF] less than 40%). In normotensive patients without these class I indications, -blocker
therapy is optional (class IIa or IIb) (Smith 2011). No large trials
have shown a survival benefit or reduction in coronary event
rates with -blocker therapy in patients with stable ischemic
heart disease. If -blocker therapy is needed to adequately control blood pressure or heart rate, it should be continued unless
contraindications or tolerance issues develop. In this situation,
alternative antihypertensive drugs should be used.
Clinical trials have shown that ACE inhibitors provide
CV-protective effects by reducing the risk of future ischemic
events, particularly in high-risk patients (Fox 2003; Yusuf
2000). The decrease in angiotensin II and increase in bradykinin may contribute to the reductions in left ventricular
hypertrophy, atherosclerosis progression, plaque rupture, and
thrombosis, as well as improved myocardial oxygen supply/
demand. As first-line antihypertensive therapy, ACE inhibitors
should be initiated and continued indefinitely in all patients
with HTN having coronary or atherosclerotic vascular disease
(Rosendorff 2015). In addition, ACE inhibitors are recommended for patients with ASCVD and an LVEF of less than
In 2015, AHA/ACC/ASH published updated blood pressure

guidelines for patients with CAD (Rosendorff 2015). Although
epidemiologic studies support a lower-is-better approach to
blood pressure in patients with atherosclerotic cardiovascular
disease (ASCVD), there is concern that lowering the DBP too
much will result in decreased coronary perfusion. The coronary circulation autoregulates so that a decrease in perfusion
pressure results in coronary vasodilation to allow consistent
blood flow. However, it is theorized that the ability to compensate with vasodilation is limited once the perfusion pressure
falls below a certain level. Unfortunately, beyond animal studies, no data on the DBP level correspond to the lower limits
of autoregulation in humans with or without CAD. In addition,
there is inconsistent evidence that lowering DBP beyond a
certain level will compromise CV outcomes.
The 2007 ACC/AHA HTN guidelines for patients with ischemic heart disease use epidemiologic studies to set a blood
pressure goal of less than 130/80 mm Hg for patients with
CAD or CAD risk equivalents (Rosendorff 2007). In 2011, ACC/
AHA published secondary prevention guidelines that updated
12
Controlling CV risk factors prevents or slows the development

of CVD (ADA 2015).
40%, diabetes, or CKD, unless contraindicated. The use of

ARBs is recommended as first-line antihypertensive therapy
in patients who are ACE inhibitor intolerant and have HF or
in those who have had an MI with an LVEF of less than 40%
The blood pressure goal for patients with diabetes has

changed several times in recent years. In January 2013, the
American Diabetes Association (ADA) recommended a higher
SBP goal of less than 140 mm Hg (previous goal: less than 130
mm Hg). The 2013 ASH/ISH blood pressure guidelines and
JNC 8 also recommended this higher SBP goal for patients
with diabetes (James 2014; Weber 2014).
The former SBP goal (less than 130 mm Hg) was based
only on epidemiologic data, not randomized controlled trials.
The ACCORD study aimed to determine whether an SBP target
of less than 120 mm Hg reduces major CV events in participants who have type 2 DM and a high risk of CV events. More
than 4700 patients were randomly assigned to intensive or
standard therapy, targeting an SBP of less than 120 mm Hg or
(Rosendorff 2015; Fihn 2012; Smith 2011).

Other first-line antihypertensive therapies for patients with
ASCVD are thiazide and thiazide-type diuretics (e.g., chlorthalidone, indapamide); in several clinical trials, these have
shown benefit in reducing cardio- and cerebrovascular events
(Rosendorff 2015).
Diabetes
Most patients with diabetes are affected by HTN, and it is

a risk factor for macro- and microvascular complications.
Because CVD is the No. 1 killer of, and main source of morbidity in, patients with diabetes, controlling CV risk factors such
as HTN in patients with diabetes is of utmost importance.
Box 1-1. Antihypertensive Therapy Recommendations for Patients with Ischemic Heart
Disease
Acute Coronary Syndrome
First-line options Drugs of choice
ACE inhibitor or ARB Particularly if MI, LVSD, DM, or proteinuria is present
-Blocker Metoprolol or bisoprolol (oral); esmolol (intravenous)
Diuretic Chlorthalidone is preferred, unless HF (NYHA III or IV) or CrCl < 30 mL/minute/1.73 m2, then loop diuretic
preferred
Second-line options Add-on therapy
Dihydropyridine CCB
Non-dihydropyridine CCB Do not use if LVSD or HF with reduced ejection fraction present. Caution when combining
with -blocker
Nitrates (long-acting)
Aldosterone antagonists If left ventricular dysfunction, HF, or DM present
Stable Angina
ACE inhibitor or ARB Particularly if MI, LVSD, DM, or proteinuria is present
-Blocker
Nitrates
Diuretic Chlorthalidone is preferred, unless HF (NYHA III or IV) or CrCl < 30 mL/minute/1.73 m2, then loop diuretic
preferred
Dihydropyridine CCB
Non-dihydropyridine CCBs Do not use if LVSD or HF is present. Caution when combining with -blocker
Aldosterone antagonist
Heart Failure with Reduced Ejection Fraction
-Blocker Carvedilol, metoprolol succinate or bisoprolol
Aldosterone antagonist If left ventricular dysfunction, HF, or DM
Nitrates
Hydralazine/isosorbide dinitrate
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; DM = diabetes mellitus; LVSD
= left ventricular systolic dysfunction; MI = myocardial infarction; NYHA = New York Heart Association.
Information from: Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease. A scientific statement from the American Heart Society, American College of Cardiology and American Society of Hypertension. Circulation
2015;131:e435-70.
13
less than 140 mm Hg, respectively. After 1 year, the mean SBP
was 119.3 mm Hg in the intensive therapy group and 133.5
mm Hg in the standard therapy group. The annual rate of the
primary outcome (composite nonfatal MI, nonfatal stroke, or
death from CV causes) was similar between groups: 1.87% in
the intensive therapy group and 2.09% in the standard therapy
group (p=0.20). There was also no difference between groups
in all-cause mortality or CV death. Strokes were reduced in the
intensive therapy group compared with the standard therapy
group (0.32% vs. 0.53%; HR 0.59; 95% CI, 0.390.89; p=0.01).
Serious adverse events attributed to antihypertensive treatment occurred in 3.3% of the intensive therapy group and 1.3%
of the standard therapy group (p<0.001). With the exception
of lower stroke risk (absolute difference 0.21%), the results of
this study showed no additional CV or mortality benefit of a
lower SBP goal (less than 120 mm Hg) but an increased rate
of adverse events (Cushman 2010).
The 2015 ADA guidelines increased the DBP goal from less
than 80 mm Hg to less than 90 mm Hg. The previous DBP goal
of less than 80 mm Hg was based primarily on a post hoc analysis of the Hypertension Optimal Treatment trial (Hansson 1998).
According to other higher-quality evidence, the ADA raised the
DBP goal in 2015 to less than 90 mm Hg, which coincides with
the 2013 ASH/ISH blood pressure and JNC 8 panel guidelines
recommendations (James 2014; Weber 2014). However, the
ADA contends that lower blood pressure targets (less than
130/80 mm Hg) are appropriate for younger patients if they can
be achieved without undue treatment burden (ADA 2015).
developing HF than do normotensive men and women. The incidence of HF is greater with higher blood pressure readings, older
age, and longer duration of HTN. Long-term treatment of both
systolic and diastolic HTN reduces the risk of HF by around 50%.
Hypertension is an important contributor to acute decompensated HF. A registry that tracks hospitalized patients
with acute decompensated HF showed that almost 50% of
patients admitted with HF had a blood pressure level greater
than 140/90 mm Hg, and almost 75% had a history of HTN.
Patients who were admitted for HF were more often significantly hypertensive with preserved systolic function than
hypotensive with reduced systolic function (Adams 2005). In
addition, the abrupt discontinuation of antihypertensive therapy may precipitate worsening HF.
The 2013 ACC/AHA HF guidelines recommend that clinicians

lower both SBP and DBP in accordance with JNC 7 (Yancy
2013). According to JNC 7, blood pressure targets in HF have not
been firmly established, but lowering SBP is almost uniformly
beneficial. In most successful trials, SBP was lowered to 110
130 mm Hg (Chobanian 2003). For example, the COPERNICUS
trial showed the benefits of carvedilol (27% reduction in the
combined risk of death or CVD [p<0.001] and 31% reduction in
the combined risk of death or HF hospitalization [p<0.001]) in
patients who had a mean baseline blood pressure of 123/76
mm Hg, suggesting that lower blood pressure is desirable in
some patients (Packer 2001). However, the benefits seen in
this trial may be the result of treatment with carvedilol, rather
than the blood pressure level. In the 2015 ACC/AHA CAD blood
pressure guidelines, a blood pressure goal of less than 140/90
mm Hg is recommended for patients with HF (class IIa, level
of evidence B) (Rosendorff 2015). Other recently published
guidelines (e.g., JNC 8 2013 ASH/ISH) do not address a blood
pressure goal for patients with HF.
Inhibitors of the RAAS may have unique advantages in the initial or early therapy for HTN in individuals with diabetes. The
HOPE trial showed that ACE inhibitors reduce major CVD outcomes (e.g., MI, stroke, death) in patients with diabetes (HOPE
2000). The ADVANCE trial showed that the combination of
perindopril and indapamide reduced not only macrovascular
complications, but also microvascular outcomes and mortality, with lower blood pressure (Patel 2007). The compelling
benefits of RAAS inhibitors in patients with diabetes and albuminuria provide added rationale for their use.
The 2015 ADA and the 2013 ASH/ISH blood pressure
guidelines recommend that therapy for patients with diabetes and HTN include either an ACE inhibitor or an ARB (ADA
2015; Weber 2014). If one class is not tolerated, the other class
may be substituted if not contraindicated. Multidrug therapy
is usually required to achieve blood pressure targets. If additional blood pressure lowering is needed after ACE inhibitor or
ARB therapy is optimized, a thiazide diuretic, -blocker, and/
or CCB should be added and optimized.
Choice of antihypertensive therapy should be guided by

HF-specific options and tailored to concomitant medical problems. Diuretic-based antihypertensive therapy prevents HF in a
wide range of patients. One trial of indapamide-based therapy
showed a number needed to treat of 52 over 2 years to prevent one
HF event (Beckett 2008). Other effective treatments to decrease
the risk of HF include ACE inhibitors, ARBs, and -blockers.
HF with Reduced Ejection Fraction
Therapies that reduce morbidity and mortality in patients

with HF also reduce blood pressure. Evidence-based -blockers (metoprolol succinate, carvedilol, or bisoprolol) and ACE
inhibitors should be used in all patients with a reduced ejection fraction (unless contraindicated) to prevent symptomatic
HF, even if they have no history of MI. In patients intolerant of
ACE inhibitors, ARBs are appropriate unless contraindicated.
Aldosterone receptor antagonists are recommended in patients
Heart Failure
Hypertension is one of the most important modifiable risk factors

for both HF with preserved ejection fraction and HF with reduced
ejection fraction. Individuals with HTN have a much higher risk of
14
For example, in the AASK study, participants were randomized to treatment to a mean arterial pressure of either less
than 92 mm Hg (equivalent to 125/75 mm Hg) or 102107 mm
Hg (equivalent to 135/85140/90 mm Hg). During the longterm follow-up of participants, benefit was associated with
the lower blood pressure target among patients with a urine
protein/creatinine ratio of greater than 220 mg/g, but not if
the urine protein/creatinine ratio was 220 mg/g or less (Appel
2010). In fact, in some analyses, there was a trend toward
worse outcomes with a low blood pressure target and ratio of
220 mg/g or less. Therefore, in adults with or without diabetes who have CKD and a urine albumin excretion greater than
30 mg/24 hours (or equivalent) and an office blood pressure
consistently greater than 130 mm Hg systolic or greater than
80 mm Hg diastolic, the Kidney Disease: Improving Global
Outcomes (KDIGO) guidelines recommend treatment to maintain a blood pressure consistently lower than 130/80 mm Hg.
However, this lower goal for patients with albuminuria is not
mentioned in either the JNC 8 or the 2013 ASH/ISH guidelines.
with New York Heart Association (NYHA) classes IIIV who

have an LVEF of 35% or less and in patients after an acute MI
with an LVEF of 40% or less with HF symptoms. Loop diuretics
do not reduce mortality in patients with HF with reduced ejection
fraction, but they are recommended in patients with fluid retention to achieve euvolemia.
HF with Preserved Ejection Fraction
Blood pressure control remains the most important consideration in patients with HF with preserved ejection fraction. In
patients with HTN having HF with preserved ejection fraction,
aggressive treatment (usually requiring multidrug regimens)
is recommended. Although strong evidence is lacking, ACE
inhibitors or ARBs are often used to treat HTN (Yancy 2013).
The TOPCAT study examined the effect of spironolactone versus placebo on HF with preserved ejection fraction.
Patients had a median ejection fraction of 54% and a median
blood pressure of 130/80 mm Hg. After a 3-year follow-up,
there was no difference in the primary outcome (composite
of CV death, aborted cardiac arrest, or HF hospitalization).
However, the spironolactone group had a significantly lower
rate of hospitalization for HF than did the placebo group
(12.0% vs. 14.2%; HR 0.83; 95% CI, 0.690.99; p=0.04). In an
exploratory post hoc analysis, marked regional variations
in outcomes were seen in the placebo group: patients from
Russia and Georgia had a much lower likelihood of a primary
outcome event than patients in the Americas. This may partly
explain why a decrease in the primary outcome was seen in
the spironolactone arm for patients enrolled in the Americas
(27.3% vs. 31.8%; HR 0.82; 95% CI, 0.690.98; p=0.026) but not
for patients enrolled in Russia or Georgia (Pitt 2014). Although
the TOPCAT study was not a blood pressurelowering trial, it
may guide the use of spironolactone in these patients, and the
expected benefit may go beyond blood pressure control.
Although the KDIGO guidelines suggest an ACE inhibitor or

ARB for adults with diabetes, CKD, and a urine albumin excretion of 30300 mg/24 hours (or equivalent), they recommend
an ACE inhibitor or ARB for patients with or without diabetes
who have CKD and a urine albumin excretion of greater than
300 mg/24 hours (or equivalent). Vasodilation of the efferent
and afferent glomerular arterioles (particularly the efferent)
results in decreased intraglomerular pressure and hence
reduction in both glomerular filtration rate and urine albumin
excretion. This is believed to result in some degree of longterm renoprotection in patients with albuminuria.
Blood pressure control in patients with CKD often requires
the use of three or more agents. With the exception of ARB or
ACE inhibitor use in patients with CKD and high concentrations
of protein excretion, KDIGO finds no strong evidence to support the preferential use of any particular agent in controlling
blood pressure in CKD, nor are there data to guide the clinician
in the choice of second- and third-line agents. However, other
recent guidelines continue to recommend an ACE inhibitor
or ARB as initial therapy for patients with CKD (James 2014;
Weber 2014). Ultimately, the choice of agents is less important than the actual reduction in blood pressure achieved. The
ACE inhibitors or ARBs are valuable antihypertensive agents
in patients with CKD and are safe to combine with most other
blood pressurereducing agents, though the risk of significant hyperkalemia warrants caution. In CKD, aldosterone
antagonists reduce urine albumin concentrations and may be
used as an adjunct to other antihypertensive agents in treating resistant HTN (Epstein 2006). Impaired renal excretion of
spironolactone and eplerenone can increase the risk of hyperkalemia; hence, their use should be limited to patients with a
CrCl greater than 30 mL/minute/1.73 m2.
Chronic Kidney Disease
Both HTN and CKD can cause and worsen each respective disease state. In patients with CKD (but not on dialysis), higher
blood pressure levels are usually associated with a higher
CVD risk. Treating HTN is fundamental to caring for patients
with CKD because premature CVD is a primary cause of death
and morbidity (KDIGO 2012).
For all adults (including those with diabetes) who have CKD
and a urine albumin excretion of less than 30 mg/24 hours
(or equivalent), recent guidelines recommend the use of drugs
to maintain blood pressure consistently less than 140/90 mm
Hg (James 2014; Weber 2014; KDIGO 2012). Several previous guidelines recommended a blood pressure target of less
than 130/80 mm Hg for all patients with CKD, irrespective of
urine protein concentration. However, recent randomized controlled trials have shown no benefit of lower blood pressure
targets in patients without proteinuria.
15
Of the currently available antihypertensive agents, thiazides and thiazide-like diuretics are most often used and have
been assessed in many randomized controlled trials involving
patients with CKD. Although thiazides are excreted by the kidney, no dose adjustment is recommended in patients with a
CrCl above 30 mL/minute/1.73 m2. As the glomerular filtration
rate falls below about 3050 mL/minute/1.73 m2, the ability of
thiazides to overcome fluid retention is diminished, though their
antihypertensive benefit may be preserved. Most clinicians
switch to a loop diuretic in patients with a CrCl of less than 30
mL/minute/1.73 m2 because of the thiazides lack of effectiveness, particularly if the blood pressure is becoming resistant to
therapy or if edema becomes a problem. On initiation of diuretics and RAAS blockers, a transient reduction in CrCl of up to
30% (and accordingly, a 30% increase in SCr concentration) has
been regarded as reasonable because of the physiologic mechanism of vasodilation in the kidney. Greater CrCl reductions
may suggest underlying renal artery stenosis or other renal disease, in which case therapy should be adjusted.
health care professionals in helping patients improve adherence and better manage their blood pressure. Moreover, the
program provides several ideas on how best to incorporate
this program into pharmacies. Million Hearts has resources
for pharmacists (e.g., posters, discussion tool, blood pressure
guide, video vignette, continuing pharmacy education) and
for patients (e.g., blood pressure journal, medication-tracking
cards). Program implementation involves three tiers: general awareness, medication adherence messaging, and blood
pressure counseling services.
Causes of Resistant HTN
Box 1-2 details various causes of pseudo-resistant and resistant HTN, including drugs and diseases. Once a patient has
been given a diagnosis of resistant HTN, it is desirable to rule
out disease-related causes. This will allow either a more targeted treatment strategy (e.g., with primary aldosteronism) or
the ability to resolve the issue without additional antihypertensive medication (e.g., with hyperthyroidism). Some conditions
are especially prevalent in patients with resistant HTN; for
example, sleep apnea (60%70%) can be treated, in part, with
continuous positive airway pressure (Vongpatanasin 2014).
It is also important to address other causes of pseudo-resistant and resistant HTN. Improper blood pressure
measurement and white-coat HTN may not necessitate any
changes to the antihypertensive regimen, whereas volume
overload may need to be addressed by lifestyle modification
or optimization of diuretic therapy.
Some clinicians may overlook drug-related causes of resistant
HTN. If a patient is prescribed inappropriate drug combinations
or inadequate doses of antihypertensive agents, the HTN may
not be truly resistant to therapy. Health care provider education
may be the most efficient way to address these issues.
Nonsteroidal anti-inflammatory drugs, which inhibit
prostaglandins, have been implicated in increasing blood
pressure and CVD risk. Prostaglandins promote vasodilation and improve the excretion of sodium and water; their
inhibition contributes to vasoconstriction and volume retention, and the blood pressure level can increase. In addition,
NSAIDs can antagonize the effects of some antihypertensive
agents and cause complications when used concurrently. The
use of NSAIDs with several antihypertensive agents (a thiazide diuretic plus an ACE inhibitor or an ARB), acute kidney
injury (AKI) may occur. In a retrospective nested case-control cohort study, use of a double-therapy combination (either
diuretics and NSAIDs or ACE inhibitors/ARBs and NSAIDs)
was not associated with an increased rate of AKI. In contrast,
use of a triple-therapy combination was associated with an
increased rate of AKI (rate ratio 1.31; 95% CI, 1.121.53). The
authors hypothesized that this occurs because of a decreased
volume into the kidney from the diuretic and the NSAID, and
the renal blood flow cannot be compensated for because of
blockade of the RAAS by the ACE inhibitor or ARB, resulting in
an increased risk of AKI (Lapi 2013).
RESISTANT HTN
Resistant HTN is defined as either a blood pressure of 140/90
mm Hg or greater while using optimally dosed antihypertensive agents from three different drug classes (including
a diuretic); or as taking agents from four or more antihypertensive drug classes regardless of blood pressure. In the
20032008 NHANES data, 8.9% of U.S. adults with HTN met
the criteria for resistant HTN (Persell 2011).
Pseudo-resistant HTN
Pseudo-resistant HTN should be ruled out before treating

resistant HTN. Causes of pseudo-resistance include drug
nonadherence and white-coat HTN (Calhoun 2008). If
patients are chronically nonadherent, modifying their antihypertensive regimens without addressing this issue will not
result in blood pressure control. Adherence rates with antihypertensive drugs are reported to be 50%70% (Calhoun 2008).
In a systematic review of randomized trials, the most successful strategy in improving adherence was simplifying the
antihypertensive treatment regimen, including reducing the
number of total daily doses. Motivational strategies (e.g., daily
drug reminder charts, modified packaging, social support,
telephone reminders) were partly successful. Patient education strategies alone were largely unsuccessful (Schroeder
2004). However, one study found that nonadherence was
related to patients lack of understanding of the causes and
effects of HTN, as well as concerns about adverse effects,
and the authors called for targeted educational interventions
(Marshall 2012).
The Million Hearts Team Up. Pressure Down program is
an educational effort sponsored by the U.S. Department of
Health and Human Services and the CDC. This program promotes team-based blood pressure care and offers support for
16
For patients with HTN and CAD, NSAIDs may increase the
risk of morbidity and mortality. In a post hoc analysis of the
INVEST trial, which enrolled patients with HTN and CAD, the
primary outcome (all-cause death, nonfatal MI, or nonfatal
stroke) occurred at a significantly higher rate in the chronic
NSAID group than in the nonchronic NSAID group (adjusted
HR 1.47; 95% CI, 1.191.82; p=0.0003). This difference was
caused by an increase in CV mortality (adjusted HR 2.26;
95% CI, 1.703.01; p<0.0001) (Bavry 2011). Thus, for patients
with HTN, it may be advisable to avoid NSAIDs, if possible,
to decrease the risk of worsening HTN, kidney disease, and
CV morbidity and mortality. However, these risks must be
weighed against benefits such as pain control.
eplerenone dose was 214 mg/day, and the mean spironolactone

dose was 152 mg/day. Changes from baseline in the eplerenone
group were SBP -9.9 mm Hg (2.3 mm Hg) and DBP -5.6 mm Hg
(1.3 mm Hg), whereas changes in the spironolactone group were
SBP -27.0 mm Hg (2.3 mm Hg) and DBP -12.5 mm Hg (1.3 mm
Hg). The lowering of both SBP and DBP was significantly greater
in the spironolactone group, but there were no significant differences in the overall rate of adverse events between eplerenone
and spironolactone (Parthasarathy 2011). Each study shows that
spironolactone can be effective at lowering blood pressure.
Box 1-2. Causes of Resistant and

Pseudo-resistant HTN
Disease Related
Sleep apnea
CKD/renovascular disease
Primary aldosteronism
Cushing syndrome
Pheochromocytoma
Coarctation of the aorta
Thyroid or parathyroid disease
Obesity
Intracranial tumor
Drug Related
Nonadherence
Inadequate antihypertensive doses
Inappropriate antihypertensive combinations
Chronic glucocorticoid steroid therapy
Nonsteroidal anti-inflammatory drugs
Stimulants
Treatment of Resistant HTN

Spironolactone
Several investigators have studied spironolactone as a strategy for treating resistant HTN. In 2002, a study of 25 patients
showed that adding spironolactone 1 mg/kg/day significantly
decreased blood pressure (p<0.013) and the mean number of antihypertensive drugs required per patient (p<0.001)
without requiring spironolactone discontinuation because
of adverse renal effects (Ouzan 2002). In a larger study
(n=76), spironolactone (12.525 mg/day) was added to each
subjects antihypertensive regimen, and if blood pressure
remained uncontrolled, the spironolactone dose was titrated
to 50 mg/day. A significant mean decrease in blood pressure
occurred, as did a significant decrease in the mean number of
prescribed antihypertensive medications from baseline compared with 6-month follow-ups (p<0.05) (Nishizaka 2003).
In a post hoc analysis of 1411 patients taking spironolactone enrolled in the ASCOT-BPLA trial, spironolactone was
mainly used as a fourth-line antihypertensive agent for uncontrolled blood pressure, with a median dose of 25 mg/day.
During spironolactone therapy, the mean blood pressure fell a
mean difference of 21.9/9.5 mm Hg (p<0.001). Spironolactone
was generally well tolerated, with 6% of participants discontinuing the drug because of adverse effects (Chapman 2007).
The ASPIRANT trial was a double-blind, placebo-controlled, multicenter study that randomly assigned 117 patients
to receive spironolactone 25 mg/day (n=59) or placebo (n=58)
in addition to their antihypertensive drugs for 8 weeks. The primary end point (a difference in the mean fall in blood pressure
on daytime ambulatory blood pressure monitoring [ABPM])
showed a significant reduction for SBP (p=0.024) between the
groups (Vclavk 2011).
Finally, the efficacy, safety, and tolerability of eplerenone were
compared with that of spironolactone in patients with primary
aldosteronism and HTN in a multicenter, randomized, double-blind
study. Patients were randomized to a 16-week treatment of spironolactone 75225 mg once daily (n=71) or eplerenone 100300
mg once daily (n=70) using a titration-to-effect design (doses
were titrated if DBP remained greater than 90 mm Hg). The mean
Methylphenidate and other prescription stimulants

Cocaine, amphetamines, other illicit drugs
Sympathomimetics
Decongestants, anorectics
Select OTC dietary supplements (e.g., licorice, ephedra,
ma huang, bitter orange)
Oral contraceptives
Adrenal steroids
Cyclosporine and tacrolimus
Erythropoiesis-stimulating agents
Other
Improper blood pressure measurement
Volume overload
Excess sodium intake

Volume retention
Inadequate diuretic therapy
Excess alcohol intake

White-coat HTN
CKD = chronic kidney disease; HTN = hypertension.

Information from: Calhoun DA, Jones D, Textor S, et al. Resistant
hypertension: diagnosis, evaluation, and treatment: a scientific
statement from the American Heart Association Professional
Education Committee of the Council for High Blood Pressure
Research. Circulation 2008;117:e510-e526; and Chobanian AV,
Bakris GL, Black HR, et al. Seventh report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. Hypertension 2003;42:1206-52.
17
Thiazide Diuretics Chlorthalidone vs.
trials directly comparing chlorthalidone with hydrochlorothi-
Hydrochlorothiazide
azide. A meta-analysis of nine trials that included more than
The use of chlorthalidone for HTN is supported by the results
50,000 patients indirectly compared hydrochlorothiazide with
of the ALLHAT study. This randomized controlled trial com-
chlorthalidone by evaluating their efficacy against common
pared chlorthalidone, lisinopril, and amlodipine in more than
comparator drugs (e.g., ACE inhibitors). Compared with hydro-
41,000 patients with HTN. At a mean follow-up of 4.9 years, the
chlorothiazide, chlorthalidone significantly reduced the risk of
primary outcome (fatal CAD or nonfatal MI) was the same in
CV events (RR 0.79; 95% CI, 0.720.88) and HF (RR 0.77; 95% CI,
the three arms. However, the chlorthalidone arm had a signifi-
0.610.98). To prevent one CV event, 27 patients would need to
cantly lower rate of HF than did the amlodipine and lisinopril
be treated with chlorthalidone instead of hydrochlorothiazide
arms, and a significantly lower rate of combined CVD out-
for at least 5 years (Roush 2012).
comes than did the lisinopril arm (ALLHAT 2002). Conversely,
However, observational data analyses comparing hydro-
there is little, if any, trial evidence to show that hydrochlorothi-
chlorothiazide with chlorthalidone are mixed. Results of
azide alone reduces CV events.
observational data from the MRFIT trial are consistent with the
Chlorthalidone is about 1.52.0 times more potent than
aforementioned meta-analysis. In that trial, the 2392 hyperten-
hydrochlorothiazide and has a longer duration of action (24
sive men treated with chlorthalidone had fewer CV events than
72 hours vs. 612 hours). A small randomized crossover trial
did the 4049 men treated with hydrochlorothiazide (HR 0.79;
showed that this longer duration of action may result in a greater
95% CI, 0.680.92) in 6 years of follow-up (Dorsch 2011). In con-
fall in nighttime blood pressure with chlorthalidone (-13.5 mm
trast, other investigators found that among almost 30,000 adults
Hg with 12.5 mg/day [force-titrated to 25 mg/day]) versus
66 years and older, chlorthalidone (mean dose 27 mg/day) was
hydrochlorothiazide (-6.4 mm Hg with 25 mg/day [force-ti-
associated with an increased risk of hospitalization for hypoka-
trated to 50 mg/day]) (Ernst 2006). There are no randomized
lemia (HR 3.06; 95% CI, 2.044.58) and hyponatremia (HR 1.68;
Patient Care Scenario

complaints are of fatigue and dry mouth. In the clinic, his
seated blood pressure taken from his right arm is 154/90
mm Hg with a heart rate of 70 beats/minute. His laboratory
results reveal K 4.1 mEq/L, SCr 1.3 mg/dL, Na 140 mEq/L,
and no albuminuria. His blood pressure was unchanged
when standing.
A 52-year-old man (height 71 inches, weight 85 kg) is

referred to the clinic for further evaluation of his blood
pressure. His medical history is significant for type 2
DM for 5 years and HTN for 10 years. His drugs include
hydrochlorothiazide 25 mg daily, candesartan 32 mg
daily, amlodipine 10 mg daily, clonidine 0.2 mg twice/
day, metoprolol succinate 100 mg daily, atorvastatin 40
mg daily, fenofibrate 145 mg daily, and metformin 1000
mg twice daily. His examination reveals no evidence of
end-organ damage and nothing remarkable except for
mild arteriolar narrowing in the fundus. The patients only
The patient is given a preliminary diagnosis of resistant HTN. What should be the next steps to confirm this
diagnosis, and what treatment plan should be designed
for him moving forward?
ANSWER
Resistant HTN is defined by either having a blood pressure of 140/90 mm Hg or greater and using optimally
dosed antihypertensive medications from three different
drug classes (including a diuretic) or taking medications
from four or more antihypertensive drug classes regardless of blood pressure. Given his seated office blood
pressure values, this patient meets this definition of resistant HTN. Ambulatory blood pressure monitoring should
be performed to verify the office readings and confirm the
diagnosis. In addition, sources of pseudo-resistance such
as nonadherence and drug-induced causes should be
considered. A review of his drug list identifies no sources
of drug-induced HTN. His symptoms of fatigue and dry
mouth are likely from adverse drug reactions (metoprolol
and clonidine). Tests to identify sources of secondary

hypertension, such as serum aldosterone concentrations
and plasma renin activity (to determine an aldosterone/
renin ratio) can also be recommended. A mineralocorticoid
receptor antagonist (e.g., spironolactone) can be added to
his regimen. Future considerations can also be given to
tapering off clonidine and metoprolol if adverse events
continue; however, metoprolol would need to be tapered
and discontinued before clonidine could be tapered to
avoid the potential for rebound hypertension. The patient
should be closely followed up to check his renal function,
serum potassium concentrations, and response of his
blood pressure to the drug regimen changes.
1. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from
the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation
2008;117:e510-26.
2. Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension
2007;49:839-45.
18
95% CI, 1.242.28). Chlorthalidone was not associated with a

reduced risk of death or CV hospitalization (HR 0.93; 95% CI,
0.811.06) compared with hydrochlorothiazide (mean dose 18
mg/day). However, because chlorthalidone is more potent than
hydrochlorothiazide, the mean daily doses in this trial may not
be comparable (Dhalla 2013).
In the absence of head-to-head trials, chlorthalidone
appears to be superior to hydrochlorothiazide in potency and,
in most studies, in reducing CV events, but it may increase the
risk of electrolyte abnormalities. These factors should be considered when choosing a thiazide diuretic.
control of their ambulatory blood pressure (56% vs. 45%;

p=0.003). In addition, patients who took at least one blood
pressurelowering drug at bedtime had a reduced risk of total
CV events (a composite of death, MI, angina, revascularization, HF, arterial occlusion of lower extremities, occlusion of
the retinal artery, and stroke) than did patients who took all
drugs on awakening (adjusted HR 0.31; 95% CI, 0.210.46;
p<0.001) (Hermida 2011b).
Changing the administration time of at least one antihypertensive medication is a cost-effective (no additional medication
required), simple strategy that results in improved ambulatory
blood pressure control and significantly reduced CV morbidity
and mortality in patients. Often, practitioners do not consider a
patients blood pressure during sleep, but these studies show
that blood pressure during this period is important.
Dosing at Bedtime
The circadian rhythm contributes to the 24-hour variation in

blood pressure and can affect the pharmacokinetics of drugs.
Because of this, ingestion time differences in hypertensive
medications may change how the body responds to them.
Blunted asleep blood pressure decline is associated with an
increased incidence of fatal and nonfatal CVD events; moreover, the asleep blood pressure mean is a better predictor of
CVD risk than the awake or 24-hour blood pressure mean.
The 2010 MAPEC study was designed to determine whether
a regimen of bedtime chronotherapy with at least one antihypertensive drug (bedtime group) exerted better blood
pressure control and CVD risk reduction than when subjects
took all medications in the morning (awakening group). After
a median follow-up of 5.6 years, patients in the bedtime group
had a significantly lower risk of total CVD events (RR 0.39
[0.290.51]; p<0.001) (Hermida 2010). These findings provided the basis for subsequent studies in this field.
In 2012, the ADA added a recommendation to administer
one or more antihypertensive drugs at bedtime (level of evidence A). This was based on a prospective randomized study
comparing patients with HTN and type 2 diabetes mellitus taking bedtime doses of at least one hypertensive agent (n=216)
with patients taking all antihypertensive drugs in the morning
(n=232) to determine whether blood pressure control and CV
risk reduction were improved. After a median follow-up of 5.4
years, patients using the bedtime dosing had a significantly
lower mean asleep blood pressure (115.0 17.1 vs. 122.4
21.8; p<0.001) and a higher prevalence of controlled ambulatory blood pressure (62.5% vs. 50.9%; p=0.013). However,
differences between groups in clinic and awake blood pressure were small and nonsignificant. Similar to patients in the
MAPEC study, patients treated at bedtime had a lower CV risk
(adjusted by age and sex) than taking all drugs on awakening
(HR 0.33 [95% CI, 0.210.54]; p<0.001). There was a significant 12% CV risk reduction for each 5-mm Hg decrease in
asleep SBP during follow-up (p<0.001) (Hermida 2011a).
Patients with CKD also benefited when at least one of their
antihypertensive drugs was administered at bedtime. After
a median follow-up of 5.4 years, patients with CKD using the
bedtime treatment strategy had a significantly lower mean
sleep-time blood pressure, and a greater proportion had
AMBULATORY AND HOME BLOOD

PRESSURE MONITORING
In ambulatory blood pressure monitoring, the patient wears a
portable blood pressuremeasuring device on the nondominant
arm for 24 hours. This provides information on blood pressure
during daily activities as well as at night during sleep. Average
daytime, nighttime, and 24-hour blood pressure readings are the
most commonly used variables in practice. A systematic review
and meta-analysis concluded that 24-hour SBP is a strong
predictor of CV events, providing prognostic information independently of conventional office blood pressure (Conen 2008).
A more recent systematic review performed for the U.S.
Preventive Services Task Force (USPSTF) examined the predictive accuracy of various blood pressure measurement
methods for CV events. Independent of office blood pressure,
ABPM independently predicted CV outcomes (HR range 1.28
1.40 in 11 studies). After an elevated blood pressure reading in
the office, 35%95% of patients (across 27 studies) remained
hypertensive with confirmatory testing. The authors concluded
that ABPM should be used as the reference standard for confirming elevated office blood pressure readings (Piper 2015).
Because of this and other studies, the USPSTF issued a
statement on Screening for High Blood Pressure in Adults in
October 2015. The recommendation stated that for patients
with an elevated blood pressure level in the office, clinicians
should confirm the hypertension diagnosis with readings
outside of the clinical setting (24-hour ABPM or home blood
pressure readings). Using this approach will help decrease
the number of patients with a false diagnosis of HTN because
of short-term elevations in blood pressure (e.g., from stress,
pain, or caffeine intake), white-coat HTN, or errors in blood
pressure measurement. However, outside confirmation may
not be needed in all cases, such as with very high blood pressure (greater than 180/110 mm Hg), in patients with signs
of end-organ damage, or in patients with HTN because of
an underlying condition (e.g., CKD) (USPSTF 2015). The
USPSTF expanded its recommendations to include home
19
heart disease, presence of a somatoform disorder, high number of antihypertensive drugs, and medication nonadherence
(Saguner 2010). The true incidence of hypertensive emergency and urgency remains largely unknown. However, recent
data from Italy show that of1000 ED visits, 4.6 were because
of hypertensive crises; of these, three-fourths were urgencies
and one-fourth were emergencies (Pinna 2014). Distinguishing
between these two distinct conditions is critical in formulating
a treatment strategy because the pharmacotherapy used to
treat them differs dramatically.
blood pressure measurement, in addition to ABPM, for confirmatory BP readings because of the potential financial
burden of ABPM for some patients. The USPSTF still considers ABPM as the reference standard for confirmation of
a HTN diagnosis.
Home blood pressure monitoring involves self-measurement of blood pressure, which offers advantages over
office-measured blood pressure because home measurements can be taken for several days at different times in the
patients own environment. Moreover, there is evidence that
home blood pressure monitoring is a significant predictor of
CV morbidity after adjusting for office blood pressure (Ward
2012). However, patients should be instructed on proper technique. Individuals should be seated with their feet flat on the
floor and their back and arm supported for 5 minutes of rest.
Two measures should be taken 12 minutes apart and the
results recorded in a logbook. Values reported by the patient
may not always be reliable, but many devices now come with
downloadable memory storage capabilities. Use of telemonitoring and smartphone applications for home blood pressure
monitoring may provide further advantage. Devices worn on
the wrist or finger are currently not recommended because of
concerns about accuracy (Pickering 2008).
The HyperLink study examined whether an intervention
combining home blood pressure telemonitoring with pharmacist case management improves blood pressure control
compared with usual care, and whether blood pressure
control is maintained 6 months after the intervention is discontinued. The patients in the intervention group received
home blood pressure telemonitors that transmitted blood
pressure data to pharmacists, who then adjusted their antihypertensive therapy. The SBP decreased more from baseline
among patients in the telemonitoring intervention group at 6
months (-10.7 mm Hg; 95% CI, -14.3 to -7.3 mm Hg; p<0.001)
and 12 months (-9.7 mm Hg; 95% CI, -13.4 to -6.0 mm Hg;
p<0.001) than did the SBP among patients in the usual care
group. This decrease persisted at 18 months (-6.6 mm Hg;
95% CI, -10.7 to -2.5 mm Hg; p=0.004) (Margolis 2013). The
HyperLink study highlights the value a pharmacist can bring
to the care team. Other studies have also shown that teambased care can lower blood pressure better than standard
care (Magid 2013; Green 2008).
Treatment of Hypertensive Emergency
Hypertensive emergencies typically present as sudden, precipitous elevations in blood pressure associated with acute
target organ dysfunction. Common presentations include
hypertensive encephalopathy, malignant HTN, acute coronary syndromes, eclampsia, aortic dissection, acute
cerebrovascular events, acute pulmonary edema, and acute
renal dysfunction. Thus, although the blood pressure itself
can often be quite high (greater than 180/greater than 120
mm Hg), these clinical signs and symptoms more commonly
denote the emergency. The initial examination of patients
should include a focused history and funduscopic, CV, and
mental examinations as well as pertinent laboratory values.
Once the hypertensive emergency has been diagnosed, and
even before laboratory results are available, drug therapy
should be initiated.
Specific blood pressure targets do not exist for patients
with hypertensive emergency. Individuals with chronic HTN
often tolerate very high blood pressure levels because of autoregulatory structural and functional changes. Thus, blood
pressure reduction should be achieved in a more controlled
fashion to avoid sudden drops that can precipitate or exacerbate target organ damage.
Unfortunately, goal blood pressure reductions are not
guided by clinical trial data. Most experts recommend no
more than a 20%25% reduction in SBP within the first 2
hours of presentation (Chobanian 2003). Reducing the DBP
by 25% within the next 26 hours toward an overall goal of
160/100 mm Hg is also reasonable. If this level of reduction is
well tolerated and the patient is clinically stable, slow reductions can continue over the next 2448 hours with a transition
to oral drugs when appropriate. This oral transition should
be made after the patient has had a 12- to 24-hour period of
clinical stability, to allow for restoration of normal autoregulation. Notable exceptions to these targets include patients with
acute aortic dissection (goal SBP less than 120 mm Hg over
20 minutes), acute intracerebral hemorrhage (goal SBP less
than 140 mm Hg within 510 minutes), and acute ischemic
stroke (goal blood pressure depends on the revascularization
strategy chosen) (Anderson 2013).
Various parenteral pharmacologic agents are available
for treating hypertensive emergency (Table 1-3). However,
relatively few have been directly compared in randomized
HYPERTENSIVE URGENCY AND

EMERGENCY
Hypertensive crisis is a broad term encompassing hypertensive
urgency and emergency; it is defined by JNC 7 as an SBP of
180 mm Hg or greater and/or a DBP of 120 mm Hg or greater
(Chobanian 2003). When individuals meet the qualifications
for hypertensive crisis and also have evidence of end-organ
damage, it is a hypertensive emergency. Those without end-organ damage are classified as having hypertensive urgency.
Risk factors for developing hypertensive crisis include female
sex, obesity, presence of either hypertensive or coronary
20
surgery acute HTN. Clevidipine maintained blood pressure

within the prespecified range better than either nitroglycerin
(p=0.0006) or sodium nitroprusside (p=0.003) and was similar to nicardipine (Aronson 2008). A more recent trial of 226 ED
patients with acute HTN showed that nicardipine use resulted
in greater achievement of target blood pressure than labetalol
(91.7 vs. 82.5%; p=0.039) within 30 minutes (Peacock 2011).
The choice of pharmacologic agent is influenced by the
clinical situation. For patients with aortic dissection who
controlled trials. A meta-analysis published in 2008 included

data from 15 studies evaluating seven drug classes for treating hypertensive emergencies. Only minor differences in blood
pressure were seen between select drug classes, with analyses
severely limited by a low number of studies, short durations of
follow-up, and few included patients (Perez 2008).
A pooled analysis of three clinical trials compared the dihydropyridine L-type CCB clevidipine with nitroglycerin, sodium
nitroprusside, or nicardipine in 1500 patients with post-cardiac
Table 1-3. Parenteral Pharmacologic Agents for Treatment of Hypertensive Emergencies
Drug
Dose
Onset of
Action
Duration of
Action
Adverse Effects
Additional Information
Clevidipine
116 mg/hr
24 min
515 min
Headache, nausea,
vomiting, reflex
tachycardia
Weight-independent dosing;
given in lipid emulsion
through dedicated IV line
Enalaprilat
1.255 mg IV
(q6hr)
1530 min
612 hr
Acute hypotension, variable Avoid in bilateral renal artery

response
stenosis, pregnancy
Esmolol
250500 mcg/
kg/min (IV
bolus); then
50100 mcg/
kg/min
12 min
1030 min
Nausea, heart block, HF
Avoid in cocaine-induced
hypertension; appropriate for
aortic dissection
Fenoldopam
0.15 mcg/kg/
min
< 5 min
~20 min
Reflex tachycardia, nausea,

vomiting, flushing,
increased ocular pressure
Caution with glaucoma;

can be used for most
hypertensive emergencies
Hydralazine
1020 mg (IV)
1020 min
14 hr
Tachycardia, flushing,
headache, vomiting,
angina pectoris
Avoid in CAD, aortic

dissection
Labetalol
2080 mg (IV
bolus); then
0.52 mg/min
510 min
36 hr
Nausea, vomiting, flushing,

heart block, OH
Avoid with heart block,

asthma, pregnancy, acute HF
Nicardipine
515 mg/hr
510 min
1530 min,
may exceed
4 hr
headache
Avoid in acute HF; weightindependent dosing
Nitroglycerin
5100 mcg/min 25 min
510 min
Headache, vomiting,
tachyphylaxis,
methemoglobinemia
Unpredictable
antihypertensive effects
Phentolamine
515 mg
12 min
310 min
headache, OH
Avoid in preexisting CAD;

useful for catecholamine
excessa
Sodium
nitroprusside
0.258 mcg/
kg/min
~20 s
12 min
Nausea, vomiting, muscle

spasm, cyanide and/
or thiocyanate toxicity,
coronary steal syndrome
Caution with high intracranial

pressure, hepatic or renal
failure; avoid in pregnancy;
shield from light
Cocaine, monoamine oxidase inhibitor crisis, pheochromocytoma.
CAD = coronary artery disease; IV = intravenous(ly); MI = myocardial infarction; OH = orthostatic hypotension; q = every.
Information from: Sarafidis PA, Georgianos PI, Malindretos P, et al. Pharmacologic management of hypertensive emergencies and
urgencies: focus on newer agents. Expert Opin Investig Drugs 2012;21:1089-106; Elliott WJ, Rehman SU, Vidt DG, et al. Hypertensive
emergencies and urgencies. In: Black HR, Elliott WJ, eds. Hypertension: A Companion to Braunwalds Heart Disease, 2nd ed.
Philadelphia: Saunders, 2013:390-5.
21
which causes a transient decrease in cardiac output and blood

pressure. The baroreflex-mediated compensatory sympathetic
system activates with a decreased parasympathetic activation,
which increases heart rate and vascular resistance to restore
cardiac output and blood pressure. However, when the autonomic system fails to trigger these compensatory mechanisms,
OH can occur. Peripheral damage of the autonomic nerves (e.g.,
by diabetes or Parkinson disease) commonly contributes to
OH. Autoimmune and neurodegenerative autonomic dysfunction can cause more pronounced OH, but this rarely occurs.
Older adults are especially prone to OH because their compensatory mechanisms diminish over time. Baroreflex sensitivity,
heart rate response, and vasoconstriction become blunted as
patients age (Shibao 2013).
Symptoms of OH (e.g., dizziness, fatigue, dim or blurred
vision, pain in the back of the neck/shoulders) occur within a
few seconds of standing. These symptoms are not present in
the supine position and should be relieved after sitting or lying
down. Symptoms are usually worse on awakening because of
nighttime pressure natriuresis, making morning orthostatic
measurements sensitive to detecting OH. The prevalence
of OH among patients 65 years and older is about 16%; this
increases as patients age. Risk factors for OH include age,
comorbid conditions, and number of drugs used (particularly
antihypertensive agents). Major CV events have been associated with OH, and it is a risk factor for syncope and falls
(Shibao 2013). In older adults, it has been identified as an independent predictor of mortality (Luukinen 1999).
The initial evaluation for OH includes blood pressure measurements at both 1 minute and 3 minutes of standing after
the patient has been supine for at least 5 minutes. This helps
determine whether there is an immediate decline in blood
pressure, when patient falls are most likely to occur, and if
there is delayed onset of blood pressure lowering. It is also
important to measure heart rate at each of these periods
because there is a compensatory mechanism for the heart
rate to increase with certain types of OH. Diagnosis may
require several measurements.
The goals of therapy are to decrease the patients symptoms,
improve functional status, and decrease the risk of falls and syncope. The goal is not to achieve a certain blood pressure target.
Once a diagnosis of OH has been confirmed, nonpharmacologic therapy should be initiated. These interventions include
eliminating any offending agents (e.g., -blockers), increasing
fluid and salt intake, avoiding standing too quickly, and initiating
exercise. Pharmacologic therapy options include fludrocortisone (which increases intravascular volume) and adrenergic
agent hypertensives (e.g., midodrine, pyridostigmine, pseudoephedrine, atomoxetine). Fludrocortisone or midodrine can be
used in patients who are not hypertensive. Midodrine can also
be used in combination with either fludrocortisone or pseudoephedrine if monotherapy is ineffective.
Droxidopa is a newly approved agent that is a structural analog of norepinephrine. In clinical trials, efficacy
require a blood pressure decrease to less than 120 mm Hg

within 20 minutes of presentation, a common recommendation is short-acting -blockers such as esmolol and labetalol.
In patients with pulmonary edema and/or HF, either nitroglycerin or sodium nitroprusside can be preferred, with diuretics
added in cases of volume overload. In patients with catecholamine excess, either the nonselective -blocker phentolamine
or the -blocker (with -blocking properties) labetalol is recommended. For individuals presenting with acute coronary
syndromes, vasodilators such as nitroglycerin, sodium nitroprusside, nicardipine, or clevidipine can be used. Thus, the
specific agent for treating patients presenting with a hypertensive emergency depends on both the end-organ dysfunction
and the patient comorbidities.
Treatment of Hypertensive Urgency
Hypertensive urgency has also been called blood pressure elevations without ongoing target organ damage. Of note, however,
hypertensive urgency can still be associated with headache,
thoracic pain, and dyspnea despite the lack of overt organ
damage. The most common cause is either inadequate antihypertensive treatment or drug nonadherence. Despite its name,
there is no great urgency to reduce blood pressure quickly. In
2013, the American College of Emergency Physicians stated
that acute treatment of blood pressure without target organ
damage may not be required (Wolf 2013). However, the statement did provide a consensus recommendation that select
patients, such as those with poor outpatient follow-up, can be
treated in the ED and then referred for continued care.
Patients with significant blood pressure elevations without ongoing target organ damage should have their pressure
decreased over 2448 hours with oral agents. This can also be
accomplished in the ED over a few hours without the need for
hospital admission. If short-acting agents are desired, commonly used options include captopril, clonidine, and labetalol.
Barring contraindications, no specific agent appears to have a
major advantage over another.
HYPOTENSION
No specified blood pressure level is considered too low in
asymptomatic patients not taking antihypertensive therapy.
As long as the patient is not having symptoms (e.g., dizziness,
fatigue, syncope), there is no concern. Overtreatment with
antihypertensive therapy can cause hypotension. There is no
evidence of benefit from an SBP less than 110 mm Hg, and
the risk of adverse effects increases with unnecessary drugs.
If this occurs, consider tapering therapy unless therapy has
benefits beyond blood pressure lowering, such as medications used to treat left ventricular systolic dysfunction.
The definition of orthostatic hypotension (OH) is a sustained
reduction of at least 20 mm Hg in SBP or of 10 mm Hg in DBP
within 3 minutes of standing. In healthy people, about 700 mL
of venous blood goes to the peripheral circulation on standing,
22
was measured by a questionnaire describing dizziness,

light-headedness, faintness, and symptoms of syncope.
Studies showed a treatment effect (decrease in dizziness)
at week 1, but no study showed a treatment effect beyond
2 weeks (Biaggioni 2015; Kaufmann 2014). Therefore, this
agents place in therapy is uncertain.
Patients with OH and HTN present a special treatment situation. There is a 2.5 times higher risk of falls in older adult patients
with OH and HTN than in patients with OH without HTN (Ooi 2000).
It is important to continue antihypertensive therapy in patients
with OH and HTN because adequately controlling blood pressure does not increase the risk of OH. Antihypertensive agents
should be initiated at low doses and titrated slowly. Angiotensinconverting enzyme inhibitors or ARBs may be beneficial in these
patients because of improved blood pressure regulation and
cerebral blood flow (Lipsitz 2005).
(ADRB1) and treatment response (Johnson 2011). A study of

white, African American, and Hispanic subjects showed greater
reductions in DBP in Arg homozygotes for Arg389Gly versus
Gly carriers (p=0.0018) (Johnson 2003). Similarly, a substudy
of INVEST found that individuals with the Ser49ARG389 haplotype had the greatest blood pressure response to metoprolol
(Pacanowski 2008). Moreover, individuals with this haplotype of
ADRB1 had higher death rates; treatment with atenolol reduced
this mortality risk versus verapamil. These two SNPs show
promise regarding the association between the ADRB1 gene
and blood pressure response to -blockers; however, additional
confirmatory studies are required.
The CACNA1C and CACNB2 genes have pharmacogenomic
data showing association with CCB use and blood pressure.
These genes code for the calcium channel, voltage-dependent, L-type, -1C and -2 regulatory subunits, respectively.
Another substudy of INVEST evaluated eight different SNPs
on the CACNA1 coding region. The rs1051375 SNP had a significant interaction with treatment strategy (p=0.0001), with
AA homozygotes showing a 46% reduction in the primary
end point (death, nonfatal MI, or nonfatal stroke) in patients
receiving verapamil sustained release versus those receiving atenolol (Beitelshees 2009). A similar study showed that
individuals with the rs2357928 GG SNP on the CACNB2 gene
receiving verapamil sustained release were more likely to
have an adverse CV outcome than were those receiving atenolol (Niu 2010). This finding was consistent across white,
African American, and Hispanic populations. Thus, it appears
that these two genes are important, not only for the regulation
of blood pressure but also for related CV outcomes in patients
receiving CCBs. Ongoing studies are aimed at further examining and replicating these relationships.
The thiazide diuretics are another antihypertensive drug
class with a fair amount of pharmacogenomic data. Most
of this information has focused on the effect of the NEDD4L
gene and the association with hydrochlorothiazide and blood
pressure. The NEDD4L gene encodes regulatory proteins that
remove sodium from the epithelial cell surface in the kidney.
Data from the NORDIL study showed a greater reduction in
SBP (p=0.047) and adverse clinical outcomes (fatal and
nonfatal stroke, fatal and nonfatal MI, and other CV deaths;
p<0.0001) in patients receiving thiazide diuretics or -blockers who were G carriers for the rs4149601 SNP of the NEDD4L
gene (Svensson-Farbom 2011). These findings were replicated
using data from white participants enrolled in the INVEST and
PEAR trials, with a greater SBP response to hydrochlorothiazide seen in the G-C haplotype of NEDD4L (McDonough 2013).
HTN AND PHARMACOGENOMICS

There is interindividual variation in blood pressure response
to antihypertensive agents. One potential explanation for this
variation is genetic polymorphisms that can lead to alterations
in either the pharmacokinetic or pharmacodynamic actions
of these agents. Thus, optimization of the pharmacologic
management of HTN using pharmacogenetic and pharmacogenomic information has received considerable attention.
Although this research is promising, most of the information
is not ready for clinical implementation. The following sections highlight the current state of knowledge, organized by
major drug class.
As previously discussed, inhibitors of the RAAS (e.g., ACE
inhibitors, ARBs) play an important role in the pharmacologic
management of HTN. Variations in several steps in the RAAS,
including the angiotensinogen enzyme (AGT), angiotensin
I enzyme, angiotensin II receptor type 1 (AGTR1), angiotensin II receptor type II (AGTR2), and bradykinin receptor, have
been assessed for their relation to drug response. In a study
of 1447 patients receiving benazepril from a 3-year postmarket surveillance trial, the AGT rs7079 (C/T) single nucleotide
polymorphism (SNP) was significantly associated with reductions in the DBP response to benazepril (Su 2007). In total, the
response to benazepril explained by variations in the AGT SNP
and AGTR1 haplotype groups were 13% for SBP and 9%9.6%
for DBP. Polymorphisms in the bradykinin receptors as well as
ACE insertion/deletion polymorphisms are also associated with
ACE-induced cough and angioedema (Mahmoudpour 2013).
Genome-wide association studies have also identified
SNPs associated with candesartan response (Turner 2012).
However, much of these data have not been replicated, and
further studies are needed in varying populations before they
can be translated to clinical practice.
Although current guidelines have recommended a lesser
role for routine -blocker use, studies have shown an association between polymorphisms in the 1-adrenergic receptor gene
CONCLUSION
Several HTN-related studies and guidelines have been published since JNC 7. Studies contributing to knowledge
regarding blood pressure goals, preferred therapies for concomitant disease states and specific populations, dosing of
23
antihypertensive drugs, and treatment of resistant HTN have

been completed. This chapter summarizes some of the more
recent changes to guidelines and therapy recommendations.
However, a single U.S. guideline with majority consensus to
manage HTN is eagerly awaited.<Prod: Insert Practice Points>
Practice Points
For patients with coronary or other atherosclerotic vascular
disease, the blood pressure goal is less than 140/90 mm
Hg according to the AHA/ACC, and initial therapy should be
with -blockers and ACE inhibitors (or ARBs if ACE inhibitor
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27
Self-Assessment Questions
Questions 1 and 2 pertain to the following case.
mg, chlorthalidone 12.5 mg, and atorvastatin 40 mg. Her

laboratory results are K 4.1 mEq/L, Na 142 mEq/L, SCr 1.3
mg/dL, CrCl 66 mL/minute/1.73 m2, total cholesterol 160
mg/dL, HDL 45 mg/dL, TG 115 mg/dL, and LDL 92 mg/dL.
She is adherent to her therapy but would prefer not to take
any additional agents. Her diabetes is well controlled, and
she does not smoke. Which one of the following would best
address this patients concern about her CV risk?
A.K., a 63-year-old white man (height 70 inches, weight 113.6

kg), presents to the clinic after not seeking health care for 5
years. He knows he has diabetes, but he is not sure how well
it is controlled. Today, his blood pressure is 138/88 mm Hg,
with repeat 138/85 mm Hg, and his heart rate is 80 beats/minute. A.K.s laboratory test results are A1C 11.1%, SCr 1.3 mg/dL
(CrCl [ideal body weight (IBW)] 60 mL/minute/1.73 m2), urine
albumin excretion 100 mg/24 hours, K 3.9 mEq/L, and Na 141
mEq/L. His physician has a plan for A.K.s diabetes treatment
but would like to know what, if anything, should be done for
the patients blood pressure according to the latest KDIGO
guidelines.
1.
A. Change the lisinopril dose to nighttime.

B. Increase the chlorthalidone dose to 25 mg/day.
C. Change all her antihypertensive medications to
nighttime.
D. Reassure the patient that no medication changes are
needed.
Which one of the following is best to recommend regarding A.K.s blood pressure?
4. A 75-year-old man (height 66 inches, weight 68 kg)

with hypertension (HTN), gastroesophageal reflux disease (GERD), and osteoarthritis presents to the clinic.
The patient is frustrated with trying to control his blood
pressure. He is adherent to a low-sodium diet, antihypertensive drugs, and regular exercise. Today, his blood
pressure is 155/90 mm Hg, and his heart rate is 80 beats/
minute. His laboratory test results include K 4.8 mEq/L,
Na 138 mEq/L, Cr 1.5 mg/dL, CrCl 38 mL/minute/1.73 m2,
and ALT 25 mg/dL. His home drugs are carvedilol 25 mg
twice daily, hydrochlorothiazide 25 mg/day, losartan 100
mg/day, amlodipine 10 mg/day, ibuprofen 800 mg twice
daily, and omeprazole 20 mg twice daily. What is the next
best step to address this patients blood pressure control?
A. Blood pressure is at goal; no action is required.

B. Blood pressure is at goal; the KDIGO guidelines do
not apply because he does not have chronic kidney
disease (CKD).
C. Blood pressure is above goal; initiate lisinopril 10 mg/
day.
D. Blood pressure is above goal; initiate atenolol 50 mg/
day.
2. One year later, A.K. presents for a follow-up. He was
admitted to the hospital last week with an ST-segment
elevation myocardial infarction (STEMI) and discharged
after stent placement. He now takes prasugrel 10 mg/day,
aspirin 81 mg/day, enalapril 2.5 mg/day, and metoprolol
succinate 12.5 mg/day. His blood pressure is 105/70 mm
Hg, with similar repeat; his heart rate is 65 beats/minute,
and his ejection fraction is 50%. He has no symptoms of
orthostatic hypotension (OH), but he asks whether his
blood pressure is too low. Which one of the following is
the best response to A.K.s inquiry?
A.
B.
C.
D.
5. A 69-year-old Hispanic woman (height 65 inches, weight

79.5 kg) with heart failure (HF) with preserved ejection
fraction presents to the clinic. She reports her home
blood pressure readings have been steadily increasing for
the past several months. She has been adherent to her
drugs: candesartan 32 mg/day and furosemide 40 mg
twice daily. She is euvolemic. Her blood pressure today
is 145/80 mm Hg, with similar repeat; her heart rate is 62
beats/minute; and her last ejection fraction was 55%. Her
laboratory results are K 4.0 mEq/L, Na 140 mEq/L, SCr
1.1 mg/dL, and CrCl (IBW) 43 mL/minute/1.73 m2. Which
one of the following is the best step to take to address this
patients blood pressure?
A. His blood pressure is too low; discontinue metoprolol

succinate.
B. His blood pressure is too low; discontinue enalapril.
C. Reassure him that his blood pressure should be this
low; no changes are needed.
D. Reassure him that there is no concern for his blood
pressure; no changes are needed.
3. A 59-year-old African American woman with diet-controlled diabetes presents to the clinic for a follow-up. She is
concerned about her cardiovascular (CV) risk because her
mother died of a myocardial infarction (MI) at age 54. The
patients blood pressure is 138/86 mm Hg, and her heart
rate is 85 beats/minute; she reports similar home blood
pressure readings. Every morning, she takes lisinopril 20
Increase his carvedilol dose to 50 mg twice daily.

Discontinue ibuprofen and start acetaminophen.
Start spironolactone 12.5 mg/day.
Increase his hydrochlorothiazide dose to 50 mg/day
A.
B.
C.
D.
28
Increase furosemide to 80 mg twice daily.

Start spironolactone 12.5 mg/day.
Start metoprolol succinate 50 mg/day.
Start eplerenone 25 mg/day.
C. Hydrochlorothiazide 25 mg/day
D. Spironolactone 25 mg/day
6. A 51-year-old white man presents for a blood pressure

recheck. During his annual physical examination 3 months
ago, his blood pressure was elevated (155/90 mm Hg). His
only significant medical history is chronic gout, for which
he takes allopurinol. He has been trying to lower the sodium
in his diet and to increase exercise. Today, his blood pressure is 152/92 mm Hg, with similar repeat, and his heart
rate is 75 beats/minute. His electrolytes and renal function
are normal. Which one of the following is the best step to
take next to treat this patients blood pressure?
A.
B.
C.
D.
10. A 61-year-old woman with ASCVD (stent placement 1

year ago) presents today for follow-up. Her blood pressure is 148/86 mm Hg, with a similar repeat, and her heart
rate is 85 beats/minute. Her laboratory values are: K 4.6
mEq/L, Na 142 mEq/L, and SCr 0.9 mg/dL. She takes lisinopril/hydrochlorothiazide 20 mg/25 mg once daily and
metoprolol succinate 50 mg/day, and she reports being
adherent to her regimen. She is reluctant to take more
blood pressure drugs because when she uses her home
blood pressure monitor the readings are usually less than
125/70 mm Hg. Which one of the following is best to recommend for this patients blood pressure management?
Start lisinopril 10 mg/day.

Start chlorthalidone 25 mg/day.
Start metoprolol succinate 50 mg/day.
Start terazosin 5 mg at bedtime.
7. An 81-year-old woman with atherosclerotic cardiovascular disease (ASCVD) (STEMI with 4-vessel coronary
artery bypass grafting 7 years ago), HTN, and CKD presents with dizziness on standing. Last week, she almost
fell after getting out of bed. She has tried increasing her
fluid and salt intake, but this has not helped. Today, her
blood pressure is 138/74 mm Hg and her heart rate is 60
beats/minute while sitting; 1 minute later she stands and
her blood pressure is 115/70 mm Hg and her heart rate
is 76 beats/minute. She takes metoprolol tartrate 50 mg
twice daily, lisinopril 20 mg/day, aspirin 81 mg/day, and
atorvastatin 40 mg/day. Which one of the following is the
next best step to treat this patients blood pressure?
A.
B.
C.
D.
A. Start felodipine 2.5 mg/day.

B. Decrease her lisinopril/hydrochlorothiazide dose to
10/12.5 mg once daily.
C. Order 24-hour ambulatory blood pressure
monitoring.
D. Ask her to check her home blood pressure both
sitting and standing.
T.S., a 57-year-old man with a 13-year history of HTN, presents to the ED with a blood pressure of 210/120 mm Hg and a
heart rate of 110 beats/minute. T.S. describes a sudden onset
of severe chest pain as sharp and tearing. A diagnosis of a
thoracic aortic aneurysm dissection is made.
Start midodrine 2.5 mg three times daily.

Discontinue all her antihypertensive drugs.
Start droxidopa 100 mg three times daily.
Lower her metoprolol dose to 25 mg twice daily.
11. Which one of the following represents the best goal for
T.S.s blood pressure reduction?
A. Achieve 170150 mm Hg SBP within the first 2 hours
of presentation.
B. Achieve 90 mm Hg DBP over the first 26 hours of
presentation.
C. Reduce SBP to less than 120 mm Hg within 20
minutes of presentation.
D. Reduce SBP to less than 140 mm Hg over 2448
hours.
P.J., a 58-year-old man (height 72 inches, weight 100 kg) with

type 2 diabetes mellitus (DM) and CKD, presents to the clinic
for a follow-up. His blood pressure today is 152/86 mm Hg,
with similar repeat, and his heart rate is 80 beats/minute. His
laboratory test results are: A1C 6.9%, SCr 1.7 mg/dL, CrCl (IBW)
42 mL/minute/1.73 m2, K 4.0 mEq/L, Na 135 mEq/L, and urine
albumin excretion 20 mg/24 hours. His home drugs are insulin
glargine, insulin aspart, and pravastatin 40 mg/day.
12. Which one of the following would best manage T.S.s

hypertensive emergency?
A. Diazoxide
B. Esmolol
C. Hydralazine
D. Minoxidil
8. Which one of the following represents the best blood

pressure goal for P.J.?
A.
B.
C.
D.
Less than 130/80 mm Hg

13. You are giving a continuing education lecture to a local

group of community pharmacists on the recent HTN
guidelines. During the question and answer portion, an
attendee asks your thoughts on treating HTN in patients
older than 80 years. Which one of the following is the best
evidence-based response to this question?
9. Which one of the following is best to initiate to address

P.J.s blood pressure?
A. Losartan 25 mg/day
B. Lisinopril/hydrochlorothiazide 20/25 mg/day
29
C. Add spironolactone 25 mg/day.

D. Send him for a consult for a renal denervation
procedure.
A. Meta-analyses have shown fewer adverse CV

outcomes with aggressive blood pressure lowering to
less than 140 mm Hg in 70- to 85-year-old patients.
B. The VALISH trial showed that achieving an SBP of
less than 150 mm Hg in patients 7084 years of age
improved outcomes.
C. The JATOS trial showed that achieving an SBP of
less than 160 mm Hg in patients 6585 years of age
improved outcomes.
D. The HYVET trial showed lower adverse CV outcomes
with lowering the blood pressure to less than 150/80
mm Hg in patients older than 80 years.
18. While completing paperwork in the clinic, a third-year

medical student asks your opinion on initiating atenolol
25 mg/day in a patient with newly diagnosed uncomplicated HTN. Which one of the following is the best
response to this question?
A. -Blockers are no longer recommended as first-line
options.
B. Carvedilol would be a better -blocker to initiate as a
first-line option.
C. Initiating atenolol sounds like a reasonable plan.
D. Make sure that a baseline corrected QT interval is
obtained before initiating atenolol.
14. A 57-year-old man is brought to the ED with significant

shortness of breath, evidence of volume overload, and a
blood pressure of 220/110 mm Hg. His medical history
is significant for hyperlipidemia, gout, diabetes, HF with
reduced ejection fraction, and coronary artery disease
(CAD). Which one of the following would best manage this
patients hypertensive emergency event?
19. Which one of the following best justifies the initiation of

chlorthalidone over hydrochlorothiazide in a patient with
HTN?
A. The ALLHAT trial showed that chlorthalidone
reduced blood pressure better than
hydrochlorothiazide.
B. Direct head-to-head trials showed lower mortality
with chlorthalidone.
C. Meta-analyses of indirect data showed improved CV
outcomes with chlorthalidone.
D. The MRFIT trial showed a higher risk of developing
diabetes with hydrochlorothiazide.
A. Esmolol
B. Labetalol
C. Nicardipine
D. Sodium nitroprusside
15. A patient who is homozygotic for the Arg389Gly phenotype of the ADRB1 gene requires blood pressure reduction.
Which one of the following would have the greatest blood
pressurelowering effect for this patient?
A. Chlorthalidone
B. Metoprolol
C. Trandolapril
D. Verapamil
20. The ALLHAT was a randomized, double-blind, active-controlled clinical trial that enrolled 33,357 patients with HTN
and at least once other coronary heart disease (CHD) risk
factor to receive chlorthalidone, amlodipine, or lisinopril.
The primary outcome was a combination of fatal CHD or
non-fatal MI. One of the secondary outcomes was HF. The
following table summarizes the data for amlodipine compared with chlorthalidone:
16. According to the JNC 8 panel author recommendations,

for which one of the following patients would a goal blood
pressure of less than 150/90 mm Hg be most appropriate?
A. A 56-year-old woman with a medical history of DM (5
years) and CKD (2 years)
B. A 62-year-old man with a medical history of
hypercholesterolemia (4 years)
C. A 58-year-old man with a recent MI (2 months ago)
D. A 45-year-old man with uncomplicated HTN
17. A 54-year-old man presents to the clinic for a follow-up

of his hypertensive drug regimen. His medical history is
significant for HTN and CAD. To control his blood pressure, he takes amlodipine 10 mg/day, lisinopril 40 mg/day,
and chlorthalidone 25 mg/day. Today in the clinic, his vital
signs include blood pressure 154/96 mm Hg and heart
rate 55 beats/minute, and his laboratory values are all
within normal values. Which one of the following would
best manage this patients HTN?
Relative Risk
95% CI
Primary end point
0.98
0.901.07
Heart failure
1.38
1.251.52
Which one of the following best describes how amlodipine compares with chlorthalidone in the ALLHAT data?
A. Decreases the primary end point but increases HF
B. Decreases both the primary end point and HF
C. Has no significant effect on the primary end point or
HF
D. Has no significant effect on the primary end point
but increases HF Learner Chapter Evaluation:
Hypertension.
A. Switch chlorthalidone to hydrochlorothiazide.

B. Increase amlodipine to 15 mg/day.
30
LEARNER CHAPTER EVALUATION: BLOOD PRESSURE MANAGEMENT

Use the 5-point scale to indicate whether this chapter prepared you to accomplish the following learning objectives:
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:

12. Distinguish key differences between various national and

international hypertension (HTN) guidelines.
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
13. Demonstrate appropriate drug selection and blood pressure goals for the treatment of HTN according to the
presence of concomitant conditions.
14. Devise an evidence-based treatment strategy for resistant HTN to achieve blood pressure goals.
1. The content of the chapter met my educational needs.
15. Justify the use of ambulatory blood pressure monitoring.
2. The content of the chapter satisfied my expectations.
16. Develop treatment strategies for hypertensive urgency

and emergency.
3. The author presented the chapter content effectively.
17. Construct appropriate drug therapy plans for the treatment of hypotension.
4. The content of the chapter was relevant to my practice

and presented at the appropriate depth and scope.

18.
Assess the potential effect of pharmacogenomics on
blood pressure.
5. The content of the chapter was objective and balanced.

6. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
19. Please provide any specific comments relating to any

perceptions of bias, promotion, or advertisement of commercial products.
7. The content of the chapter was useful to me.

8. The teaching and learning methods used in the chapter
were effective.
20. Please expand on any of your above responses, and/or

provide any additional comments regarding this chapter:
9. The active learning methods used in the chapter were

effective.
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.
31
Dyslipidemia
By Laura H. Waite, Pharm.D., BCPS, CLS, BC-ADM; and Yvonne L. Phan, Pharm.D., BCPS
Reviewed by Mark J. Cziraky, Pharm.D., CLS, FAHA, FNLA; Cassandra D. Benge, Pharm.D., BCPS, AQ-Cardiology, AACC; and Sossity A.
Riordan, Pharm.D., BCPS, BC-ADM
LEARNING OBJECTIVES
1. Distinguish between dyslipidemia treatment recommendations from the National Cholesterol Education Panel Adult
Treatment Panel III, the American College of Cardiology/American Heart Association, and the National Lipid Association.
2. Using available assessment tools, classify a patients risk of cardiovascular disease.
3.
Using recommendations from major organizations (e.g., American Diabetes Association, Kidney Disease: Improving
Global Outcomes) and individual patient risk factors, design an effective dyslipidemia treatment strategy.
4. Distinguish the benefits and risks of widespread statin use as first-line management of dyslipidemia.
5.
Evaluatebased on current evidencethe role of nonstatin therapies in the management of lipid disorders.
6. Analyze novel mechanisms of action of emerging therapies to address dyslipidemia.
ASCVD
CAC
CHD
CKD
FRS
GFR
HeFH
HoFH
hs-CRP
KDIGO
Lp-PLA 2
MI
NHLBI
NLA
PCSK9
RCT
SBP
TLC
Atherosclerotic cardiovascular
disease
Coronary artery calcium
Coronary heart disease
Chronic kidney disease
Framingham Risk Score
Glomerular filtration rate
Heterozygous familial
hypercholesterolemia
Homozygous familial
hypercholesterolemia
high-sensitivity C-reactive protein
Kidney Disease: Improving Global
Outcomes
Lipoprotein-associated phospholipase A 2
Myocardial infarction
National Heart, Lung, and Blood
Institute
National Lipid Association
Proprotein convertase subtilisin/
kexin type 9
Randomized controlled trial
Systolic blood pressure
Therapeutic lifestyle change
INTRODUCTION
For more than a decade, the medical community has followed the
guidelines recommended by the National Cholesterol Education
Program (NCEP) Adult Treatment Panel (ATP)specifically, ATP III and
subsequent 2004 update (Grundy 2004; NCEP 2002). Management
has focused primarily on coronary heart disease (CHD) risk assessment based on identified cardiovascular (CV) risk factors, myocardial
infarction (MI) risk, and MI prediction (Table 2-1). In the United States,
providers most commonly predicted risk by using the Framingham
Risk Score (FRS), which was then correlated to numeric lipid parametersspecifically, LDL and non-HDL cholesterol. In comparison
to prior versions, ATP III and its update in 2004 also recommended
aggressive LDL goals, optional goals, and the use of combinations
of drugs in patients with CV risk whose LDL goals remained unmet.
Although therapeutic lifestyle changes (TLCs) were included in
the recommendations for disease state management, aggressive
drug therapy was the focal point. In general, statins were considered
first-line agents in all patients, without contraindications, to achieve
indicated LDL levels. Nonstatins were used as add-on therapies
in patients with mixed dyslipidemia (e.g., adjunctive niacin and/or
fenofibrate for elevated TG and/or low HDL) or uncontrolled hypercholesterolemia (e.g., adjunctive bile acid sequestrant).
Patients and practitioners gauged their progress by using these
numeric goals. In addition, managed care organizations and health
systems used these recommendations to monitor patient progress and
to profile prescriber performance. However, some practitioners questioned the evidence supporting the utility of the numeric therapy goals,
and, more important, the selection of adjunctive nonstatin therapies to
33
Dyslipidemia
achieve those goals. Patients reaching the numeric target still
(ACC/AHA) expert panel constructed a different approach to

CV risk reduction, modeling treatment according to the drug
and dose used in pivotal clinical trials enrolling at-risk patients
(Stone 2014). Risk stratification became a straightforward
approach that identified patients who clearly benefit from evidence-based treatment with a moderate to highintensity
statin. In addition, the historical risk calculator that limited risk
assessment to CHD was refined to enable calculation of risk of
disease in noncoronary vessels. Most important, the new calculator encompassed a greater percentage of the U.S. population.
Even the approach to dyslipidemia management underwent
a complete paradigm shift, from numeric targets to trial-supported regimens for broadly defined patient populations, which
created a startling reaction in the medical community and
affected a significant proportion of the American population.
Notably, the recommendations pinpointed the gaps in scientific evidence, leading some health care practitionersand
patientsto reject the new management approach by seeking
out other guidelines that supported their standard practice or by
creating a hybrid approach that combined previous lipid parameter targets with new recommended regimens in specified patient
populations. To date, little guidance exists in managing patients
not fitting into the categories that have clear evidence-based benefit from aggressive treatment, such as individuals with other
high-risk conditions (e.g., HIV, chronic kidney disease [CKD;
defined as kidney damage for > 3 months by either structural
or functional abnormalities or GFR < 60 mL/min/1.73 m2 for >
3 months], rheumatologic diseases). Lipidology organizations
such as the National Lipid Association (NLA) set forth additional
guidelines in an attempt to bridge some of the gaps. However, the
best approach to CV risk reduction remains elusive. Health care
practitioners are left to sort through the available evidence for
individualization of patient care.
underwent recurrent events and died at unacceptable rates.

Evidence began to accumulate that cast doubt on the correlation of outcomes with the use of any drug class except statins.
During the guideline update development process, an
American College of Cardiology/American Heart Association

with the following:
Basic knowledge of the pathophysiology that leads
to atherosclerosis in dyslipidemia
General knowledge of mechanisms of action of
currently available drugs for dyslipidemia
Components of appropriate therapeutic lifestyle
changes
ADDITIONAL READINGS
National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). Third Report of the
National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) final report. Circulation
2002;106:3143-421.
Grundy SM, Cleeman JI, Merz CN, et al.
Implications of recent clinical trials for the National
Cholesterol Education Program Adult Treatment
Panel III guidelines.Circulation2004;110:227-39.
HISTORICAL APPROACH TO
DYSLIPIDEMIA TREATMENT
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013

ACC/AHA Guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the Task Force on
Practice Guidelines. Circulation 2014;129:S1-S45.
The link between atherosclerosis and dyslipidemia is well

established and well understood. The normal pathophysiology of lipid metabolism involves the hepatic production
of lipoprotein particles, which include an apolipoprotein B
(apoB) molecule surrounding a phospholipid shell that contains an inner core of cholesterol and triglycerides (Ganong
2006). ApoB binds to receptors in various tissues throughout
the body, activating enzymes that enable particle hydrolysis
to deliver cholesterol and triglycerides to organs that require
those elements for function. Apolipoprotein A (apoA) molecules are produced by the liver and collect excess cholesterol
and triglycerides from general circulation and tissues where
they are no longer needed. The process is known as reverse
cholesterol transport. Abnormalities in the lipid metabolism
process can directly lead to CV injury and the development
of an atherosclerotic plaque. Specifically, apoB lipoprotein
particles can enter the coronary artery wall, triggering an
Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC

Guideline on lifestyle management to reduce
cardiovascular risk: a report of the Task Force on
Practice Guidelines. Circulation 2014;129:S76S99.
Jacobson TA. NLA Task Force on statin safety
2014 update. J Clin Lipidol 2014;8:S1S4.
Jacobson TA, Ito MK, Maki KC, et al. National Lipid
Association recommendations for patient-centered
management of dyslipidemia: Part 1 full report. J
Clin Lipidol 2015;9:12969.
Jacobson TA, Maki KC, Orringer C, et al. National
Lipid Association Recommendations for PatientCentered Management of Dyslipidemia: Part 2. J
Clin Lipidol 2015;doi:10.1016/j.jacl.2015.09.002.
34
Dyslipidemia
Table 2-1. LDL Goals and Cut Points for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories
Risk Category
Goal
(mg/dL [mmol/L])
Level at Which to Initiate TLC

(mg/dL [mmol/L])
Level at Which to Consider

Drug Therapy (mg/dL [mmol/L])
High risk:
CHDa or CHD risk equivalentsb
(or 2+ risk factorsc with FRS
10-year risk >20%)
<100 [2.59]
Optional goal:
<70 [1.81]
100 [2.59]
100 [2.59]
(<100 [2.59]:
consider drug options)
FRS 10-year risk <130 [3.36]

> 10%20%
Optional goal:
<100 [2.59]
130 [3.36]
130 [(>3.36)]
(100129 [2.593.35]: consider
drug options)
FRS 10-year risk <130 [3.36]

< 10%
130 [3.36]
160 [4.14]
160 [4.14]
190 [4.91]
(160189 [4.144.90]:
LDL-lowering drug optional)
Moderate risk:
2+ risk factors
Lower risk: 01 risk factor (or FRS

10-year risk) <10%)
<160 [4.14]
CHD includes a history of myocardial infarction, unstable angina, stable angina, coronary artery procedures (angioplasty or bypass
surgery), or evidence of clinically significant myocardial ischemia.
CHD risk equivalents include diabetes, 2+ risk factors with FRS >20%, and noncoronary forms of atherosclerotic disease (e.g.,
peripheral arterial disease, abdominal aortic aneurysm, or carotid artery disease).
c
FRS is calculated when two or more of the following risk factors are present: cigarette smoking; hypertension (BP 140/90 mm Hg
or on antihypertensive medication); HDL <40 mg/dL; premature family history of CHD (CHD in male first-degree relative <55 years of
age; CHD in female first-degree relative <65 years of age); and patient age (men 45 years; women 55 years).
CHD = coronary heart disease; FRS = Framingham Risk Score.
Information from Grundy SM, Cleeman JI, Bairey Merz CN, et al, for the Coordinating Committee of the National Cholesterol
Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III
guidelines. Circulation 2004;110:227-39. (Optional LDL goals included on the basis of available clinical trial results and were
included in the 2004 update.)
b
ATP III and Update
inflammatory process and oxidizing the lipoproteins to create a foam cell full of macrophages with a necrotic lipid core.
As the foam cell grows and matures into an atherosclerotic
plaque, the artery wall expands into the vascular lumen and at
best negatively affects blood flow or at worst ruptures into the
circulation, leading directly to ischemic events in the coronary,
peripheral, and cerebral vasculature and, possibly, death.
Because of that link between lipid particles and atherosclerosis development, dyslipidemia management plays a major
role in reducing subsequent CV events. Knowledge of that
pathophysiology has provided the medical community with
several physiologic targets for mitigating those processes.
Notably, the many steps in the hepatic synthesis of lipoprotein
particles and their components form the focus of the most
commonly used drug therapies. Decreased hepatic synthesis
results in compensatory up-regulation of lipoprotein receptors on the liver, which increases the clearance of circulating
lipoproteins as well. Additional therapies target the hydrolysis
process at the cellular level, genetic mutations throughout the
metabolic process, and the role of apoA lipoproteins to reduce
the amount of excess cholesterol and triglycerides available
to contribute to plaque development. However, none of the
available drug therapies have completely eliminated CV risk,
and the clinical community has struggled to identify the most
effective risk-reduction approach.
In 1988, the National Heart, Lung, and Blood Institute (NHLBI)

produced initial guidelines for cholesterol management.
As evidence evolved, the ATP released updates that further
honed management recommendations. In 2001, the ATP III
report cited evidence demonstrating that aggressive LDL lowering through judicious use of pharmacologic therapy and
TLC resulted in both primary and secondary prevention of CV
events; that update also began to recognize the contribution
of risk from noncoronary vessels. The guidelines provided
a stepwise approach to stratification of risk in each individual patient by applying major CV risk factors and a calculated
10-year risk of CHD by using the Framingham Risk Score to
determine ideal numeric LDL levels (see Table 2-1). Secondary
targets addressed components of the metabolic syndrome
and non-HDL, wherein the recommended numeric goal was
30 mg/dL above the LDL goal. To achieve these targets, the
guideline focused on initiating and intensifying LDL-lowering
therapy with statins, bile acid sequestrants, or nicotinic acid
(niacin). Once the LDL goal had been attained, when needed,
consideration turned to the addition of niacin or a fibric acid
derivative to assist in lowering TG or increasing HDL and
therefore reaching the non-HDL goal. Because of lack of evidence, the guidelines did not provide HDL goals; and because
35
Dyslipidemia
of concern for acute pancreatitis, TG became the primary

focus of therapy only when greater than 500 mg/dL.
After ATP III publication, several major trials were released
that advocated for an increasingly aggressive dyslipidemia
management approach. Subsequently, in 2004, a subgroup
of the ATP III panel published an update that addressed the
new evidence and altered risk stratification. The approach for
determining individual patient risk remained the same; however, the LDL goals became more stringent (see Table 2-1).
The authors suggested earlier use of niacin and/or fibric acid
derivatives in combination with LDL-lowering drugs to assist
patients in achieving the LDL goal. The update did say that if
patients were unable to attain those targets, it was reasonable
to aim for an LDL reduction of 30%40% from baseline, and
that all patients, at any level of risk, would benefit from intensive TLC as described in ATP III. This update also included
evidence-based recommendations for older patients.
With the release of that update, almost all health care practitioners had a usable framework for dyslipidemia management
that was widely accepted for almost a decade. However, as
experts began to closely examine evidence released in subsequent years, the focus of further guideline updates shifted to
a holistic approach that simplified risk stratification and drug
therapy away from a titrate-to-target approach.
doses of statins to reduce ASCVD and did not support specific

numeric lipid goals. The panel further justified its approach by
saying that patients had experienced positive outcomes with
high-intensity LDL-lowering therapy whether or not a specific
LDL target was reached.
Another major difference was the distinct lack of support
for any nonstatin pharmacologic intervention for statin-tolerant patients; the expert panel expressed concern about the
routine use of an adjuvant nonstatin to attain an arbitrary
numeric lipid target without supporting evidence that such
therapy was affecting patient outcomes positively. Third, the
panel designated pooled cohort equations as the preferred
method to estimate 10-year and lifetime risk for CHD and
stroke in non-Hispanic white and African American men and
women. The authors were clear that their recommended novel
approach to lipid management in the 2013 ACC/AHA guidelines was based solely on data from RCTs published within
a narrow time window; specifically, information from epidemiologic or observational studies was not included, which
significantly narrowed the focus of this guideline.
In a manner similar to ATP III, the 2013 guidelines continued a stepwise approach for patient risk assessment. The
authors determined four main groups of patients with proven
benefit from statin therapy: (1) patients with clinical ASCVD;
(2) patients with LDL greater than 190 mg/dL; (3) patients
4075 years old with diabetes mellitus (DM) and with LDL
of 70189 mg/dL who were not classified in groups 1 and 2;
and (4) patients 4075 years old with LDL of 70189 mg/dL
and a 10-year ASCVD riskas calculated by the pooled cohort
equationsof greater than 7.5% who were not classified in any
other group. Of note, the pooled cohort equations calculation
was required in only two sets of patients: in the DM group to
assist in determining moderate versus high risk of an ASCVD
event; and in the general population to define group 4, the primary prevention group.
In general, the guidelines recommended high-intensity statin therapydefined as a daily dose of a statin that could lower
LDL from baseline by more than 50%for individuals in groups
1 and 2 and for high-risk individuals in group 3, whereas moderate-intensity statin therapy (defined as a daily dose of a
statin that could lower LDL from baseline by 30%50%) was
appropriate for older patients in group 1, for patients with low
to moderate risk in group 3, and for most patients in group 4.
However, the authors emphasized the need for individualized
treatment plans that would account for comorbidities, nontraditional risk factors, and patient investment.
As noted above, the guidelines did not recommend any additional therapy beyond appropriately dosed statins, and they
advocated periodic monitoring of LDL levels only for assessing adherence, not for reaching a specific numeric target. The
guideline also emphasized the utility of TLC in reducing overall ASCVD risk, outlined in detail in an accompanying guideline
document released simultaneously. Notably, the 2013 ACC/AHA
guidelines excluded patients with New York Heart Association
NEW DYSLIPIDEMIA MANAGEMENT

GUIDELINES
2013 ACC/AHA Guideline on the Treatment of
Blood Cholesterol in Adults
During the process of updating the ATP III guidelines, the

NHLBI transferred the work to several professional organizations that collaborated to produce the final consensus
document. In late 2013, the ACC/AHA released cholesterol
management guidelines that targeted overall atherosclerotic
cardiovascular disease (ASCVD) risk in the general adult population. The expanded focus on ASCVD versus CHD facilitated
the inclusion of the known risk of noncoronary disease events
linked to atherosclerosis, including symptomatic carotid
artery disease, stroke/transient ischemic attack, peripheral
artery disease, and abdominal aortic aneurysm, all of which
had been considered in the ATP III report as only diseases that
conferred risk that was equivalent to CHD.
The 2013 ACC/AHA recommendations differed significantly
from ATP IIIand the 2004 updatein that the complicated
patient risk stratification was supplanted with recommendations with widespread applicability for practitioners. One
major difference, which generated national discussion,
involved the abolishment of LDL and non-HDL numeric treatment goals. The rationale for the change was based on the
expert panels interpretation of clinical trial evidenceparticularly on evidence that lacked randomized controlled trial
(RCT) data designed to explore LDL targets. The panels interpretation supported only aggressive lipid lowering with fixed
36
Dyslipidemia
class IIIV ischemic systolic heart failure as well as patients

receiving dialysis, citing a lack of clinical trial evidence to
demonstrate benefit in those populations. The guidelines also
failed to provide recommendations on the management of
patients with TG exceeding 500 mg/dL, a population that would
predominantly benefit from nonstatin therapy.
Because many clinicians treat patients in those subgroups
and because some of those patients exhibit characteristics
that would presumably require dyslipidemia management, the
elimination of those populations left many unanswered questions. More important, many patients were not as easily risk
stratified as the guidelines suggested they were, and the concept of simply initiating therapy with no goal to guide progress
or quantify risk reduction made both patients and practitioners leery of accepting the new management approach.
Some clinicians therefore considered selectively choosing
elements from both the ATP and ACC/AHA guidelines (e.g.,
classifying a patient into a statin benefit group to assist with
initial choice of statin therapy and dose but then continuing to
aim for a specific numeric LDL target).
non-HDL for risk prediction of ASCVD over LDL because of the

more comprehensive inclusion of all atherogenic lipoproteins
(e.g., LDL, intermediate-density lipoprotein, very-low-density
lipoprotein [VLDL], and VLDL remnants) that could contribute to the development of ASCVD. In addition, the document
offered goals of therapy for apoB as an optional secondary
target as well as lifestyle recommendations for reducing metabolic syndrome parameters similar to those in ATP III. The
document also recommended patient risk assessment in a
stepwise approach based on a patients traditional cardiac
risk factors as described in ATP III, with the subsequent use of
either the FRS or the Pooled Cohort Equations to further refine
risk within each patient subgroup (Table 2-2).
That approach resulted in the definitions of high-risk and
very-high-risk patient populations mirroring those in the 2013
ACC/AHA guidelines, with the addition of late-stage (specifically, greater than 3B but not end-stage) chronic kidney
disease patients. As part of an overall emphasis on individualized patient risk assessment, the NLA guidelines focused
on several nontraditional risk factors in an overall ASCVD risk
assessment to guide therapy. The factors included severe
manifestations of traditional risk factors, indicators of subclinical or inflammatory disease, elevations in specific lipid
biomarkers, and urine albumin/creatinine ratio.
Finally, similar to the 2013 ACC/AHA guidelines, Part 1 of
the NLA recommendations gave considerable credence to
TLC, together with pharmacologic therapy when indicated. The
authors supported the definitions of high-intensity and moderate-intensity statin therapy as proposed by the 2013 ACC/
AHA guidelines and acknowledged the preponderance of evidence supporting statin therapy as first-line pharmacologic
therapy. However, in contrast to the 2013 ACC/AHA guidelines
and beyond the original scope of ATP III, the NLA supported
additional or alternative lipid-lowering therapies (e.g., bile acid
sequestrants, cholesterol absorption inhibitors, nicotinic acid,
fibrates, omega-3 fatty acids) for patients who could not tolerate
statins or who had lipid abnormalities in parameters other than
LDL. The authors concern was that the clinical trial data that did
not support combination therapies with statins included patient
populations with low levels of atherogenic cholesterol at baseline, and therefore potential benefit could still exist for patients
with high atherosclerotic burden. The authors also included
information on treatment options for patients with severely elevated levels of atherogenic lipoproteins in disease states such
as homozygous familial hypercholesterolemia (HoFH) or heterozygous familial hypercholesterolemia (HeFH), including
apoB synthesis inhibitors, microsomal triglyceride transfer protein inhibitors, and LDL apheresis.
In late 2015, the NLA published the second part of its dyslipidemia management recommendations, intended to complement
and expand Part 1 of the NLA recommendations, as well as
to answer unanswered questions in the ACC/AHA guidelines
(Jacobson 2015). This document provided increased clarity
regarding lifestyle therapies by including nutrition and exercise,
National Lipid Association Guidelines
In late 2014, the National Lipid Association published Part 1 of

its own set of recommendations to bridge the gaps between the
various guidelines (Jacobson 2015). The NLA document incorporated elements of both ATP III and the 2013 ACC/AHA guidelines
but with more specific guidance on how to approach (1) patients
for whom appropriate therapy was not obvious and (2) populations not included in the 2013 guidelines. In contrast to the 2013
ACC/AHA guidelines, the NLA recommendations incorporated
evidence from both RCTs and epidemiologic, genetic, metabolic, and mechanistic studies. The authors emphasized that a
focus only on LDL lowering omitted other important atherogenic
lipoproteins that could contribute to ASCVD. In support of that
concern, the authors identified non-HDL as a coprimary target
of therapy together with LDL. Although they concurred with the
2013 ACC/AHA guidelines that the intensity of lipid-lowering therapy should be tailored to an individual patientlevel assessment
of risk, they noted the continued utility of numeric goals in correlating the intensity of therapy to the likelihood of disease. They
also focused on the value of communication between patient
and provider in monitoring progress and risk reduction with
those numeric treatment targets.
To that end, the 2014 NLA guidelines reintroduced a similar classification of LDL, HDL, TG, and non-HDL levels that
mirrored the ATP III recommendations. The authors also
specified numeric treatment goals that were simpler than
those in ATP III; specifically, the recommendations advocated
an LDL goal of less than 100 mg/dL for all but the highest-risk
patients, with a lower goal (less than 70 mg/dL) in patients
with ASCVD or DM with two or more major ASCVD risk factors or evidence of end organ damage. The recommendations
included a non-HDL goal of 30 mg/dL higher than the LDL
goal, noting that evidence did support the superiority of
37
Dyslipidemia
strategies for optimizing patient adherence, and implementation of team-based collaborative careincluding care by
pharmaciststo improve overall quality. The guidelines specifically mentioned pharmacists as team members who can
identify medication nonadherence and devise methods to assist
patients in overcoming barriers to adherence. In addition, Part
2 expanded management recommendations to include special
patient populations beyond those of any previous guideline. The
authors offered guidance for the treatment of children and adolescents, older patients, women (pregnant and nonpregnant),
diverse ethnic and racial groups, and patients with high-risk conditions such as HIV or rheumatologic diseases.
In a deviation from other guidelines, the NLA recommended
a higher risk threshold for treatment of older patients, including a careful risk-benefit analysis as well as the consideration
of HIV and rheumatoid arthritis as ASCVD risk factors in risk
calculation. Statins, together with TLC, were emphasized as
the treatments of choice for most patients, including patients
with ethnic diversity or noncardiovascular high-risk conditions. For patients with TG of 500 mg/dL or greater, fibric
acids and omega-3 fatty acids were recommended as firstline therapies. However, in patients with residual ASCVD risk
despite maximum statin use and lifestyle therapy, the recommendations extended to the use of nonstatin lipid-altering
therapiesincluding (in order of preference) ezetimibe, bile

acid sequestrants (specifically, colesevelam) and extended-release niacinto further lower atherogenic cholesterol.
The authors identified the following as patients for whom combination therapy might be appropriate: high-risk or very-high-risk
patients with less than desirable response to appropriate statin
therapy, patients with recurrent or progressive ASCVD despite
appropriate statin therapy, patients with familial hypercholesterolemia (FH) who do not have optimal levels of atherogenic
cholesterol, and patients after acute coronary syndrome receiving at least a moderate-intensity statin. Notably, the document
also included a statement regarding the newly approved proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors role in
therapy; PCSK9 is further discussed later in this chapter.
Overall, Part 2 of the NLA recommendations provided guidance for the treatment of patients who are not as easily risk
stratified as suggested in the 2013 ACC/AHA guidelines. as
well as for situations in which guidance for the general population is not easily applicable.
Additional Dyslipidemia Management
Guidelines
For clinicians looking for alternative perspectives, the

International Atherosclerosis Society in late 2013 published
Table 2-2. Sequential Steps in ASCVD Risk Assessment

Identify very-high-risk or high-risk
conditions
Very high risk

ASCVD
DM with 2 major ASCVD risk factors or end-organ damagea
High risk
DM with 01 major ASCVD risk factors
CKD stage 3B or 4b
LDL 190 mg/dL
Count major ASCVD risk factors
If 01 and no other major indicators of higher risk, assign to low-risk category.

(Consider assigning to higher-risk category based on presence of other risk
indicators.)
If 3 major ASCVD risk factors, assign to high-risk category.
If there are 2 major ASCVD risk

factors, consider additional testing
(i.e., biomarkers) and quantitative
risk scoring
Assign to high-risk category if quantitative risk scoring reaches high-risk thresholdc or

if one of the risk clinical indicators is present.
Assign to moderate-risk category ifbased on above stepno indication is present to
assign to high risk category.
End-organ damage indicated by CKD (eGFR <60 mL/minute/1.73 m2), retinopathy, or increased albumin-to-creatinine ratio (30 mg/g).
For patients with CKD stage 3B (eGFR, 3044 mL/minute/1.73 m2) or stage 4 (eGFR, 1529 mL/m/1.73 m2), not recommended to
use risk calculators. Stage 5 CKD or on hemodialysis is a very high-risk condition; however, future studies are needed to determine
effectiveness of lipid-altering therapies in such patients.
c
High-risk threshold is defined as FRS 10-year risk 10%; ACC/AHA Pooled Cohort Equations 10-year risk 15%; Framingham longterm risk 45%. Those and other available risk calculators vary in the clinical outcomes predicted, in the risk factors included in their
calculation, and in the time frames for their predictions; therefore, clinical judgment is recommended in interpretation of risk factors.
ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; DM = diabetes mellitus; eGFR = estimated
glomerular filtration rate.
Information from Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered
management of dyslipidemia: Part 1 full report. J Clin Lipidol 2015;9:12969.
b
38
Dyslipidemia
global recommendations for dyslipidemia management (Grundy

2013). This guideline focuses on non-HDL as the most important atherogenic lipoprotein and incorporates geographic areas
of the world into risk stratification. The authors also emphasize TLC as the primary recommended treatment modality for
patients needing primary prevention, and reserve drug therapy
for patients at high risk who need secondary prevention.
In addition, in 2012, the American Association of Clinical
Endocrinologists released guidelines to assist endocrinologists in the management of patients with dyslipidemia
(Jellinger 2012). This document expands on information in
ATP III to include additional disease states conferring CV risk
that endocrinologists commonly encounter, and the authors
emphasized nontraditional risk factors such as inflammatory
biomarkers. Although maintaining LDL and non-HDL numeric
treatment targets identical to those in the ATP III 2004 update,
the guideline encourages practitioners to consider alternative lipid targets, including apoB, HDL, and TG. Clinicians may
find all of the documents useful in defining the right treatment
approach for each patient.
however, the definition of highest risk varied between the

documents. The 2013 ACC/AHA guidelines simplified risk stratification into four major statin benefit groups, with a focus on
LDL. The 2014 NLA recommendations (1) cautioned that some
of those groups derived risk from nonlipid risk factors and (2)
reminded clinicians that population statistics cannot always be
appropriately applied at the individual patient level. Thus, the
NLA incorporated the ATP III risk stratification approach based
on major cardiac risk factors and then added risk indicators
(e.g., coronary artery calcium [CAC], high-sensitivity C-reactive
protein [hs-CRP]) as part of the individualized risk assessment
process. Furthermore, the NLA recommendations in both Parts
1 and 2 addressed specialized populations with dyslipidemia,
such as those with FH. The 2013 ACC/AHA guidelines largely
dismissed the ATP III recommendations for combination dyslipidemia therapy with nonstatin therapies for more-intensive
risk reduction, citing a lack of RCT evidence in support of a
difference in clinical outcomes. The NLA recommendations,
however, still advocated the use of combination therapy, noting that the lack of benefit in RCT was largely because of the
patient population included in those trials and that patients with
low atherogenic lipoprotein burdens would not likely benefit as
much as patients at higher risk.
As the medical community moves forward from the ATP III
recommendations and into the more recent guidelines with a
robust evidence base, debate will likely remain as to the most
appropriate approach to dyslipidemia management.
COMPARISON OF PREVIOUS AND

CURRENT DYSLIPIDEMIA
TREATMENT APPROACHES
To duly apply the information from each, clinicians should note
the differences in scope between ATP III, the 2013 ACC/AHA
guidelines, and the NLA recommendations with regard to the target audience and patient populations. In developing the ATP III
report, the NCEP focused on the general population of the United
States and included all health care providers treating patients
with any degree of dyslipidemia. However, because of criticism of
the complexity of risk stratification, the 2013 ACC/AHA guidelines
attempted to simplify the approach to dyslipidemia management
for general health care practitioners, who are not lipid specialists
and who practice primarily in primary care settings. In contrast,
the NLA recommendations required more involvement in risk
assessment and incorporated several specific populations that
are managed by both generalists and specialists.
The diversity of audiences is reflected in the major differences between the documentsmost notably, the elimination
of treatment goals from the 2013 ACC/AHA guidelines and a
focus on overall ASCVD risk reduction versus the more-complicated but more-patient-specific risk determination and
subsequent goals of therapy for LDL and non-HDL in both ATP
III and the NLA recommendations. However, although specific
numeric targets for lipid parameters remained in the NLA recommendations, the NLA widened its focus beyond that of ATP
III to all atherogenic lipoproteinsdespite the lack of RCT evidence but with a strong evidence base nonethelessto assist
in risk stratification and discussed the utility of alternative
lipid targets such as apoB and LDL particle number.
All of the documents agreed that more-aggressive risk
reduction should be implemented in patients at highest risk;
CARDIOVASCULAR RISK
ASSESSMENT
Framingham Risk Score
The FRS is a well-established algorithm that has been

endorsed by the AHA and adopted by the European and British
CV societies. Risk factors such as age, total cholesterol, HDL,
systolic blood pressure (SBP), treatment for hypertension,
and cigarette smoking are measured in individuals with at
least two risk factors to estimate the relative risk and absolute risk of a cardiac event (MI, CHD, death) in the next 10
years. However, the FRS is limited by an exclusively non-Hispanic white sample population and narrowly defined CHD end
points. Diabetes mellitus was initially considered a CHD risk
equivalent but was removed because it was not supported by a
systematic review that showed different total CHD event rates
between patients with DM without prior MI and nondiabetic
patients with previous MI (Bulugahapitiya 2009). In addition,
the FRS may inaccurately classify younger individuals and
women with high risk factor burden as having low 10-year predicted risk (Mosca 2011; Cavanaugh-Hussey 2008).
Pooled Cohort Equations
The 2013 ACC/AHA guidelines reiterate the importance of

absolute risk estimation in determining primary prevention
treatment decisions. Noting FRS limitations for estimating
39
Dyslipidemia
10-year CHD risk, the ACC/AHA Risk Assessment Work

Group established a novel risk assessment tool, the Pooled
Cohort Equations, to estimate 10-year ASCVD risk (Goff
2014). Those equations contain many of the same risk factors
as the FRS (which were derived from the original cohort of
the Framingham Heart Study and the Framingham Offspring
Study) but with additional risk factors. These added factors
were based on pooled data from racially and geographically
diverse community-based epidemiologic cohorts, including
the Atherosclerosis Risk in Communities (ARIC) study, the
Cardiovascular Health Study, and the Coronary Artery Risk
Development in Young Adults study (Fried 1991; ARIC 1989;
Friedman 1988). Those pooled data consisted of untreated
individuals, with a total of 11,240 non-Hispanic white women
with 902 ASCVD events, 9098 non-Hispanic white men with
1259 events, 1647 African American men with 238 events, and
2641 African American women with 290 eventsall of them
4079 years of age. Accordingly, the Pooled Cohort Equations
are sex- and race-specific estimates of the 10-year risk of
ASCVD among non-Hispanic white and African American
men and women 4079 years of age.
The equations incorporate age, total cholesterol, HDL, SBP,
use of antihypertensive medication, smoking status, and DM
status. Because the presence of DM is not considered a CHD
risk equivalent, this necessitates an inclusion as a predictor
variable that allows further risk stratification. Multivariable
Cox proportional-hazards regression is used to calculate the
10-year absolute risk of ASCVD, which includes the prediction
end point that includes fatal and nonfatal stroke. That expansion is consistent with evidence addressed by the AHA and
the American Stroke Association for inclusion of stroke in CV
risk prediction instruments. And because stroke constitutes a
significant proportion of cardiovascular disease (CVD) events
in African Americans and women, that novel risk assessment
tool identifies those who may be at risk and would benefit from
consideration of statin treatment. Compared with the FRS, the
expansion to include stroke end points, together with sex- and
race-specific variables, facilitates the identification of at-risk
women and African Americans at much younger ages.
Despite notable advantages over the FRS, this tool also has
limitations, such as the small number of African Americans
included in the pooled cohorts and its limited applicability (because of sparse data) to Hispanic Americans and
Asian Americans. In addition, lack of data for younger and
older adults decreases the robustness of these risk-assessment algorithms. Most significant, as the use of the Pooled
Cohort Equations expands, concerns have emerged regarding the vastly increased numbers of patients who qualify
for drug treatment based on this method of risk stratificationparticularly in the primary-prevention population. The
guideline authors and others have defended the tools validation process and maintain that the classifications defined
in the guidelines are appropriate, but other practitioners cite
possible flaws in the application of the dataduring derivation
of the equationsthat directly contribute to the potential

for overtreatment (Lloyd-Jones 2014; Muntner 2014; Ridker
2013). Those controversial issues lead to support of the ACC/
AHA work groups recommendation for continued research to
understand and prevent ASCVD in all racial and ethnic groups,
across all age groups, and in both men and women.
Appropriate Selection of Risk Stratification
Tools
Recognizing the advantages and disadvantages of the different available risk assessment calculators, the NLA leadership
acknowledges three common risk calculatorsthe ATP III
FRS, Pooled Cohort Equations, and the Framingham longterm-risk calculatornoting that clinicians may prefer a
different risk calculator. In any event, clinicians should be
aware of the different composite outcomes from the use of
each different calculator (e.g., CHD events, ASCVD events, CV
mortality), the different risk factors included in a calculation,
and the different time frames for risk prediction (e.g., 5 years,
10 years, long term, or lifetime). Table 2-3 provides links to
several risk assessment tools for clinicians. Of note, the effect
of their use on hard end points is not clearly defined.
Lifetime vs. 10-Year Risk Prediction
The Pooled Cohort Equations enable clinicians to calculate

both 10-year and lifetime risk of ASCVD based on more risk
factors. Long-term or lifetime risk estimation is recommended
for individuals 2059 years of age who are free from ASCVD
and are without high short-term risk. The recommendation is
based on numerous epidemiologic studies that showed the
development of atherosclerosis may be related to risk factors
that are potentially modifiable. Therefore, the primary goal of
long-term or lifetime risk assessment is to provide risk information and context so as to motivate therapeutic lifestyle
modification in younger individuals. Similar to 10-year risk of
ASCVD, the estimates of lifetime risk are most applicable to
non-Hispanic whites.
TRADITIONAL AND
NONTRADITIONAL RISK FACTORS
Both the FRS and the Pooled Cohort Equations share
similar traditional covariates (age, sex, smoking, SBP, antihypertensive drug use, total cholesterol, and HDL). Although
the potential utility of novel risk markers in addition to established risk factors has been considered, novel risk markers
inclusion in ASCVD risk stratification has not been formally
evaluated in RCTs. Despite insufficient prospective data, the
NLA recommended that providers evaluate all atherogenic
lipoproteins (e.g., non-HDL, apoB) in determining therapy.
Beyond LDL
Atherogenic dyslipidemia is usually identified in patients with

obesity, the metabolic syndrome, insulin resistance, and type
40
Dyslipidemia
guidelines, joined by Part 2 of the NLA recommendations, also
2 DM. In addition to being recognized clinically by an elevated

number of LDL particles, atherogenic dyslipidemia is recog-
point out the importance of reducing elevated levels of ath-
nized by an increase in serum TG and a reduction in HDL. All
erogenic cholesterol beyond LDL through multiple modalities,
three components have been recognized as independent risk
including lifestyle changes and drug therapies.]
factors for ASCVD events, and based on positive outcomes
Several approaches are available when intensive statin
from multiple RCTs, LDL is lipid-lowering therapys primary
therapy is not enough to lower LDL and non-HDL to desired
target for reducing CV risk. However, existing data have
targets. Lowering atherogenic lipoproteins can be achieved
demonstrated that significant residual risk of ASCVD events
by combining statin therapy with nonstatin therapy, as pre-
remainsdespite reductions in LDL level (Jacobson 2011;
viously mentioned. However, the added benefit of targeting
Drexel 2010; Rosenson 2010). Consequently, by citing numer-
atherogenic lipoproteins with combination therapies remains
ous clinical trials that have demonstrated the reduction of
controversial because of a lack of mortality reduction in clini-
ASCVD risk in proportion to the amount of LDL and non-HDL
cal trials. Notably, although apoB concentration is recognized
reduction in both primary and secondary settings, authors of

previous guidelines (ATP III and update) and the NLA expert
as an alternative secondary target because it serves as a
panel recommend that once the LDL goal has been attained,
direct indicator of the number of circulating particles with
the non-HDL goal should become the next focus. Those
atherogenic potential, an expert panel of lipidologists favors
Table 2-3. Common Cardiovascular Risk Calculators for U.S. Patients

Calculator
Comments
2013 Pooled Cohort Equations

Cardiovascular Risk Calculator
Part of the 2013 ACC/AHA cholesterol guidelines to determine the need for statin
therapy
Estimates 10-year risk of first atherosclerotic CVD
Based on data from untreated whites and African Americans with or without DM
4079 years of age
Estimates lifetime risk of atherosclerotic cardiovascular disease in individuals
2059 years of age
Framingham Coronary Heart Disease

10-Year Riska
Estimates 10-year risk of CVD

Based on data from predominantly whites 3074 years of age without CVD
Separate calculators for men and women
National Cholesterol Education

Program (NCEP) Adult Treatment
Panel III (ATP III) Risk Assessment
Tool (based on Framingham Heart
Study)
Estimates 10-year risk of CHD

For adults 20 years and older without heart disease or DM
Not recommended for patients with DM because it is considered coronary
disease equivalent
Does not include family history
Reynolds Risk Score
ARIC CHD Risk Calculator
Estimates 10-year risk of heart attack or CHD risk in adults

For people 4565 years of age with or without DM
Estimates 10-year risk of heart attack, stroke, or other major heart disease
Based on data from Womens Health Study and Physicians Health Study II
Separate calculators for women and men
For people 4580 years of age without DM
Among other risk factors, also includes family history and hs-CRP
Special Populations
American Diabetes Associations

Diabetes My Health Advisor Risk
Assessment Tool
Estimates 10-year risk of heart attack or stroke and 8-year risk of DM

Can be considered for people with or without DM and/or with or without CVD
Archimedes model
United Kingdom Prospective

Diabetes Study Risk Engine
Based on data from the UK Prospective Diabetes Study and for patients with DM
without known heart disease
Estimates 10-year risk of fatal and nonfatal coronary heart disease and fatal and
nonfatal stroke
Validated in a multigenerational population from Framingham, Massachusetts
CHD = coronary heart disease; CVD = cardiovascular disease; DM = diabetes mellitus.
41
Dyslipidemia
using non-HDL given that it is universally available at no additional expense (Davidson 2011).
In addition, raising HDL levels to enhance their antiatherogenic properties may also be beneficial (Barter 2011).
Although the direct mechanistic relationship is not fully understood, HDL and its components may exert a positive array of
effects that can reduce ASCVD events, as documented in
numerous epidemiologic studies (Chapman 2011; Fruchart
2008). That led to the incorporation of the HDL level in risk
factor counting and quantitative ASCVD risk assessment.
Although HDL levels may increase in small increments from
the implementation of TLC, many patients still require pharmacotherapy. Unfortunately, only a few drug therapies affect
HDL levelsspecifically, nicotinic acid and fibrates. Because
those drugs also lower apoB-containing lipoproteins, it is not
possible to attribute any benefit of these therapies specifically
to increases in HDL. Future research is required to examine
the clinical effect of selectively raising HDL levels.
unknown causes of premature ASCVD. Fortunately, Lp(a) is

included as part of some advanced lipid tests for seamless
addition to monitoring parameters in patients who require
supplementary assessment.
Coronary Artery Calcium
Coronary artery calcium represents a calcific atherosclerosis

process and correlates well with the overall burden of atherosclerosis in the coronary arteries (Wexler 1996). The ability to
detect and quantify CAC by applying available imaging methods and scoring systems has generated significant interest
in the medical community. A study that followed more than
10,000 asymptomatic participants for about 5 years and compared cardiac risk factors such as family history of coronary
artery disease, hypercholesterolemia, hypertension, smoking,
and DM with CAC score demonstrated the superiority of using
CAC score over the existing risk-factor-based paradigms (e.g.,
the FRS) (Shaw 2003).
The 2007 ACC/AHA clinical expert consensus document
on CAC suggests that scanning can be considered as a way of
increasing the level of accuracy of risk stratification in intermediate-risk individuals (those with 10%20% 10-year risk of
estimated coronary events) to possibly (1) reclassify patients
to a higher risk status based on high CAC scores and (2) modify therapy accordingly (Greenland 2007). Notably, the recent
2014 NLA work group viewed CAC measurement as particularly useful in low- to moderate-risk individuals who fall into
the range of 7.5%14.9% 10-year risk based on the Pooled
Cohort Equations or 5.0%9.9% based on the FRS. Thus,
Part 2 of the NLA recommendations says CAC scores may be
useful for further stratifying risk in the older population. An
indicator of high-risk status is a CAC score of >300 Agatston
units or >75th percentile for a patients age, sex, and race or
ethnicity. Because the reference tool was based on results
from participants who were mostly white, African American,
Hispanic, or Chinese and 4585 years of age, the tool is applicable only to those four populations within that age range.
Selected Inflammatory Markers

Lipoprotein (a)
Multiple clinical studies have shown that lipoprotein (a) [Lp(a)]

serves as an additive to other CV risk factorsindependent
of LDL, non-HDL, and the presence of other CV risk factors
(Erqou 2009; Bennet 2008). Lipoprotein (a) is composed of an
LDL particle that has a second apoprotein in addition to apoB,
linked by a disulfide bond. Levels of Lp(a) vary significantly
from one individual to another and are highly influenced by
genetic factors. Lp(a) appears to be atherogenic by interfering with fibrinolysis of thrombi on the surfaces of plaques.
Although the Lp(a) concentration may become elevated in
certain inflammatory states, it typically is a very stable parameter and is unaffected by diet and most drugs. Therefore, a
single measure is adequate to rule out Lp(a) as an important
contributor to CVD risk in an individual patient.
Although elevated levels of Lp(a) (>50 mg/dL, which is
above the 80th percentile) are associated with an increase
in ASCVD, the lowering of Lp(a) plasma levels has not been
clearly demonstrated to reduce CV risk. As such, Lp(a) measurement is not recommended in patients with low risk (<5%
10-year CHD event risk) as part of an initial clinical assessment or in patients already receiving treatment. In selected
patients with intermediate risk (5%20% 10-year CHD event
risk), CHD or CHD risk equivalents, premature family history
of CHD, or established CHD with a history of recurrent events
despite appropriate therapy, an Lp(a) measurement can be
considered only for initial clinical assessment. On-treatment
monitoring of Lp(a) levels can also be considered in patients
with CHD or CHD risk equivalents or premature family history
or in patients with established CHD with histories of recurrent events. In addition, Part 2 of the NLA recommendations
says the measurement of Lp(a) levels may be useful in African
American patientsespecially those with family histories of
Lipoprotein-Associated Phospholipase A2
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an

inflammatory enzyme, produced by macrophages and neutrophils predominantly from atherosclerotic plaques; it appears
to be related to plaque inflammation and may be linked
to plaque rupture (Macphee 2006). Inhibition of Lp-PLA2
activity reduces the development of advanced coronary atherosclerotic plaque progression and has been documented
to independently predict risk of CHD events, stroke, and mortality in both primary and secondary settings (Nordestgaard
2010; Daniels 2008; Wilensky 2008).
Results from several epidemiologic studies, including the
ARIC study, have shown that when both Lp-PLA2 and hs-CRP
are elevated, the risk of CHD events and stroke increase 4-fold
and 11-fold, respectively, compared with patients with low
concentrations of both markers (Ballantyne 2004). Therefore,
42
Dyslipidemia
the NLA consensus panel endorsed the use of Lp-PLA2 for

the assessment of CHD event and stroke risk in intermediate- or moderate-risk populations and in additional selected
patients. However, despite encouraging data from previous
studies, recent large RCTs showed that treatment with darapladib, a selective Lp-PLA2 antagonist, did not improve clinical
outcomes in patients with stable or unstable coronary artery
disease (ODonoghue 2014; White 2014). Thus, the benefit of
lowering Lp-PLA2 on CVD events and mortality is unclear.
primary prevention. Subsequently, practitioners could choose

to use the more-detailed risk assessment championed by the
NLA recommendations in patients for whom therapy is not
straightforwardspecifically, those who have additional risk
not accounted for by the major statin benefit groups or those
who were excluded from the ACC/AHA guidelines. In addition,
specific lipid goals may enhance adherence among patients
who wish to self-monitor progress and who place a high value
on active ASCVD risk reduction. Both documents agree that
involving the patient in decision-making throughout the treatment process is crucial to improving outcomes; therefore, the
most important function of this clinical controversy may lie
in stimulation of conversation between provider and patient.
Since the release of the 2013 ACC/AHA guidelines, many
practitioners have adopted hybrid approaches to dyslipidemia management that include elements of both the 2013
ACC/AHA guidelines and the ATP III report and update. This
is not an unreasonable perspective given the positive attributes and major differences between the documents. For
practitioners wishing to treat patients in this manner, a potential approach is to follow the 2014 NLA recommendations,
driven by evidence-based literature and expert opinion to fill
the gaps, which include elements of both ATP III and the ACC/
AHA guidelines. However, because all documents encourage individualized risk assessment and treatment, the most
appropriate plan for each patient is one that the practitioner
and the patient develop together, with expectations by both
parties that the plan should evolve in response to publication
of relevant literature and risk assessment strategies.
LDL Particle Number
Each LDL particle contains a core of lipidpredominantly cholesterolsurrounded by phospholipids with mainly apoB on
the surface. Typically, LDL and LDL particle (LDL-P) concentrations are correlated. However, discordance between LDL
and LDL-P (>12% between the two markers) has been identified in several studies (Otvos 2011; Kannel 1979). Based on
those epidemiologic studies, LDL-P was found to be a better
predictor of CVD events in discordant patients.
The LDL-P level can be measured either in the blood by nuclear
magnetic resonance spectroscopy or through the LDL-P portion
of the apoB measurement. Because of the cost involved, the NLA
expert consensus panel does not recommend LDL-P measurement in low-risk patients but states that measurement should be
considered in patients with intermediate risk (5%20% 10-year
CHD event risk), family histories of premature CHD, or histories
of recurrent events. Once patients are on therapy, LDL-P levels
may be measured in selected individuals with intermediate risk
who have been treated to LDL and non-HDL goals (in individuals
with CHD or CHD risk equivalents, histories of recurrent events,
or family histories of premature CHD) so that intensification of
therapy can be considered if appropriate.
The targeted LDL-P goal is less than 1100 nmol/L for veryhigh- to high-risk patients and less than 1440 nmol/L for
moderately-high- to moderate-risk patients. Additional data
are required to determine cost-effectiveness in clinical practice and assessment of the superiority of treating LDL-P levels
instead of LDL and non-HDL. Treatment options that lower
LDL-P levels include niacin, fibrates, or either class in combination with statins.
Benefit vs. Risk Assessment of Statin Use
All of the available literature points to the indisputable benefits of statins as first-line therapy for management of
dyslipidemia. Widespread use for almost 3 decades will likely
continue to expand in the face of new guidelines (e.g., 2013
ACC/AHA) that recommend therapy in increasing numbers of
lower-risk individuals. All agents in this class are fairly well
tolerated; however, even rare adverse events may become
amplified in a patient population of millions; therefore a benefit-versus-risk assessment becomes paramount.
In 2006, an NLA expert task force published a paper
evaluating statin safety in four areas of the body most susceptible to adverse effects: the muscles, liver, kidneys, and
brain (McKenney 2006). Subsequently, the FDA made labeling changes to the entire statin class as well as to individual
agents to better reflect the critical analysis of available data.
In short, the FDA relaxed monitoring requirements for liver
function tests during statin therapy, from a routine measurement to baseline measurement and with only symptom-driven
reassessment. In addition, labeling information now includes
possible rare cognitive and metabolic effects of statins; and
stricter dose-related usage warnings were implemented for
both lovastatin and simvastatin.
APPLICATION OF
RECOMMENDATIONS TO PATIENT
CARE
Selecting Appropriate Guidelines
To take advantage of the most comprehensive evidence base,

health care practitioners treating patients with dyslipidemia
should evaluate at a minimum both the 2013 ACC/AHA guidelines and the 201415 NLA recommendations to determine
which information is most applicable to their patient populations. Though patients could likely receive appropriate
therapy with the simplistic approach of the ACC/AHA guidelines, some patients may become overtreatedspecifically for
43
Dyslipidemia
In 2014, the NLA paper was updated based on new evidence

clarifying both the benefits and the risks of statin therapy (NLA
2014). The updated publication included information regarding
statin use and cognition, glucose effects, increased DM risk,
hepatic function, muscle toxicity, drug interactions, and statin
intolerance. Although the document answered many questions
regarding statin safety, it included (1) the affirmation of statin
safety in patients with certain types of hepatic dysfunction (i.e.,
nonalcoholic fatty liver disease, autoimmune hepatitis) and
liver transplant, (2) the impact of physical activity on statin-associated muscle symptoms, and (3) the utility (and safety) of
switching to a different member of the statin class in the presence of statin intolerance. The NLA task force that wrote the
document confirmed the overall safety of statin use and noted
that for most patients, the decrease in CV events up to and
including death far outweighs the risks of therapy. However,
they encouraged a risk-benefit analysis before treatment of
patients and emphasized the need for individualized patient
care. Clinicians involved in caring for patients requiring statins
will likely find both of those statin safety documents to be useful references throughout the process.
fibric acid derivatives, because of insufficient evidencein

patients with fasting serum TG greater than 1000 mg/dL.
The National Kidney Foundations Kidney Disease
Outcomes Quality Initiative (NKF-KDOQI) released a commentary on the 2013 KDIGO guidelines that provided additional
clarity for treatment of this patient population (Sarnak 2015).
Although concurring with KDIGO in regard to the elimination of LDL treatment targets, avoidance of statins in dialysis
patients, use of statins in renal transplant (after a careful
drug interaction evaluation), and the approach to hypertriglyceridemia, the NKF-KDOQI favored a general-population
recommendation for individuals with CKD (eGFR <60 mL/minute/1.73 m2) older than 50 years, noting that such patients
are likely to have a 10-year ASCVD risk exceeding 7.5% and
would therefore qualify for statin therapy per other guideline
recommendations.
Although both the 2013 ACC/AHA guidelines and the 2014
NLA recommendations provide guidance specific to patients
with DM, the American Diabetes Association (ADA) restructured those recommendations together with the approach to
risk stratification and treatment. The dyslipidemia management approach in the 2015 ADA Standards of Medical Care
in Diabetes mirrored that of the 2013 ACC/AHA guidelines,
with diabetic patients aged 4075 years qualifying for either
moderate-intensity or high-intensity statin therapy. The ADA
also recommends statin therapy for patients younger than
40 years with overt CVD or CVD risk factors, defined as LDL
of 100 mg/dL or greater, hypertension, smoking, and/or overweight/obesity. Specific recommendations are summarized
in Table 2-5.
In a major departure from all guideline recommendations,
the ADA noted a lack of utility for risk predictionspecifically,
the Pooled Cohort Equationsin diabetic patients, deferring to
the presenceor absenceof the above-mentioned CVD risk
factors as a more accurate predictor of future CV risk. The ADA
guideline did not recommend the use of pharmacologic therapy
with niacin or fibric acid derivatives in combination with statins,
citing lack of evidence; however, the authors noted the exception of hypertriglyceridemia, when the combination could be
considered as a way of avoiding pancreatitis (e.g., TG >1000).
Finally, as expected, the ADA strongly supported lifestyle modifications for all types of dyslipidemia in all diabetic patients,
and the statin intensity recommendations were specified as an
addition to lifestyle changes in all risk categories.
Patients with hypertriglyceridemia present a clinical
conundrum in regard to appropriate management. Typically,
treatment for elevated TG (e.g., 500 mg/dL) has focused on
preventing the development of acute pancreatitis; however,
data indicate that any degree of TG elevation contributes to the
atherogenicity of lipoproteins and increases CV risk. Because
of a lack of clinical trials demonstrating improved outcomes
solely with TG lowering, many guidelines have steered away
from recommending numeric targets, but the risk remains
(Berglund 2012).
Special Populations
Based on the advent of controversy and a paradigm shift away

from treating to target, other professional organizations issued
dyslipidemia recommendations for specific patient populations.
In late 2013, the Kidney Disease: Improving Global Outcomes
organization (KDIGO) published treatment guidelines covering
pediatric and adult patients with any degree of CKD (glomerular
filtration rate [GFR] categories G1G5), including dialysis and
kidney transplantation (Table 2-4). The international team of
authors included evidence from RCTs, post hoc, and subgroup
analyses conducted specifically in patients with CKD and recommended a simplistic treatment approach similar to that of
the 2013 ACC/AHA guidelines, including abolishment of LDL
numeric treatment targets. The guidelines maintain the diagnosis of CKD as a CHD risk equivalent, noting the elevated CV
risk in patients with CKD compared with the general population
regardless of LDL levels. For specific treatment recommendations, see Table 2-4.
Notably, the guidelines recommend against initiating statin therapy in patients receiving hemodialysis or peritoneal
dialysis, citing a lack of evidence of benefit in that population,
although maintenance therapy could be continued if a patient
later began dialysis. Citing a heightened concern about
potential statin toxicity, the document provides a table of recommended statin agents together with doses that have been
studied and found safe in the CKD population; recommendations for patients with estimated GFR (eGFR) of less than 60
mL/minute/1.73 m2 generally did not include high-intensity
statins, as defined in both the 2013 ACC/AHA guidelines and
the 2014 NLA recommendations. Finally, for hypertriglyceridemia, intensive TLCs were recommended as the primary
treatment strategy, with pharmacologic treatmentexcept
44
Dyslipidemia
Table 2-4. Pharmacologic Cholesterol-Lowering Treatment in Adults with CKD

Grade
Recommendation
1A
Treatment with a statin or statin/ezetimibe combination in adults aged >50 years with eGFR <60 mL/minute per 1.73 m2
but not treated with chronic dialysis or kidney transplantation (GFR categories G3aG5)
1B
Treatment with a statin in adults aged >50 years with CKD and eGFR >60 mL/minute per 1.73 m2 (GFR categories
G1G2)
2A
Recommend a statin in people with >1 of the following risk factors in adults aged 1849 years with CKD not on dialysis
or post kidney transplantation:
Known coronary disease (MI or coronary revascularization)
Prior ischemic stroke
Diabetes mellitus
Estimated 10-year incidence of coronary death or nonfatal MI >10% (use any validated risk prediction tool)
2A
Treatment with a statin or statin/ezetimibe combination is not recommended to be initiated in adults with dialysisdependent CKD
2C
Treatment with lipid-lowering agents should be continued in patients already receiving statins or statin/ezetimibe
combination at the time of dialysis initiation
2A
Treatment with a statin is suggested in adult recipients of kidney transplants
2D
TLC is suggested in adults with CKDincluding those treated with chronic dialysis or who have had kidney
transplantsand hypertriglyceridemia
Recommended doses of statins in adults with CKD
Statin
eGFR G3aG5, including patients receiving dialysis or who have had

kidney transplants (mg/day)
Lovastatin
Not studied
Fluvastatin
80
Atorvastatin
20
Rosuvastatin
10
Simvastatin/ezetimibe
20/10
Pravastatin
40
Simvastatin
40
Pitavastatin
GFR categories (mL/minute/1.73 m2) description and range: G3a (mildly to moderately decreased) = 4559; G3b (moderately to
severely decreased) = 3044; G4 (severely decreased) = 1529; G5 (kidney failure) <15.
Grading guidance: Level 1 = We recommend; Level 2 = We suggest; Grade A = High; Grade B = Moderate; Grade C = Low; Grade D =
Very low.
CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; MI = myocardial infarction; TLC = therapeutic lifestyle
change.
Information from Wanner C, Tonelli M and the Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group
Members. KDIGO Clinical Practice Guideline for Lipid Management in CKD: summary of recommendation statements and clinical
approach to the patient. Kidney International 2014:85;13039.
All recommendations for both general and special patient

populations strongly encourage TLCs that focus on diet
and exercise, weight reduction, and blood glucose management to reduce TG levels; drug therapy is widely accepted
for patients with very high TG levels (e.g., 1000 mg/dL). In
fact, the NLA recommendations maintain the NCEP ATP III
approach of making TG the primary target of therapy when TG
levels exceed 500 mg/dL. However, the use of drug therapy
(i.e., nicotinic acid, fibric acid derivatives, and omega-3 fatty
acids) in patients with moderately elevated TG is a matter

of clinical debate. Some professional organizationsincluding the International Atherosclerosis Society, the American
Association of Clinical Endocrinologists, and the NLA
emphasize the importance of non-HDL as a treatment target
to allow for aggressive management of patients with even
mildly elevated TG levels (200499 mg/dL). Therefore, for
many patients with hypertriglyceridemia, it is reasonable to
target non-HDL in addition to LDL as a method of mitigating
45
Dyslipidemia
residual ASCVD risk, recognizing that very limited data exist

on the most optimal method for doing so.
Other populations that have presented treatment challenges
include the pediatric population as well as both adult and pediatric patients with FH. In 2011, the NHLBI released a guideline
document focused on childhood CV risk reduction, including
lipid management (Expert Panel 2011). Specific to dyslipidemia in children, the guideline recommends lipid screenings
based on age, comorbidities and family history; thresholds for
appropriate apolipoprotein levels; and a treatment approach
focused on nutrition and exercise for all children, followed by
statin therapy in very high risk children ages 10 years old and
older (or 8 years old and older with selected high risk conditions
or risk factors, including FH). Those guidelines recommended
more-aggressive statin therapy in children than did previous
guidelines but with emphasis on a complete CV risk assessment and communication with the patient and family.
Simultaneously, the NLA recommended universal cholesterol screening beginning at age 2 in patients with positive
family history or CHD and at 911 years old for all other individuals, with a goal of screening every individual by age 20 years
to identify those who would benefit most from statin therapy
(particularly those with FH). Also in 2011, the NLA published
guidance for the screening, diagnosis, and management of
both adult and pediatric patients with FH, intended to assist
both primary care practitioners as well as lipid specialists in
caring for those populations (Goldberg 2011). Specifically, the
document noted LDL cut points at which the diagnosis of FH
should be strongly considered, including LDL of 250 mg/dL
or greater in patients 30 years or older, LDL of 220 mg/dL or
greater in patients 2029 years old, and LDL of 190 mg/dL
or greater in patients younger than 20 years. The guideline
emphasized lifestyle changes and aggressive statin therapy
in patients of all ages with FHwith combination therapy
as warrantedand a low threshold for referral to a lipid specialist. But even though both the NHLBI and NLA guidelines
provided additional insight for those patient populations, clinicians still must evaluate each patients individual risk in the
context of the guidelines to determine appropriate therapies.
NONSTATIN THERAPIES
The use of adjuvant nonstatin therapy for CV risk reduction fell
out of favor after several recent RCTs questioned its efficacy
in combination with statins. The preponderance of evidence
overwhelmingly supports statins as first-line therapies for
reducing ASCVD risk, and all major guidelines strongly agree
on the statin-first approach. Statins are inexpensive, most
are generic, and as a class, they demonstrate a favorable
risk-benefit profile in the general population. However, some
patients experience intolerance or adverse effects, and some
data indicate a possible connection with memory impairment
and the development of type 2 DM (e.g., one study found that
the number needed to harm with development of type 2 DM is
1 out of 225 patients treated for 4 years). Additionally, some
patients suffer from dyslipidemias beyond LDL abnormalities that are more effectively treated with alternative classes
of agents, as previously discussed. Therefore, prudent clinicians understand the mechanisms and potential therapy roles
of nonstatin agents in the management of dyslipidemia.
Ezetimibe
Ezetimibe is the only cholesterol absorption inhibitor available in the United States. It inhibits cholesterol absorption at
the intestinal brush border and decreases LDL levels by 13%
20%, which equates to three statin dose titration steps (the
rule of 6). Although it may have a minimal effect on other lipid
parameters, clinically the role of ezetimibe focuses on LDL
and thus non-HDLlowering.
Table 2-5. Recommendations for Statin Treatment in Patients with Diabetes
Risk factors
Age (years)
Recommended statin dosein

addition to lifestyle therapy
Monitoring with lipid panel
None
<40
4075
>75
None
Moderate
Moderate
Annually or as needed to monitor

adherence
CVD risk factorsa
<40
4075
>75
Moderate or high
High
Moderate or high
Annually or as needed to monitor

adherence
Overt CVDb
<40
4075
>75
High
High
High
CVD risk factors: overweight/obesity, smoking, hypertension, and LDL cholesterol 100 mg/dL
Overt CVD: previous cardiovascular events or acute coronary syndromes

CVD = cardiovascular disease.
Information from American Diabetes Association. Cardiovascular disease and risk management. Sec. 8. In Standards of Medical
Care in Diabetes 2015. Diabetes Care 2015; 38(Suppl. 1):S49S57.
46
Dyslipidemia
benefit on mortality) in those with established coronary artery

disease (Coronary Drug Project 1975). The 15-year follow-up
of the Coronary Drug Project demonstrated an 11% reduction
in mortality with the use of niacin versus placebo during the
trial (Canner 1986). Niacin is known to significantly decrease
LDL, non-HDL, and TG, with a potent effect on increasing HDL
as well. Although the mechanism of niacin has not been fully
elucidated, niacin is postulated to decrease free fatty acid
mobilization from adipocytes and to decrease the production of apoB, both of which reduce the hepatic production of
VLDL particles. Niacin also decreases catabolism of apoA-1
to maintain the structure and function of HDL particles.
Because of the highly desired effects of niacin on all major
lipid parameters, the ATP III report and subsequent update
advocated niacin therapy as an effective method of reducing
CV risk beyond statin therapy alone, yet several major clinical
trials released since the ATP III report have not reported benefits on mortality when niacin has been used in combination
with statins (HPS2-THRIVE 2014; AIM-HIGH 2011). That neutral mortality finding and adverse-event profile, despite potent
effects on lipids, led the authors of the 2013 ACC/AHA guideline
to avoid recommending combination therapy with niacin for the
purpose of reducing CV risk. In contrast, the NLA recommendations commented that those trials had encompassed a patient
population that had already achievedor almost achieved
lipid parameter goals on statin monotherapy. Therefore, the
NLA still noted niacins potential utility in patients receiving
statins who had not yet achieved goal LDL and non-HDL levels.
In patients with hypertriglyceridemia (defined as TG
greater than 1000 mg/dL) for whom the acute risk of pancreatitis overrides the longer-term risk of ASCVD, niacin is more
widely accepted. Niacin has demonstrated a sex-dependent,
dose-dependent, and baseline TGdependent effect. In general, niacin is associated with a TG reduction of 5%50%. For
patients with dangerously elevated TG levels, niacin could
prove useful in acutely lowering those levels. The 2013 ACC/
AHA guidelines did not comment on treatment for this population, but the 2011 AHA statement on TG and CVD noted that
a combination of statins and niacin increases plaque regression (Miller 2011). The 2014 NLA recommendations promote
niacin as one of the first-line options if TG exceeds 1000 mg/
dL and as a possible TG-lowering agentwith a statin as an
alternativeif TGs are 500999 mg/dL.
Overall, ezetimibe is well tolerated and is regarded as a relatively low-risk intervention for patients with LDL or non-HDL
that exceeds the levels desired. However, although ezetimibe
effectively lowers LDL, there were few data to correlate that
reduction with improved outcomes (in particular, mortality) at
the time of guideline development. Thus, the role of ezetimibe
has been relegated largely to that of a substitution for statin
therapy in patients with statin intolerance or in patients taking statins that required additional LDL lowering to achieve the
historical guideline-recommended goals of therapy. However,
with the 2015 publication of the Improved Reduction of
Outcomes:Vytorin Efficacy International Trial, detailed in the
following, some practitioners are again using ezetimibe as an
adjuvant. Part 2 of the NLA recommendations recommends
ezetimibe as the first-line therapy adjuvant to statins for further lowering of atherogenic cholesterol.
Bile Acid Sequestrants
As the name of the class implies, these drugs are anion

exchange resins that bind bile acids in the intestine and promote excretion in the feces, decreasing the enterohepatic
circulation of bile acids. That in turn reduces the hepatic cholesterol concentration, resulting in an up-regulation of LDL
receptors on the liver to retrieve LDL particles from the general circulation and a reduction in overall LDL levels. Three
preparations are available in the U.S. market: cholestyramine,
colestipol, and colesevelam.
Bile acid sequestrants demonstrate significant LDL lowering (15%30%), but the effects on non-HDL and HDL are
minimal, and paradoxically, some patients experience mild
elevations in TG. These agents are not systemically absorbed
but remain in the GI tract, leading to GI intolerance (e.g., constipation, bloating, flatulence); drug-drug interactions (e.g.,
malabsorption of fat-soluble vitamins); and resultant vitamin
deficiencies. Notably, data from the early 1980s demonstrated
a reduction in a composite end point of nonfatal MI and CHD
death with cholestyramine versus placebo; however, in the
modern era of statin therapy, a complete lack of data exists
to prove the utility of these agents in current clinical practice
(Lipid Research Clinics 1984).
Several clinical trials have shown that colesevelam has glucose-lowering effects in addition to LDL effects in patients
with type 2 DM, and that colesevelam can be considered for
use in combination with antidiabetes therapies. However,
long-term use of bile acid sequestrants as monotherapy may
up-regulate hepatic biosynthesis of cholesterol, and therefore the role of bile acid sequestrants remains largely as an
adjunct for additional LDL lowering in patients who cannot
achieve desired LDL targets with other available therapies.
Fibric Acid Derivatives
Fibric acid derivatives (fibrates) available in the United States

include gemfibrozil, fenofibrate, and fenofibric acid. These
agents are similar to niacin in that they positively affect major
lipid parameters, thereby demonstrating significant reduction
in TG, an increase in HDL, and reduction in LDL; they also may
increase LDL in patients with very high TG caused by changing
particle morphology, generally considered a benefit in regard
to CVD risk. Again, because of those lipid effects, the ATP III
report and subsequent update advocated fibrate therapy as
Nicotinic Acid (Niacin)
Before the modern statin era, the NHLBIs Coronary Drug

Project demonstrated a positive benefit of niacin (3.0 g/day)
on the reduction of nonfatal MI and stroke (albeit without a
47
Dyslipidemia
an effective method of reducing CV risk beyond statin therapy

aloneparticularly in patients with elevated non-HDL. As with
niacin, before the modern statin era, fibratesspecifically,
gemfibrozildemonstrated benefits on CV event rates, with a
significant increase in HDL; however, more recent studies with
fenofibrate/fenofibric acid have not demonstrated benefits on
mortality when fibrates are used in combination with statins
(Robins 2001).
The FIELD study and the ACCORD-Lipid study, conducted
in large populations of high-risk patients with type 2 DM, failed
to demonstrate overall benefit or CV mortality benefit when
fenofibrate was added to statin therapy. However, in ACCORDLipid, the subgroup with both high TG and low HDL experienced
a 30% reduction in the primary outcome in patients on fenofibrate compared with placebo. The results in this subgroup
are similar to the post hoc analyses of prior studies, including
the FIELD study. In addition, there was a significant trend for
treatment effect by sex, with women receiving more significant benefit with fenofibrate. Nonetheless, the role of fibrates
in reducing ASCVD risk remains controversial.
Like niacin, fibrates demonstrate significant benefit on TG
lowering (generally, 20%50%); therefore, to avoid the development of acute pancreatitis, they are included in the 2014
NLA recommendations as first-line drug therapy options if TG
exceeds 1000 mg/dL and as possible first-line optionswith a
statin as an alternativeif TG is 500999 mg/dL.
LDLdespite maximally recommended or maximally tolerated

statin therapy. Several clinical trials in recent years, although
not producing definitive answers, have contributed data
toward shaping the medical communitys approach to this difficult patient population.
AIM-HIGH
As practitioners debated the most appropriate management

of patients who remained at risk despite maximal statin therapy, the positive lipid effects of niacin did not go unnoticed.
The purpose of the AIM-HIGH trial was to establish the role
of niacin in the setting of intensive LDL control in regard to
clinical outcomes. More than 3400 patients with established
ASCVD and receiving simvastatin with or without ezetimibe
were randomized to receive either extended-release niacin
(15002000 mg/day) or placebo. The investigators used the
statin with or without ezetimibe to maintain a low LDL level of
4080 mg/dLat or below the goal for very-high-risk patients
per all available guidelines at the time of the study. The primary end point targeted the time to first event of a composite
outcome that included CHD-related death, nonfatal MI, ischemic stroke, acute coronary syndrome hospitalization, or
coronary/cerebral revascularization. Although niacin was
associated with increased HDL and decreased TG and LDL
beyond those increases and decreases in the control group,
those lipid benefits did not correlate to an improvement in clinical outcomes, thereby showing no difference between the
groups with regard to the primary end point at 36 months (HR
1.02; 95% CI, 0.871.21; p=0.79). In fact, the trial was stopped
18 months early because of lack of efficacy and an increased
rate of ischemic stroke in the niacin group.
When the AIM-HIGH study was released, the results added
to the confusion over whether the goals of therapyspecifically for LDLwere adequate for maximally reducing risk and
whether specific pharmacologic agents at specific doses
should be the focus of the therapy. The study results also magnified the controversy about the true role of lipid parameters
besides LDL in the pathogenesis of ASCVD. The major criticism of this trial had to do with the patient population, which
intentionally had very low levels of atherogenic lipoproteins
and which did not represent the patient population for which
the available guidelines recommended combination therapy.
Nevertheless, the results did not favor the use of niacin in
combination with statin therapy for reducing ASCVD risk.
Long-Chain Omega-3 Fatty Acids
Much attention in recent years has centered on the benefits

of fish oils in a variety of disease states, primarily as nutritional supplements. In the United States, four prescription
products are available that offer high concentrations of longchain omega-3 fatty acids: icosapent ethyl and omega-3
ethyl esters. For the purpose of dyslipidemia management,
fish oils at very high doses demonstrate significant reduction in TG lowering. Long-chain omega-3 fatty acids have
very little role in the treatment of patients outside those with
significantly elevated TGs, and through lipid-related mechanisms such as the Outcomes Study to Assess Statin Residual
Risk Reduction with Epanova in High CV Risk Patients with
Hypertriglyceridemia, research is ongoing to determine the
impact on overall ASCVD risk. Like niacin and fibrates, the
2014 NLA recommendations name those products as firstline drug therapy options if TGs exceed 1000 mg/dL and as
a possible first-line optiontogether with statinsif TGs are
500999 mg/dL.
HPS2-THRIVE
On the heels of the tremendous controversy involving the AIMHIGH trial, the Heart Protection Study 2Treatment of HDL
to Reduce the Incidence of Vascular Events (HPS2-THRIVE)
study was published in 2014. That trial also examined the
effect of niacin in combination with statin therapy on the incidence of clinical outcomes. More than 25,000 patients with
ASCVD who were receiving statin-based LDL-lowering therapy (simvastatin 40 mg daily with or without ezetimibe 10 mg
NEW EVIDENCE FOR USE OF

NONSTATIN AGENTS
A major unresolved issue that has plagued all guideline recommendations to date involves the appropriate management
of patients who experience recurrent CHD events or who continue to have high CHD or ASCVD riskincluding very high
48
Dyslipidemia
daily to achieve total cholesterol level of 135 mg/dL or less)

were randomized to receive either placebo or 2000 mg of
niacin with 40 mg of laropiprant daily via titration from starting dose. Laropiprant is a prostaglandin D2 antagonist with
efficacy in reducing the flushing response from niacin; the
intention was to improve adherence to niacin therapy without affecting ASCVD risk. The primary end point was the first
major vascular event, defined by investigators as nonfatal
MI, death related to coronary causes, stroke, or the need for
revascularization. As with AIM-HIGH, the niacin group experienced the expected lipid benefits of increased HDL and
decreased LDL versus the placebo group. However, there
was no differencebetween the niacin and placebo groups
in the incidence of major vascular events (HR 0.96; 95% CI,
0.901.03; p=0.29) at 3.9 years. Neither was there a significant difference between groups in the rates of major vascular
events in the population of patients with low HDL and high TG
levels, the population for which the ATP III report and update
recommended niacin. In addition, patients in the niacin group
experienced statistically significantly higher rates of adverse
effects, some of which had not been reported previously with
niacin. Hazards included disturbances in DM control, new DM
diagnoses, GI effects, myopathy, skin-related events, infection, and bleeding. Therefore, the investigators concluded that
extended-release niacin plus laropiprant did not provide benefit in reducing ASCVD risk but did increase the risk of adverse
effects, and they urged practitioners to consider those risks
when prescribing therapy.
This study echoed the findings of AIM-HIGH in that combination therapy with niacin and statins did not reduce ASCVD
risk. Again, these high-risk patients entered the study with
very low levels of atherogenic lipoproteins, which was the
major criticism of AIM-HIGH; however, the authors explored
the patient population with abnormalities in lipid parameters beyond LDL and still did not note a difference in vascular
events (the study was not specifically powered to address
those subgroups). Although many of the adverse effects
observed in the study are known adverse effects of niacin,
some of them (e.g., infection, bleeding risk) were more concerning; and the contribution of laropiprant to that occurrence
is still unknown. Thus, the controversy continues about the
appropriate use of nonstatin therapy in patients who remain
at risk despite adequate use of statin therapy.
simvastatin 40 mg/ezetimibe 10 mg daily in combination.
IMPROVE-IT
EMERGING THERAPIES FOR

DYSLIPIDEMIA
Patients were followed for a minimum of 2.5 years (overall

study duration was about 7 years), and the composite primary end point included CV death, MI, ischemic stroke,
hospitalization for unstable angina, or coronary revascularization more than 30 days after randomization. As expected,
ezetimibe reduced LDL levels better than did statin monotherapyby about 17 mg/dL, which corresponded to a 24%
further lowering in LDL compared with monotherapy. The
difference in the primary end point favored the combination
therapy group, with a 2.0% absolute risk reduction (HR 0.936;
95% CI, 0.8870.99; p=0.016) and a needed-to-treat number
of 50. Benefit emerged after 1 year of treatment. Regarding
individual components of the primary end point, investigators noted statistically significant relative risk reductions of
13% in the risk of MI and 21% in the risk of ischemic stroke,
as well as a significant overall 10% reduction in the risk of CV
death, nonfatal MI, or nonfatal stroke. The trial was designed
as an intention-to-treat study, and when on-treatment analysis was performed, the results for the combination therapy
group versus the statin monotherapy group were even more
striking, with an NNT of 38.
Even though considered by most experts to be only a modest benefit in terms of end pointsbecause there were no
differences between the groups in CV mortality or all-cause
mortalitythis was the first sign of evidence that ezetimibe
could significantly reduce rates of MI and ischemic stroke
from its benefits on major lipid parameters. For clinical benefit per millimole of LDL reduction, the hazard ratio was 0.80
in IMPROVE-IT compared with 0.78 observed with statins.
As such, this study rechallenged the notion of LDL lowering
beyond statin therapyslightly different from the 2013 ACC/
AHA guidelines recommendationsand proponents of ezetimibe pointed to this study as useful data for expanding the
role of ezetimibe in clinical practice. Criticisms of the trial
included the use of simvastatin 40 mg dailya moderate-intensity statin that would not be recommended for this patient
population based on new guidelinesand a high patient dropout rate (42%) that occurred equally between the two groups.
Nonetheless, IMPROVE-ITs positive outcomes may influence
the next set of guidelines for targeting percent LDL lowering
with a variety of lipid-lowering therapies. {PROD: Insert
IMPROVE-IT was the first major RCT to investigate the efficacy of ezetimibe in combination with a statin versus statin
monotherapy on ASCVD outcomes. Specifically, more than
18,000 patients at 1147 sites in 39 countries who had experienced acute coronary syndrome within the previous 10 days,
who had LDL of 50125 mg/dL (or 50100 mg/dL if previously
receiving cholesterol-lowering drug), and who had received
standard medical and interventional therapy were randomized to receive simvastatin 40 mg daily as monotherapy or
Although management of dyslipidemia has become increasingly efficient, significant concern still remains about the
residual risk for patients who are seemingly appropriately
treated. Therefore, the quest for development of the ideal agent
to address dyslipidemia is ongoing. In the past few years,
many novel pharmaceutical agents have entered late-stage
trials or become available to specific patient populations so
49
Dyslipidemia
patients with high ASCVD risk who were receiving maximally
as to establish roles in therapy as alternative agents to statins

or as combination agents for use with statins.
tolerated statin therapy were assigned to either alirocumab or

placebo as adjunct therapy (ODYSSEY LONG TERM 2015). At
Proprotein Convertase Subtilisin/Kexin Type 9

Enzyme Inhibitors
the end of the 78-week study, patients who had received alirocumab experienced a statistically significant 62% LDL decrease
This class of drugs inhibits the proprotein convertase subtilisin/kexin type 9 enzyme, which plays a major role in the
breakdown of hepatic LDL receptors and is typically up-regulated in the presence of statins. The inhibition of this enzyme
enables more efficient hepatic uptake of LDL, decreasing
serum LDL levels by more than 50% in most cases. This mechanism was discovered barely more than a decade ago, and
already targeting this pathway are five agents: alirocumab,
evolocumab, and three additional agents in the pipeline.
One recent major trial, ODYSSEY LONG TERM, supports the
addition of alirocumab to statin therapy to reduce both lipid
parameters and, possibly, overall CV events. More than 2300
versus the placebo group; a post hoc analysis noted a statistically significant lower rate of major adverse CV events in the
alirocumab group versus placebo.
Several phase III clinical trials explored the use of evolocumab
as part of various therapies with a range of possible dosing strategies. The MENDEL-2 trial focused on about 600 patients with
LDL equal to or less than 190 mg/dL and 10-year CHD risk (per
the FRS) of 10% or less in a six-arm design, comparing evolocumab injections both biweekly and monthly with placebo and
ezetimibe (Koren 2014). Overall, both doses of evolocumab
resulted in an LDL decrease of about 56% versus placebo and an

four beers per week, and tries to follow a low-cholesterol
A 56-year-old man presents to the primary care clinic

for lipid management. He has a medical history of hypertension, dyslipidemia, obesity, and type 2 DM. He is
adherent to his medications, which are aspirin, amlodipine, lisinopril, metformin, glipizide, and rosuvastatin
40 mg orally daily. He smokes 10 cigarettes per day
decreased from one pack per day 6 months ago, drinks
and low-sodium diet. His fasting lipid panel is as follows:

total cholesterol = 196 mg/dL, HDL = 29 mg/dL, TG = 358
mg/dL, and LDL = 95 mg/dL (goal LDL 70 mg/dL per NLA
recommendations). What is the next step in managing this
patients dyslipidemia?
ANSWER
All available evidence supports continued lifestyle

modifications, including complete smoking cessation
and reduction in alcohol use, as well as optimal control
of hypertension and DM. All guidelines and professional
organizations agree on this approach. However, beyond
TLC and maximum statin therapy, the 2013 ACC/AHA
guidelines did not provide specific guidance for any additional pharmacologic treatment of this patient population,
citing a lack of evidence. Similarly, the 2015 ADA recommendations did not move beyond maximal statin therapy.
Therefore, for clinicians who wish to address residual
ASCVD risk, the NLA recommendations encompass the
sole perspective for intensification of pharmacologic
therapy. Despite receiving the maximal dose of a high-intensity statin, this patients LDL remains above the NLAs
recommended goal for very-high-risk patients. In addition, the patients non-HDL is 167 mg/dLwell above his
LDL goal of 30 mg/dL. Part 1 of the NLA recommendations advocates the use of adjunctive nonstatin therapies
to reduce levels of atherogenic cholesterol, naming
cholesterol absorption inhibitors, bile acid sequestrants,

fibric acids, omega-3 fatty acids, and nicotinic acid as
available options for that purpose. Part 2 of the NLA recommendations more specifically directs clinicians toward
the use of ezetimibe, colesevelam, and extended-release
niacin (in order of preference) as second-line therapy.
Ezetimibe is well tolerated and would bring both LDL and
non-HDL levels toward goal, but positive-outcomes data
exist only in secondary prevention. Colesevelam provides LDL reduction and additional blood glucose control
that could prove useful in a diabetic patient; however,
caution is warranted in a patient with elevated TG at baseline. Extended-release niacin would have the most potent
effect on HDL and TG for impacting the non-HDL, but trials have failed to demonstrate positive outcomes with
combination therapy; and blood glucose control is of concern. Thus, with no perfect option, any of these therapies
would be reasonable in this patient, so a risk-benefit analysis, including patient preference, would be necessary to
select the preferred approach.
1. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia:
Part 1 full report. J Clin Lipidol 2015;9:129-69.
2. Jacobson TA, Maki KC, Orringer C, et al. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia:
Part 2. J Clin Lipidol 2015;doi:10.1016/ j.jacl.2015.09.002
50
Dyslipidemia
LDL decrease of about 39% versus ezetimibe, with no difference

between the groups in terms of adverse events.
The DESCARTES trial investigated 900 patients who were
receiving diet alone, atorvastatin 10 mg daily, or atorvastatin 80 mg daily with or without ezetimibe and randomized
those patients to either monthly evolocumab or placebo
(Blom 2014). The results demonstrated statistically significant decreases in LDL with evolocumab versus placebo in all
groups, with an overall reduction of 57% from baseline in the
entire cohort, which persisted even in the presence of high-intensity statin therapy. Two extension studies conducted with
patients who had participated in previous phase II or III trials
of evolocumabOSLER-1 and OSLER-2compared the addition of evolocumab with standard therapy for hyperlipidemia
versus the use of standard therapy alone (OSLER 2015). The
investigators defined standard therapy as appropriate guideline-directed therapy for the level of ASCVD risk present in
each patient; almost 70% of the patients in the study were
receiving statin therapy. Evolocumab decreased LDL by 61%
in the overall population and statistically significantly reduced
the incidence of CV events at 1 year by 53% versus standard
therapy alone. Finally, evolocumab has been studied in both
statin-intolerant patients and HeFH with a more than 50% LDL
reduction in those patient populations as well (RUTHERFORD
2015; Stroes 2014).
In mid-2015, both alirocumab and evolocumab received
FDA approval for use in patients with HeFH and patients
with clinical ASCVD who are receiving maximally tolerated
statin therapy and who still require further LDL lowering.
Evolocumab also received approval for use in patients with
HoFH. Because large-scale, long-term clinical outcomes
data are not expected until 2017, the benefit-risk ratio has not
yet been fully elucidated, and the role for addressing residual ASCVD risk remains unclear. However, for practitioners
with limited options, this class of agents represents a novel
approach to managing difficult dyslipidemias.
Part 2 of the NLA recommendations, the only guideline to
address this class thus far, suggests that these agents could
be used in patients with ASCVD and LDL of 100 mg/dL or
greater who are receiving maximally tolerated statin with or
without ezetimibe therapy, as well as in patients with HeFH
without ASCVD but with LDL of 130 mg/dL or greater who
are on maximally tolerated (high-intensity) statins. The NLA
also notes that those agents could be considered in patients
who are statin intolerantalthough not FDA approved for this
indication. Both agents are administered as subcutaneous
injections and are well tolerated overall, with the most predominant adverse effects being mild injection-site reactions
and muscle aches.
administration of these agents is a reduction in LDL together

with a significant increase in HDL levels, the clinical benefit
of which has not been fully elucidated. The first agent in this
class, torcetrapib, effectively produced beneficial changes
in lipid parameters but was not brought to the U.S. market because of an increase in deaths and CV events toward
the end of late-phase clinical trials. Although many possible causes of those negative outcomes have been explored,
development of additional agents in the class has continued,
with emphasis on long-term-safety data.
A second agent, dalcetrapib, did not demonstrate meaningful efficacy, and recent clinical trials have been halted;
however, two additional agents, anacetrapib and evacetrapib,
are still under investigation. In the DEFINE trial, anacetrapib
was compared with placebo in more than 1600 patients either
with coronary artery disease or at high risk of disease who
were receiving statins (Cannon 2010). Administration of anacetrapib resulted in a 40% decrease in LDL and a 138% increase
in HDL at 24 weeks, with no noted concerns about the development of CVD. In phase II trials, evacetrapib monotherapy
reduced LDL 14%36% from baseline as monotherapy and
11%14% in combination with statin therapy. Evacetrapib also
increased HDL by 54%129% when used both as monotherapy and in combination with statinsagain, with no concerns
about CVD. There was no difference between the groups
with regard to treatment-related adverse eventsspecifically,
adverse effects on blood pressure or mineralocorticoid activity. Large phase 3 trials are currently ongoing for both agents
to further investigateand, hopefully, rule outconcern about
long-term development of CVD and death. Until those trials
are completed, doubt remains as to the appropriate role of
those agents in therapy (Mohammadpour 2013).
Newly FDA-Approved Drugs for HoFH
In recent years, increased attention has focused on the

uniquely challenging disease of homozygous familial
hypercholesterolemia. Patients with HoFH are typically characterized by LDL levels that exceed 400 mg/dL, with minimally
functional hepatic LDL receptorsa condition that leads
to early CVD and death. Low-density lipoprotein apheresis
is considered the standard of care but is not an ideal longterm management strategy. Because such patients require
LDL reduction well beyond the capability of traditional dyslipidemia agents, the search for a beneficial and safe drug for
use either as monotherapy or in combination has intensified.
Recently, two new drugs have become available to patients
with this disorder under FDA-mandated risk evaluation and
mitigation strategy programs.
Lomitapide is a microsomal triglyceride transfer protein
inhibitor that decreases the assembly of apoB particles in
both the GI tract and the liver (Rader 2014). That decrease in
turn results in fewer LDL particles in the plasma that are available to participate in plaque development. Although effective
in reducing LDL levels in patients with HoFH, GI side effects
Cholesterol Ester Transfer Protein Inhibitors
This class of drugs demonstrates a unique mechanism

of action by inhibiting cholesterol ester transfer protein, a
major step in reverse cholesterol transport. The result of
51
Dyslipidemia
are common, together with fat-soluble vitamin deficiencies

and hepatotoxicity caused largely by increases in hepatic fat.
Thus, lomitapide is restricted to certified prescribers, and all
patients receiving this drug are enrolled in a registry to track
long-term safety.
Mipomersen, an antisense inhibitor of apoB synthesis,
results in dramatic LDL reduction by decreasing the production of all particles requiring apoB. The product is available
only as a subcutaneous injection, with injection site reaction
emerging as the most common adverse effect. Additional
adverse effects include flulike symptoms, increased levels of
hs-CRP, and hepatotoxicityagain, because of increases in
hepatic fat. Like lomitapide, mipomersen is restricted to certified prescribers; and patients are automatically enrolled in a
registry to ensure appropriate use.
Practice Points
The 2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic CV risk in adults
introduces a new, more simplistic risk stratification and
treatment approach to the general population with dyslipidemia by following a narrowly defined evidence base that
eliminates numeric lipid treatment targets and focuses
on appropriate statin use. The National Lipid Association
recommendations for patient-centered management of
dyslipidemia maintain numeric lipid treatment targets, a
focus on overall atherogenic cholesterol burden, and the
use of combination therapies in patients with residual
risk. The intended scopes of the publications differ, and
therefore, the most optimal dyslipidemia management
would likely judiciously apply both approaches, focusing on
patient-provider communication.
Patients in special populationssuch as those with chronic
kidney disease, diabetes mellitus, hypertriglyceridemia,
and familial hypercholesterolemia as well as pediatrics
may benefit from additional recommendations found in
disease-specific dyslipidemia management guidelines.
Multiple tools exist for quantifying ASCVD risk, but none
of them has become established as a superior option; and
clinicians should account for the limitations of each tool
when incorporating results into their decision-making.
Nontraditional ASCVD risk factors may be useful in individualizing risk assessment in patients with unclear need for
pharmacological therapy, but benefit has not been proved
definitively in randomized controlled trials.
The use of nonstatin therapies either as monotherapy or in
combination with statins has been significantly affected by
new evidence published in recent yearsspecifically, from
AIM-HIGH, HPS2-THRIVE, and IMPROVE-IT.
Emerging therapies for dyslipidemia, including the PCSK9
inhibitors and the cholesterol ester transfer protein inhibitors, show promise for treating patients with residual ASCVD risk; however, the roles of those inhibitors in therapy
will become better defined once ongoing trials exploring
outcomes data have been completed.
CONCLUSION
It has always been prudent for health care practitioners treating patients with dyslipidemia to determine which of the
existing literature is most applicable to their patients, but that
determination has become complicated by the significant
amount of information that has emerged in the past few years.
Multiple organizations published guidelines and recommendations are at best complementary and at worst conflicting,
and they require increased diligence on the part of clinicians in
their selections of the most appropriate management tactics.
Most patients could likely receive overall appropriate therapy
with the simplistic approach of the 2013 ACC/AHA guidelines, but it would not be unreasonable to incorporate NLA
recommendations or other disease-specific guidelinesspecifically, for patients in whom therapy is not straightforward.
Despite differences between the documents, all of them agree
that involving the patient in decision-making throughout the
treatment process is crucial for improving outcomes; and
therefore, this clinical controversys most important function
may lie in the stimulation of conversation between the health
care practitioner and the patient for determination of the best
course of action. {PROD: Insert Practice Points box here}
protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in
Communities (ARIC) study.Circulation 2004;109:837-42.
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55
Dyslipidemia
Questions 2128 pertain to the following case.
B. Individuals with clinical ASCVD, 4075 years of age,

and LDL 70189 mg/dL
C. Individuals with HTN or DM, 4075 years of age, and
LDL 70189 mg/dL
D. Individuals without clinical ASCVD or DM, 4075
years of age, LDL 70-189 mg/dL, and 10-year ASCVD
risk 7.5%
M.J. is a 65-year-old Hispanic woman with a medical history of

hypertension (HTN), obesity, osteoarthritis, and nonalcoholic
fatty liver disease; she presents to clinic for lipid management. She has no complaints today. Her father died at age 50
from complications of coronary artery disease. Her mother,
who is still living, has type 2 diabetes mellitus (DM). M.J.s
home drugs include hydrochlorothiazide 25 mg daily, amlodipine 5 mg daily, doxazosin 4 mg at bedtime, and ibuprofen 200
mg as needed for knee and back pain. She smokes 1 pack per
day and drinks moderately at social events, but has never used
illicit drugs. Baseline laboratory tests drawn 2 weeks ago are
as follows: TC 252 mg/dL, LDL 165 mg/dL, HDL 35 mg/dL, TG
260 mg/dL, and glucose 105 mg/dL. Her blood pressure (BP)
is 138/78 mm Hg. M.J. is not on any specific diet, does not
exercise, and has no history of kidney dysfunction.
25. Which one of the following best describes M.J.s lipid

parameters that are NOT at goal according to Part 1 of the
NLA Recommendations for Patient-Centered Management of Dyslipidemia?
A. HDL/non-HDL
B. LDL/TG
C. LDL/non-HDL
D. HDL/TG
26. Based on the ACC/AHA guidelines and NLA recommendations, which one of the following is the best treatment
option for M.J.?
21. According to the National Cholesterol Education Program

(NCEP) Adult Treatment Panel III (ATP III) Risk Assessment tool, which was based on the Framingham Heart
Study, which one of the following best describes M.J.s
risk of a coronary heart disease event?
A. Rosuvastatin 10 mg daily and therapeutic lifestyle

changes
B. Simvastatin 40 mg daily
C. Therapeutic lifestyle changes only
D. Atorvastatin 5 mg daily and therapeutic lifestyle
changes
A. 10%
B. 18%
C. 26%
D. 34%
27. Which one of the following best explains the choice of a

specific guideline to guide management of M.J.?
22. According to the NCEP ATP III/ATP III 2004 update, which
set of cholesterol goals is most appropriate for M.J.?
A. NCEP ATP III because her LDL is below goal.

B. 2013 ACC/AHA guideline because her TG is above
goal
C. NLA Recommendations because her non-HDL is
above goal
D. 2013 IAS guideline because her HDL is below goal
A. LDL < 100 mg/dL (optional < 70 mg/dL) and non-HDL

< 130 mg/dL (optional < 100 mg/dL)
B. LDL < 100 mg/dL and non-HDL < 130 mg/dL
C. LDL < 130 mg/dL (optional < 100 mg/dL) and nonHDL < 160 mg/dL (optional < 130 mg/dL)
D. LDL < 160 mg/dL and non-HDL < 190 mg/dL
28. Based on the 2014 NLA Statin Safety Update, which of the
following is most likely to be of concern in initiating statin
therapy in M.J.?
23. Which one of the following best describes M.J.s risk of a

negative outcome based on the Pooled Cohort Equations?
A. 20.7% 10-year risk of atherosclerotic cardiovascular
(CV) disease
B. 4% 10-year risk of myocardial infarction and coronary
death
C. 8% lifetime risk of coronary heart disease
D. 13.4% lifetime risk of heart attack, stroke, or other
major heart disease
A.
B.
C.
D.
T.K. is a 44-year old African-American man with a medical history of HTN, depression, and gout. He presents to his primary
care physicians office requesting evaluation for dyslipidemia
treatment. T.K. quit smoking 20 years ago when his mother
died suddenly of an MI at age 48, and he is very anxious to prevent a similar event. He goes to the gym daily for at least an
24. According to the 2013 ACC/AHA Blood Cholesterol Guideline, which major statin benefit group best categorizes
M.J.?
A. Individuals with primary elevations of LDL 160 mg/
dL or HDL < 40 mg/dL
Presence of nonalcoholic fatty liver disease

Risk of developing dementia
Risk of developing DM
Risk of intolerance because of osteoarthritis
56
Dyslipidemia
C. LDL < 130 mg/dL and non-HDL < 160 mg/dL

D. LDL < 160 mg/dL and non-HDL < 190 mg/dL
hour and eats a low-sodium, low-cholesterol diet. His home

drugs include lisinopril 20 mg daily, escitalopram 10 mg daily,
and allopurinol 100 mg daily. His BP is 128/70 mm Hg. His
fasting lipid panel is as follows: TC 200 mg/dL, HDL 48 mg/
dL, TG 210 mg/dL, and LDL 110 mg/dL. All other laboratory
tests are within normal limits. T.K. has a 3% risk of CHD in the
next 10 years (NCEP ATP III risk assessment tool) and a 6.5%
10-year risk of ASCVD per the Pooled Cohort Equations.
32. According to the 2013 ACC/AHA Blood Cholesterol Guideline, which one of the following is the most appropriate
therapy for T.Y.?
A.
B.
C.
D.
29. Which one of the following nontraditional risk factors

would most assist in further ASCVD risk stratification of
T.K.?
33. T.Y.s cardiologist is interested in adding ezetimibe to

her regimen, citing the IMPROVE-IT trial as his rationale. What is the most appropriate response to give T.Y.s
cardiologist?
A. Coronary artery calcium

B. Lp(a)
C. LDL-P
D. Lp-PLA2
A. The IMPROVE-IT trial demonstrated a reduction in a

composite endpoint of CV death, MI, ischemic stroke,
hospitalization for unstable angina, and coronary
revascularization in patients who received ezetimibe
in addition to simvastatin. This patient meets the
inclusion criteria for the trial and would likely benefit
from ezetimibe in combination with a statin.
B. The IMPROVE-IT trial did not demonstrate a
reduction in either CV or overall mortality when
adding ezetimibe to simvastatin. Therefore,
ezetimibe is unlikely to provide any clinical benefit in
this patient and should not be added to her therapy.
C. Although the IMPROVE-IT trial demonstrated benefit
when ezetimibe was added to statin therapy in
regards to MI, ischemic stroke, and a composite
endpoint of CV death, nonfatal MI, or nonfatal stroke,
there was a very high patient dropout rate in the
study that negated the positive results. Therefore, no
evidence supports adding ezetimibe to this patients
therapy.
D. The IMPROVE-IT trial demonstrated a significant
reduction in a composite CV endpoint in patients
who received ezetimibe in addition to simvastatin.
Since the trial specifically studied the combination
of ezetimibe and simvastatin 40 mg daily, ezetimibe
should only be added if simvastatin 40 mg daily is
also used.
30. T.K. asks if he should initiate statin therapy. Which one of

the following is the most appropriate answer to give T.K.?
A. A family history of myocardial infarction can increase
your risk, and statins can lower that risk. It would be
reasonable to initiate a statin in your situation.
B. Based on your laboratory results and personal
history, your risk of having a myocardial infarction in
the next 10 years is very low. The optimal approach
to reducing your CV risk at this time is initiating/
continuing appropriate therapeutic lifestyle changes.
C. Statins are very well tolerated with minimal side
effects, especially in younger patients. Because you
have a family history of premature CV disease, the
benefits outweigh your risks of therapy, and a statin
is clearly indicated.
D. In order to decide whether statin therapy is
appropriate for you, several more lab tests are
required. There is not enough information to
determine your treatment plan at this time.
T.Y. is a 56-year-old postmenopausal Asian-American woman

who presents to the emergency room with chest pain indicative of angina. She reports no significant medical history.
Fasting laboratory tests reveal glucose 90 mg/dL, TC 270 mg/
dL, HDL 31 mg/dL, LDL 120 mg/dL, and TG 590 mg/dL. Her
BP is 166/90 mm Hg; she states that this is normal for her.
Based on EKG findings, T.Y. is given a diagnosis of non-ST
segment elevation myocardial infarction (NSTEMI). Left heart
catheterization shows 80% occlusion in the proximal left
anterior descending artery, but T.Y. refuses to undergo stent
placement.
J.J. is a 50-year-old white man who presents to the primary

care clinic for lipid management. His medical history includes
HTN, STEMI 8 years ago (intervened with drug eluting stent),
CKD Stage G2, obesity, and dyslipidemia. He is adherent to his
home drugs, which include aspirin 81 mg daily, amlodipine 5
mg daily, lisinopril 20 mg daily, and rosuvastatin 40 mg daily.
He has unsuccessfully tried to quit smoking over the past 10
years but has decreased to a half-pack per day. He has been
following a low-cholesterol and low-sodium diet for 6 months
with 2 glasses of red wine each night. A fasting lipid panel
31. According to the NLA recommendations, which set of

LDL and non-HDL goals are most appropriate for T.Y.?
A. LDL < 70 mg/dL and non-HDL < 100 mg/dL
B. LDL < 100 mg/dL and non-HDL < 130 mg/dL
Niacin ER 500 mg daily

Lovaza (omega-3 fatty acid) 2 g twice daily
Atorvastatin 80 mg daily
Rosuvastatin 10 mg daily
57
Dyslipidemia
LDL 125 mg/dL, receiving high-intensity statin

therapy
obtained today shows TC 218 mg/dL, HDL 25 mg/dL, TG 415

mg/dL, and LDL 110 mg/dL.
34. Which of the following best describes J.J.s goals of therapy for LDL?
L.S. is a 30-year-old woman who presents to the clinic for disease state management. She tells you that she was at a health
fair 6 months ago and was diagnosed with diabetes because
she had a non-fasting glucose of 210 mg/dL. Both her parents
have DM but are still living. For the past 6 weeks, L.S. has been
engaged in her health by incorporating food portion control
and choosing healthier food options. She does not smoke, but
admits to drinking socially. L.S. walks 30 minutes/day, 5 days
per week, to work. Her laboratory results are as follows: TC 210
mg/dL, HDL 28 mg/dL, LDL 128 mg/dL, TG 270 mg/dL, A1C
8.0%, and fasting glucose 198 mg/dL. All other labs are within
normal limits. Her BP is 128/70 mm Hg.
A. <70 mg/dL per both the 2013 KDIGO guideline and

the NLA recommendations
B. <70 mg/dL per the 2013 KDIGO guideline but no
numeric goal of therapy per the 2013 ACC/AHA
guideline
C. No numeric goal of therapy per the 2013
KDIGO guideline but <100 mg/dL per the NLA
recommendations
D. No numeric goal of therapy per both the 2013 KDIGO
guideline and the 2013 ACC/AHA guideline
35. J.J.s physician is concerned about residual ASCVD
risk and asks if the addition of niacin would benefit this
patient. What is the most appropriate response to give
J.J.s physician?
37. Which one of the following would be best to discuss with

L.S. before initiating a treatment plan for dyslipidemia?
A.
B.
C.
D.
A. The patient likely has minimal residual risk, since he is

being appropriately managed per the 2013 ACC/AHA
guidelines by receiving the maximum dose of a highintensity statin. The addition of niacin is unnecessary.
B. Neither the AIM-HIGH trial or the HPS2-THRIVE trial
demonstrated a reduction in CV outcomes when
extended-release niacin was added to aggressive
LDL lowering therapies, despite a positive impact on
multiple lipid parameters. Therefore, the benefit of
adding niacin remains unclear.
C. The NLA recommendations suggest the addition of
niacin as the preferred adjunctive therapy in patients
with elevated triglycerides and low HDL. Niacin
would also help reduce this patients LDL and is
appropriate to initiate.
D. Niacin causes a number of significant adverse
effects that outweigh any possible benefit in
patients with chronic kidney disease. Alternatively,
this patient should focus on therapeutic lifestyle
changes, including smoking cessation, reduction in
alcohol use and initiation of an exercise program.
38. Which one of the following best describes the recommended approach to L.S.s dyslipidemia management
according to the 2015 ADA guideline?
A. Calculate her 10-year risk of ASCVD with Pooled
Cohort Equation and treat based on result
B. Initiate moderate to high statin therapy
C. Address dyslipidemia treatment after blood glucose
control is achieved
D. Target LDL <100 mg/dL and non-HDL <130 mg/dL
39. Six months after beginning therapy for dyslipidemia, L.S.s
laboratory test results are as follows: TC 173 mg/dL, LDL
98 mg/dL, HDL 29 mg/dL, and TG 230 mg/dL. According
to the NLA recommendations, which one of the following
is the most appropriate non-HDL goal for L.S.?
A.
B.
C.
D.
36. Which one of the following patients is the best candidate

for alirocumab?
< 70 mg/dL
< 130 mg/dL (optional <100 mg/dL)
40. Which one of the following nonstatin therapies would be

best for L.S.?
A. A 35-year-old woman with homozygous familial

hypercholesterolemia, LDL 350 mg/dL, receiving
moderate intensity statin therapy and lomitapide
B. A 69-year-old man with DM and MI 2 years ago, LDL
140 mg/dL, receiving high intensity statin therapy
plus ezetimibe
C. A 24-year-old woman with polycystic ovarian
syndrome, LDL 195 mg/dL, intolerant of statin
therapy
D. A 50-year-old man with chronic kidney disease,
premature family history of MI and current smoker,
Contraceptives (or plans to conceive)

Muscle aches while walking to/from work
Family history of dementia or memory problems
Increased DM risk with statin therapy
A. Colestipol
B. Fenofibrate
C. Omega-3 fatty acids
D. Alirocumab
58
Dyslipidemia
Learner Chapter Evaluation: Dyslipidemia.

32. Distinguish between dyslipidemia treatment recommendations from the National Cholesterol Education
Panel Adult Treatment Panel III, the American College of
Cardiology/American Heart Association, and the National
Lipid Association

Strongly agree

Agree

Neutral

Disagree

Strongly disagree

33. Using available assessment tools, classify a patients risk

of cardiovascular disease
3 4.

Using recommendations from major organizations
(e.g., American Diabetes Association, Kidney Disease:
Improving Global Outcomes) and individual patient risk
factors, design an effective dyslipidemia treatment
strategy.

35. Distinguish the benefits and risks of widespread statin

use as first-line management of dyslipidemia

36. Evaluatebased on current evidencethe role of nonstatin therapies in the management of lipid disorders
37.. Analyze novel mechanisms of action of emerging therapies to address dyslipidemia

were effective.


effective.


were effective.
59
Dyslipidemia

By Kristen T. Pogue, Pharm.D., BCPS, AQ-Cardiology; and Claire P. Walter, Pharm.D., BCPS
Reviewed by Christina Rose, Pharm.D., BCPS; and Ashlee Sommer, Pharm.D., BCPS
LEARNING OBJECTIVES
1. Evaluate the role of anticoagulation in the treatment of pulmonary arterial hypertension (PAH).
2. Distinguish the differences in pharmacology, pharmacokinetics, drug-drug interactions, and adverse events between
endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclins, and selexipag.
3. Design a pharmacotherapy plan for a patient with PAH using the various monotherapies or combination therapy on the
basis of current evidence and guidelines.
4. Develop an approach to manage complications associated with PAH-specific therapies.
ACCP
American College of Chest

Physicians
CCB
Calcium channel blocker
CTEPH
Chronic thromboembolic pulmonary hypertension
ERA
Endothelin receptor antagonist
ERS
European Respiratory Society
ESC
European Society of Cardiology
ET Endothelin
IPAH
Idiopathic pulmonary arterial
hypertension
mPAP
Mean pulmonary arterial pressure
6MWD
6-minute walk distance
PAH
Pulmonary arterial hypertension
PDE-5
Phosphodiesterase type 5
P-gp P-glycoprotein
PH
Pulmonary hypertension
PVR
Pulmonary vascular resistance
REMS
Risk Evaluation and Mitigation
Strategies
RV
Right ventricle
sGC
Soluble guanylate cyclase
WSPH
World Symposium on Pulmonary
Hypertension
INTRODUCTION
Pulmonary hypertension (PH) is a chronic, life-threatening disease
defined as elevated pressures in the pulmonary vasculature that are
consistently above normal. Because PH has many etiologies, the
World Health Organization (WHO) created a clinical classification
system that categorizes the potential causes of PH according to similarities in pathophysiology, hemodynamics, and treatment options
(Table 3-1). Groups 25 include PH caused by left heart disease,
lung diseases and/or hypoxia, chronic thromboembolic pulmonary
hypertension (CTEPH), and unclear multifactorial mechanisms,
respectively. The primary treatment goals of groups 25 are to treat
the underlying disease. Group 1 PH, or pulmonary arterial hypertension (PAH), is the subject of this chapter. Targeted therapies for PAH
have lacked benefit in the other WHO groups, except for riociguat in
the treatment of CTEPH (Simonneau 2013).
Epidemiology and Review of PAH Pathophysiology
Recent registry data, including the Scottish, French, American,

British, and Spanish registries, estimate the prevalence of PAH to be
726 cases per 1 million adults. With the increased availability of new
treatment options, median survival has improved in recent years. In
the 1980s, the median survival was 2.8 years, improving to 7 years in
the late 2000s. This can likely be attributed to the increased availability of treatment options. More recently, the mean age at diagnosis has
also increased from 36 years to 5065 years, according to recent registry data (McGoon 2013).
Pulmonary arterial hypertension is a progressive disease that
affects the distal pulmonary arteries. The arteries have vessel
thickening, endothelial and smooth muscle cell dysfunction and
61
Table 3-1. WHO Clinical Classification of PH

Classification
(group)
Description
PAH; includes idiopathic, heritable, drug/toxin induced, CT disease (i.e., scleroderma), portal HTN, congenital and
HIV infection
PH caused by left heart disease
PH caused by lung disease and/or hypoxia
CTEPH
PH caused by unclear multifactorial mechanisms
CT = connective tissue; CTEPH = chronic thromboembolic pulmonary hypertension; HTN = hypertension; PAH = pulmonary arterial
hypertension; PH = pulmonary hypertension.
Information from Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll
Cardiol 2013;62:D34-41.
proliferation, fibrosis, inflammation, and thrombosis. Several

mechanisms contribute to these abnormalities. These mechanisms include the diminished production of the vasodilatory
and antiproliferative substances nitric oxide and prostacyclin
and increased formation of the vasoconstrictor and proliferative compounds thromboxane A 2 and endothelin-1 (ET-1).
This causes a disparity between the vasoconstrictive and
vasodilatory response of the vessels, leading to an increase
in vascular tone and proliferative changes in the pulmonary
arteries. Current pharmacotherapy options target these pathways. As PAH progresses, right heart dysfunction can occur.
The increased afterload provided by the pulmonary arteries
can induce hypertrophy and dilation of the right ventricle (RV).
This may lead to right heart failure and is a poor prognostic
factor (Galie 2015a).

with the following:
General knowledge of the diagnostic tests used in
the evaluation of PAH
General knowledge of the pathophysiology of right
heart failure development in PAH and drug-induced
causes of PAH
Role of calcium channel blockers in the treatment
of PAH
General knowledge of previously available PAH
therapy, including bosentan, ambrisentan sildenafil, and tadalafil
Table of common laboratory reference values\
Definition, Diagnosis, and Treatment Goals
ADDITIONAL READINGS
Pulmonary hypertension is defined by a mean pulmonary arterial pressure (mPAP) of 25 mm Hg or greater at rest measured
by right heart catheterization. The definition of PAH includes
the same mPAP requirement, but it is further defined by a pulmonary capillary wedge pressure of 15 mm Hg or less and an
elevated pulmonary vascular resistance (PVR) of greater than
3 Wood units (millimeters of mercury per liter per minute) to
exclude pulmonary venous hypertension, such as pulmonary
hypertension caused by left heart disease. Although these
hemodynamic measurements define PAH, further testing is
required for the diagnosis of PAH to exclude other etiologies
(Hoeper 2013; Galie 2015a).
Patients may present with dyspnea on exertion, syncope,
fatigue, decreased exercise capacity, chest pain, or weakness.
If the disease has progressed to include right heart dysfunction,
signs and symptoms of right heart failure may be evident as
well. These include orthopnea, peripheral edema, liver congestion, and abdominal bloating. Chest radiography and ECG may
provide helpful evidence to suggest PH. Transthoracic echocardiography may be used for noninvasive screening of PH
Pulmonary Hypertension Association. www.
phassociation.org
American College of Chest Physicians.
Pharmacologic Therapy for Pulmonary Arterial
Hypertension in Adults: CHEST Guideline and
Expert Panel Report. Chest 2014;146:449-75.
Fifth World Symposium on Pulmonary Arterial
Hypertension. Updated treatment algorithm of
pulmonary arterial hypertension. J Am Coll Cardiol
2013;62:D60-72.
European Society of Cardiology, European
Respiratory Society, International Society of Heart
and Lung Transplantation, Association for
European Paediatric and Congenital Cardiology.
Guidelines for the diagnosis and treatment of
pulmonary hypertension. Eur Respir J
2015;46:903-75.
62
by providing estimations of PAPs and characterizing RV size

and function. Right heart catheterization is required for diagnosis, and pulmonary vasoreactivity testing can occur during
the catheterization. Vasoreactivity testing involves baseline
measurement of hemodynamics, followed by administration
of a potent vasodilator (inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine) and repeat hemodynamic
measurement. Patients are considered vasoreactivity responders if, after receipt of the vasodilator, they have mPAP reductions
of 10 mm Hg or more to an absolute of less than 40 mm Hg with
no reduction in cardiac output. The minority of patients with
diagnoses of PAH will have a positive response (around 15%),
but it is still pertinent to do vasoreactivity testing to guide initial
treatment (Sitbon 2005).
Pulmonary arterial hypertension is a diagnosis of exclusion and requires testing to exclude other etiologies of PH.
Pulmonary function testing, arterial blood gas analysis, and
computed tomography determine any contribution of lung
diseases. Ventilation/perfusion scans evaluate patients for
CTEPH (Hoeper 2013; Galie 2015a).
Treatment goals are important to guide the therapy for
patients with PAH. Patients who achieve these goals have a
better prognosis. However, no single factor can accurately
determine prognosis, and several variables must be assessed.
Two registries have explored potential predictors of prognosis. The French Registry determined that sex, functional
class, exercise tolerance, and hemodynamics were predictors
of survival. The REVEAL registry determined that the same
elements as the French registry, together with the etiology of
PAH, were predictors of survival (McLaughlin 2013).
These treatment goals are based on symptoms, hemodynamics, and exercise tolerance. The treatment goals include the
following: attaining WHO functional class I or II (Table 3-2), normal
or near-normal RV size and function, hemodynamic parameters
showing normalization of RV function, 6-minute walk distance
(6MWD) greater than 380 m, cardiopulmonary exercise testing
that includes peak O2 consumption greater than 15 mL/minute/
kg and ventilator equivalent for CO2 less than 45 L/minute/L/minute, and normal brain natriuretic peptide (BNP) concentrations
according to age and sex. Clinical response and treatment goals
should be reassessed 36 months after initiating therapy. The

6MWD is the primary end point used in most studies of PAH therapy (McLaughlin 2013). However, patients with severely reduced
baseline 6MWD and functional class IV symptoms likely will not
be able to achieve the goal of 380 m and functional class I symptoms in the first 3 months of therapy.
THERAPEUTIC OPTIONS
Nonpharmacologic and Adjunctive Therapies
Many nonpharmacologic and adjunctive therapies should be

considered in treating patients with PAH (Box 3-1). These include
calcium channel blockers (CCBs), physical activity, O2 supplementation, contraception, anticoagulation, diuretics, and digoxin.
Calcium channel blockers have been shown to improve
mPAP, PVR, and WHO functional class in patients with PAH
who had an initial response to CCB administration (Rich
Box 3-1. Initial Nonpharmacologic and

Adjunctive Treatments for PAH
Treat corrective causes of hypoxemia; avoid dehydration,

pain, fatigue, high altitude, smoking, iron deficiency, etc.
O to maintain O saturation > 90%

Supervised exercise activity (avoid strenuous exercise)
Warfarin (INR 1.52.5) if IPAH, heritable PAH, or PAH
2
caused by anorexigens, or associated PAH
Diuretics may be used for symptom management of fluid
overload
Digoxin may be used for atrial tachyarrhythmias
Immunization (influenza and pneumococcal)
Avoid pregnancy; discuss effective birth control with
women of childbearing potential
Positive response to acute vasoreactivity testing: initiate
oral CCB for WHO functional classes IIII, and continue if
sustained response; discontinue and consider PAH-specific therapies if no sustained response
CCB = calcium channel blocker; INR = international
normalized ratio; IPAH = idiopathic pulmonary arterial hypertension; PAH = pulmonary arterial hypertension; VTE = venous
thromboembolism.
Table 3-2. Classification of PAH Symptoms: WHO/Modified NYHA Functional Classification

Class
Definition
No symptoms (dyspnea, fatigue, syncope, chest pain) with ordinary physical activity
II
Symptoms with ordinary daily activities that slightly limit activity level
III
Symptoms with less-than-ordinary daily activities that severely limit activity level
IV
Symptoms at rest; cannot conduct normal daily activities without symptoms
NYHA = New York Heart Association.

Information from: DAlonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a
national prospective registry. Ann Intern Med 1991;115:343-9.
63
Digoxin administration has shown increases in cardiac output of around 10% and decreased sympathetic activation in
patients with PAH with isolated RV failure in the short term;
however, longer-term data do not exist (Rich 1998). Digoxin
remains reasonable to consider in patients with PAH who
develop atrial tachyarrhythmias.
1987). In addition, nonrandomized data with CCBs in vasoreactivity responders have shown improved survival at 5 years
compared with nonresponders (94% vs. 55%, p=0.003) (Rich
1992). Amlodipine, nifedipine, and diltiazem have been evaluated. Doses suggested as targets are much higher than those
used for other indications: amlodipine 40 mg daily, nifedipine
extended release 240 mg/day, and diltiazem immediate release
720 mg/day (Woodmansey 1996; Rich 1992; Rubin 1983).
Verapamil should be avoided because of its negative inotropic
effects, and data are lacking for use of other agents. Although
CCBs do not carry an approved indication for the treatment of
PAH, they should be considered first line in patients with WHO
functional class IIII who respond to vasoreactivity testing.
If CCB use fails to improve WHO functional class, alternative
PAH-specific therapies should be considered.
Supervised exercise training is supported by both controlled and uncontrolled trials of deconditioned patients who
have had improvements in exercise and functional capacity
as measured by the 6MWD, WHO functional class, and quality
of life and cardiorespiratory function (Grunig 2012). Patients
should be instructed to avoid strenuous activity that leads
to severe breathlessness or other distressing symptoms.
Oxygen supplementation is recommended for patients with
O2 saturations less than 90% or arterial blood O2 pressure
greater than 60 mm Hg and in patients with planned air travel
or travel to high altitudes if baseline oximetry is less than 92%.
These recommendations are based on the known pulmonary
vasoconstrictive response to hypoxemia and PVR reductions
in patients with PAH because there are no data from random-
Anticoagulation
Pathophysiologic changes leading to increased thrombotic

potential have been identified in the PAH population, including alterations in both coagulation and fibrinolysis. Pathologic
thrombosis and thrombotic arteriopathy in the pulmonary vasculature are thought to contribute to vascular remodeling and
disease progression (Johnson 2006). This prompted investigation into the benefits of therapeutic anticoagulation in the
PAH population. Data analyses supporting the use of anticoagulation have been confined to small, mainly retrospective
cohort or case series. Data have not shown consistent mortality benefit and have included predominantly patients with
idiopathic PAH (IPAH). Most of these studies were conducted
before many of the currently available PAH therapies, which
adds to the controversy. Current guidelines support the use of
anticoagulation therapy in patients with idiopathic, heritable,
and anorexigen-associated forms of PAH. Anticoagulation
may also be considered in patients with associated PAH.
When evaluating the addition of anticoagulation in the PAH
population, the level of evidence supporting this recommendation must be acknowledged and the risk of bleeding for
the individual patient weighed while recognizing the need for
additional research to guide therapy (Galie 2013, 2015a).
Further investigations into the benefits of anticoagulation
therapy have recently been evaluated in several PH registries.
COMPERA is a prospective, noninterventional registry of
patients with PH treated at 41 PH centers in seven European
countries (Olsson 2014). The effects of anticoagulation on
survival in 1283 patients from COMPERA with various forms
of incident PAH were retrospectively evaluated from May 2007
to April 2013. In the overall cohort that included patients with
all forms of PAH, mortality during the 3-year follow-up was
numerically lower in anticoagulated patients than in those not
anticoagulated; however, this did not reach statistical significance. In the patient cohort with IPAH, 66% of the 800 patients
had received anticoagulation at some point. Anticoagulation
was associated with lower mortality (14.2% vs. 21.0%) during
the 3-year follow-up (p=0.006). In light of differences in baseline hemodynamics and use of combination therapy during
follow-up in patients receiving anticoagulation versus those
who did not, a matched-pairs analysis based on sex, age,
WHO functional class, and PVR was performed. One hundred
sixty-eight pairs were randomly selected for analysis, and the
mortality benefit remained in favor of anticoagulation (14.9%
vs. 25.6%, p=0.017). After multivariate analysis, anticoagulation remained an independent predictor of improved mortality
in IPAH (HR 0.79; 95% CI, 0.660.94; p=0.007). This effect was
ized controlled trials.

Many women of childbearing potential are given a diagnosis of PAH, and it is imperative to discuss contraception
strategies with these patients. Physiologic changes in pregnancy and during labor can lead to catastrophic hemodynamic
stress in women with PAH, with previous reports of maternal
mortality as high as 50% (Weiss 1998). A more recent report
suggests improved pregnancy outcomes in patients with
well-controlled disease, but the general recommendation is
still to avoid pregnancy in all patients with PAH.
Consensus is lacking on the recommended pharmacologic
agent for contraception in PAH. Hormonal contraceptives
containing estrogen are generally not recommended because
of the concern for increased thrombotic risk, but this may
be mitigated in patients receiving concomitant anticoagulation therapy. Implanted or injected progesterone-only agents
may therefore be a better alternative. However, concomitant agent-specific Risk Evaluation and Mitigation Strategies
(REMS) requirements (Table 3-3), as well as the effects of
PAH-specific therapies on the CYP3A4-mediated metabolism
of hormonal contraceptives (Table 3-4), must be considered
when choosing an individualized contraception plan.
Additional supportive treatment with diuretics to control
symptoms of fluid overload caused by right heart failure is
warranted, although this is based solely on clinical experience.
64
Table 3-3. REMS Program Requirements for PAH-Specific Therapies

Drug
Bosentan
Macitentan
Riociguat
Prescriber, pharmacy; patient (q1yr),

hospital (q3yr)
Prescriber, female patient, hospital, pharmacy
Monitoring
Baseline and monthly LFTs (all) and

pregnancy test (FRP)
Baseline and monthly pregnancy test (FRP)
Medication guide
Medication guide (FRP, prepubertal); program guide (FRP)
IUD or tubal sterilization alone;

hormonal PLUS barrier; 2 barrier;
partner vasectomy PLUS hormonal or
barrier
Same as bosentan; can also have progesterone implant as lone

method
Required document(s)
Acceptable
contraception
Inpatient dispensing
Outpatient dispensing
Ambrisentan
Participant
enrollmenta
Hospital may only dispense

7-day supply on discharge;
medication guide
Maximum 30-day supplyb,c;

medication guide; confirm
pregnancy test completed
Maximum 30-day supplyb; medication

guide; confirm laboratory tests
completed; document reason for
discontinuing therapy
Hospital may only dispense 15 days

on discharge
Maximum 30-day supplyb,d; medication
guide; confirm pregnancy test
completed
Reenrollment interval is given if specified by the program.
Process for extended travel exists.

Only noted for FRP.
d
Only noted for prepubertal and FRP.
FRP = female of reproductive potential; IUD = intrauterine device; LFT = liver function test (aminotransferase and bilirubin); q = every;
REMS = Risk Evaluation and Mitigation Strategies.
b
c
Table 3-4. Endothelin Receptor Antagonists

Drug
Bosentan
Dosing Regimen and

Administration
Oral
62.5 mg BID; titrate to
125 mg BID after 4 wk
Use not recommended
in moderate to severe
hepatic impairment
Adverse Effects
Drug Interactions
PK/PD
Hepatotoxicity, edema,
anemia, teratogenicity,
headache, hypotension,
respiratory tract
infection, arthralgia,
sinusitis
Contraindicated with
cyclosporine and glyburide
Bosentan induces CYP2C9
and CYP3A4 substrates
Avoid use with CYP2C9
and CYP3A4 inhibitors
and inducers
Hormonal contraceptives,
simvastatin, and other
CYP3A4-metabolized statins,
rifampin, lopinavir/ritonavir
Half-life: 5 hr
Substrate and inducer of
CYP2C9 and CYP3A4
Ambrisentan
Oral
5 mg daily; titrate to 10
mg daily if tolerated
Use not recommended
in moderate to severe
hepatic impairment
Peripheral edema,
headache, anemia,
teratogenicity, flushing,
nasal congestion,
sinusitis, transaminitis
Avoid use with cyclosporine
Half-life: 15 hours
Metabolized by CYP3A4,
CYP2C19, and UGTs
Substrate of OATPs
and P-gp
Macitentan
Oral
10 mg daily
Anemia, teratogenicity,
nasopharyngitis,
pharyngitis, bronchitis,
headache, transaminitis
Avoid use with strong CYP3A4

inducers and inhibitors
Half-life: 16 hr and 48
hr (active metabolite)
Metabolized by
CYP3A4 (major) and
CYP2C19 (minor)
BID = twice daily; OATP = organic anion transporting polypeptides; P-gp = P-glycoprotein; PK/PD = pharmacokinetics/pharmacodynamics; UGT = UDP-glucuronosyltransferase.\
65
worsening PAH. Worsening PAH was defined as all three of

the following: decrease in 6MWD of 15% or more from baseline, worsening PAH symptoms, and need for additional PAH
treatment. Most patients were receiving background therapy
that included phosphodiesterase type 5 (PDE-5) inhibitors.
The primary end point occurred in 46.4%, 38% (vs. placebo HR 0.70; 97.5% CI, 0.520.96; p=0.01), and 31.4% (vs.
placebo HR 0.55; 97.5% CI, 0.390.76; p<0.001) of patients in
the placebo, macitentan 3-mg, and macitentan 10-mg groups,
respectively, over a median of 115 weeks. The largest component of the primary end point was worsening PAH. Death or
hospitalization because of PAH was significantly reduced in
both macitentan groups compared with placebo. The 6MWD
and WHO functional class also improved significantly. In this
study, headache, nasopharyngitis, and anemia were the most
common adverse effects associated with macitentan over
placebo. Peripheral edema and elevated liver enzymes were
similar between study and placebo groups. Of the patients
randomized, 12.4%, 13.6%, and 10.7% discontinued treatment
because of adverse events in the placebo, macitentan 3-mg,
and macitentan 10-mg groups, respectively (Pulido 2013).
Although SERAPHIN used an event-driven strategy, it did
not provide a head-to-head comparison with other PAH therapies. Macitentan may be considered as an option for ERA
therapy. Drug-specific considerations must be made when
determining which ERA to use (see Table 3-4).
not seen in other forms of PAH, and anticoagulant use was

associated with an insignificant increase in risk of death in both
this cohort and the subset of patients with PAH associated with
scleroderma. This study highlights the importance of the judicious use of anticoagulation confined to the IPAH population.
A subsequent analysis was provided by the REVEAL registry, a multicenter, observational, U.S.-based registry of patients
with WHO group I PAH. Patients initiated on warfarin were evaluated and matched at study enrollment according to study site,
etiology, and status of diagnosis (Preston 2014). After adjusting for baseline risk score, there was no difference in survival in
patients with either IPAH or systemic sclerodermaassociated
PAH, in contrast to the European analysis. Inconsistent mortality effects, together with difficulties in assessing the safety
and quality of anticoagulation in registry data, add unanswered
questions to the controversy and variations in practice.
Endothelin Receptor Antagonists
In October 2013, macitentan joined bosentan and ambrisentan as the third oral endothelin receptor antagonist (ERA)
available in the United States. Like bosentan, macitentan is
a dual ERA that prevents binding of ET-1 at both the ETA and
ETB receptors. However, unlike bosentan, macitentan has
higher affinity and sustained occupancy of the ETA receptors.
Macitentan is approved for the treatment of PAH to delay disease progression and reduce hospitalizations.
Macitentan is metabolized primarily by CYP3A4 and
CYP2C19 to an active metabolite with half-lives of 16 hours and
48 hours, respectively. Macitentan does not inhibit or induce
the CYP enzyme system and is not a substrate or inhibitor of
the P-glycoprotein (P-gp) system. However, strong CYP3A4
inhibitors or inducers should be avoided with macitentan
use. No dose adjustments are necessary for concomitant use
with sildenafil. Similar to other ERAs, macitentan is associated with embryo-fetal toxicity. Women are required to enroll
in a REMS program. This program requires pregnancy tests
before initiation and monthly during treatment and specific
contraception use during treatment. Because of these REMS
requirements, all ERA agents, including macitentan, must be
obtained through specialty pharmacies.
Macitentan was the first ERA to use morbidity and mortality
as a primary end point in a large, long-term, phase III trial. The
fifth World Symposium on Pulmonary Hypertension (WSPH)
emphasized the importance of adopting morbidity and mortality end points in future phase III trials of PH. The SERAPHIN
study was a multicenter, double-blind, placebo-controlled,
event-driven trial that explored the long-term treatment effect
of macitentan on morbidity and mortality. Seven hundred forty-two patients with WHO functional class IIIV PAH were
randomized to three study groups: placebo, macitentan 3 mg
once daily, or macitentan 10 mg once daily. The composite
primary end point was time from initiation of therapy to first
event, defined as death from any cause, lung transplantation, atrial septostomy, initiation of parenteral prostanoids, or
Soluble Guanylate Cyclase Stimulators
Riociguat is the first in a new class of drugs for PAH called soluble guanylate cyclase (sGC) stimulators, targeting endothelial
dysfunction and reduced synthesis of nitric oxide associated
with PAH. Riociguat has two distinct mechanisms of action. It
sensitizes sGC to endogenous nitric oxide by stabilizing binding and directly stimulates sGC independent of nitric oxide.
Binding of nitric oxide and riociguat to sGC increases production of cyclic guanosine monophosphate (cGMP). Cyclic GMP
regulates proliferation, fibrosis, vascular tone, and inflammation of the pulmonary arterial smooth muscle.
Riociguat is the first agent with FDA-approved labeling for
use in two different PH WHO groups. It is indicated to improve
exercise capacity and WHO functional class and delay clinical
worsening in PAH. It is also the first drug indicated for use in
inoperable CTEPH or recurrent/persistent CTEPH after surgical treatment to improve exercise capacity and WHO functional
class. Riociguat should be initiated at 1 mg orally three times
daily and titrated by 0.5 mg every 2 weeks, as tolerated, to a
maximal dose of 2.5 mg three times daily. If there is concern for
hypotension, dosing may be initiated at 0.5 mg three times daily.
Riociguat is metabolized by the CYP enzyme system (CYP
1A1, 3A, 2C8, and 2J2) and is a substrate of P-gp. Drug interactions should be evaluated before initiation; strong CYP
and P-gp inhibitors and strong CYP inducers may significantly affect riociguat exposure, requiring dose adjustments.
Antacids should also be avoided because they decrease
66
riociguat absorption. Like the ERAs, riociguat has a REMS

program because of the risks of teratogenicity, which requires
enrollment by female patients, prescribers, hospitals, and
pharmacies; baseline and monthly pregnancy tests; and dispensing from certified outpatient pharmacies (see Table 3-3).
Patients who smoke may require doses higher than 2.5
mg three times daily because of the induction of CYP1A1
by cigarette smoke. Plasma concentrations in smokers are
reduced by at least 50% compared with those in nonsmokers.
Nitrates and PDE-5 inhibitors are contraindicated with riociguat because of the risk of nitric oxidemediated hypotension.
The most common adverse reactions associated with riociguat are hypotension, dyspepsia/gastritis, headache, nausea,
and diarrhea (Table 3-5). These adverse reactions, especially
hypotension, may limit the ability to titrate riociguat.
The PATENT-1 trial was a 12-week, multicenter, double-blind, randomized, placebo-controlled study of patients
with symptomatic PAH. Four hundred forty-three patients
with predominantly WHO functional class IIIII were randomized to receive placebo, riociguat titrated to 2.5 mg three times
daily, or riociguat titrated to 1.5 mg three times daily. The primary end point was change in 6MWD at 12 weeks. About half of
the patients included were receiving background therapy, with
most of them receiving an ERA. Patients randomized to riociguat had significantly improved 6MWD compared with placebo.
The 6MWD had increased by 30 m in the 2.5-mg riociguat group
and decreased by 6 m in the placebo group (p<0.001). Patients

whose dose was capped at 1.5 mg had an increase in 6MWD
compared with placebo. However, analysis of the 1.5-mg dose
was only exploratory and descriptive. Secondary end points
that were significantly improved in the riociguat 2.5-mg group
included PVR, WHO functional class, Borg dyspnea score, time
to clinical worsening, and quality-of-life scores. Hypotension
occurred significantly more often in the riociguat group than in
placebo (10% vs. 2%, p=0.005). Eight patients (3%) in the 2.5-mg
riociguat group and nine patients (7%) in the placebo group discontinued therapy because of adverse events (Ghofrani 2013).
Riociguat cannot be used with PDE-5 inhibitors but can be
considered an alternative to PDE-5 inhibitors as a modulator
of the nitric oxide pathway. The sGC stimulators have a theoretical benefit over the PDE-5 inhibitors. Phosphodiesterase
type 5 inhibitors prevent the breakdown of cGMP in the pulmonary smooth muscle through the nitric oxide pathway.
However, patients with PAH are inherently deficient in nitric
oxide. Riociguat directly stimulates the formation of cGMP
through sGC independently of nitric oxide and sensitizes sGC
to nitric oxide. This theoretical benefit has not been evaluated
in clinical trials, and it is unclear whether this difference in
mechanism affects clinical outcomes. Studies are evaluating
the conversion from PDE-5 inhibitors to riociguat in patients
who have had inadequate response to PDE-5 inhibitors.
Table 3-5. PDE-5 Enzyme Inhibitors and sGC Stimulator

Drug
Dosing Regimen and

Administration
Adverse Effects
Drug Interactions
PK/PD
PDE-5 Inhibitors
Sildenafil
Oral
20 mg three
times daily
IV available (dosed 10
mg three times daily)
Headache, dyspepsia,
flushing, epistaxis, dizziness,
insomnia, hypotension,
visual changes, tinnitus
Contraindicated with nitrates

Potent CYP3A4 inhibitors
and inducers
May potentiate effects of
antihypertensive agents
Half-life: 4 hr
Metabolized by
CYP3A4 (major)
and 2C9 (minor)
Tadalafil
Oral
40 mg once daily
Renal adjustment
required
flushing, nasopharyngitis,
respiratory tract infection,
hypotension, vision
changes, tinnitus, nausea

Potent CYP3A4 inhibitors
and inducers
May potentiate effects of
Half-life: 35 hr
Metabolized
by CYP3A4
Oral
1 mg three times daily,
titrate by 0.5 mg every
2 wk as tolerated to
maximum of 2.5 mg
three times daily
gastritis, dizziness,
nausea, diarrhea,
hypotension, vomiting,
anemia, gastroesophageal
reflux, constipation

and PDE-5 inhibitors
Strong CYP and P-gp/BCRP
inhibitors and inducers
Antacids, smoking
decrease concentrations
Half-life: 12 hr
Metabolized by
CYP 1A1, 3A,
2C8, and 2J2
Substrate of
P-gp and BCRP
sGC Stimulator
Riociguat
BCRP = breast cancer resistance protein; IV = intravenous(ly); PDE-5 = phosphodiesterase type 5; P-gp = P-glycoprotein; sGC = soluble
guanylate cyclase.
67
Prostacyclins
for patients unable to tolerate the subcutaneous route and

requires further dilution of the supplied product with sterile water, 0.9% sodium chloride, or one of the commercially
available alkaline glycine buffer diluents. Use of one of the
glycine diluents is recommended because they have been
associated with a lower incidence of bloodstream infections
(Rich 2012). Treprostinil has shown improvements in 6MWD,
hemodynamics, and symptoms; these improvements were
more pronounced in patients with worse baseline clinical status and in those achieving higher doses. The most common
adverse event was infusion-site reaction when using the subcutaneous route (85% of patients), leading to discontinuation
in 8% of patients (Simonneau 2002).
Prostacyclin is a potent vasodilator that also has antiplatelet

and antiproliferative properties. Synthetic prostacyclin analogs
have been developed to use these properties in the treatment
of PAH (Jones 1995). Parenteral prostacyclins are recommended for use in patients with PAH having more severe WHO
functional class IIIIV symptoms. These agents may be considered as initial therapy in patients with class III symptoms
having rapid disease progression or poor prognostic features.
Parenteral therapy, specifically epoprostenol, should be considered for all patients with class IV symptoms. Inhaled agents
are recommended for use in patients with WHO functional
class III as initial therapy, with a lower-level recommendation in
patients with class IV symptoms. Oral formulations available in
the United States were only recently addressed in the European
guidelines due to more recent availability. Oral treprostinil has
a class IIb recommendation for monotherapy in functional
class III patients, the lowest recommendation, because of the
limited data discussed (Taichman 2014; Galie 2013, 2015a).
Abrupt therapy discontinuation must be avoided because this
can result in rebound increases in pulmonary pressures, flash
pulmonary edema, and possibly death. This is particularly troublesome with parenteral formulations and those with shorter
half-lives. Table 3-6 provides an overview of these agents.
Inhaled Agents
Inhaled prostacyclins can be used to avoid the complications

associated with continuous parenteral administration and
minimize systemic adverse effects. Iloprost offers improved
stability and a longer half-life (2030 minutes) than epoprostenol, and it was the first inhaled prostacyclin to be
investigated in PAH. Administration requires the use of a jet
nebulizer device six to nine times daily, with each treatment
taking 410 minutes in addition to device preparation and
cleaning. Iloprost monotherapy improved the composite of
improvement in 6MWD of at least 10% and WHO functional
class at 12 weeks in 203 patients with predominantly IPAH or
inoperable CTEPH (16.8% iloprost vs. 4.9% placebo, p=0.007),
as well as overall improvement in 6MWD, quality of life, and
hemodynamics. The median inhaled dose of 30 mcg/day correlates with 0.37 ng/kg/minute, substantially lower than the
doses required for parenteral administration. Although overall
tolerability was good, iloprost was associated with flushing
and jaw pain, similar to the parenteral prostacyclins. Cough
and bronchospasm were also adverse effects of concern
(Olschewski 2002). Two trials evaluating the efficacy of adding iloprost to stable bosentan therapy produced conflicting
results (Hoeper 2006; McLaughlin 2006).
Treprostinil has also been studied and approved for inhaled
use in PAH to improve the demanding dosing scheme of iloprost. Treprostinils prolonged half-life allows for dosing four
times daily with a reduced treatment time of 3 minutes or less
for the maximum of 9 breaths per dose. Limited data exist for
monotherapy; however, treprostinil was studied in 235 patients
with PAH having predominantly class III symptoms receiving background bosentan or sildenafil for at least 3 months.
The results showed improved 6MWD by 20 m at 12 weeks
(p=0.0004) when treprostinil was at peak concentration (1060
minutes after inhalation). Benefit emerged at 6 weeks, which
was sustained at 12 weeks, even at treprostinil trough concentrations (at least 4 hours after inhalation). The treatment effect
was more pronounced in patients with lower baseline 6MWD
and those receiving background bosentan than in patients
receiving sildenafil. Quality of life was also improved, as was
the N-terminal prohormone of BNP; however, there was no
Parenteral Agents
Epoprostenol, a synthetic prostacyclin analog, was approved

for use in the United States in 1995 and was the first agent to
show a survival benefit in IPAH (Barst 1996). It has also shown
improvements in 6MWD, WHO functional class, hemodynamics, and quality of life. Epoprostenol is supplied as a freeze-dried
powder and has a short half-life of 35 minutes, requiring continuous intravenous administration by an indwelling catheter using
an ambulatory infusion pump. The initial formulation of epoprostenol requires dissolution with a product-specific alkaline
glycine buffer and is stable at room temperature for only 8 hours,
necessitating ice packs for cooling during administration. A subsequent thermostable epoprostenol formulation is stable for 24
hours at room temperature and may be mixed with either sterile water or 0.9% sodium chloride. Of note, although no potency
difference exists, these formulations are not interchangeable.
However, because of the improved stability and ability to mix
up to a 1-week supply of drug at a time, this newer product has
become the agent of choice for initiation at many PAH centers.
Another longer-acting prostacyclin analog, treprostinil,
is available for continuous subcutaneous or intravenous
infusion. Treprostinil, which is supplied as a solution, has
a half-life of 4 hours and is stable at room temperature for
at least 48 hours once diluted. Subcutaneous administration is preferred and is possible because of the prolonged
half-life and stability, the use of a more compact pump, and
no required dilution. However, tolerability can be an issue
with the subcutaneous route because of significant infusion-site pain. Intravenous administration should be reserved
68
Table 3-6. Prostacyclins

Drug
Dosing Regimen and

Administration
Adverse Effects
Drug Interactions
PK/PD
Epoprostenol
(generic, Flolan,
Veletri)
Continuous IV infusion
2 ng/kg/min and may titrate by 2
ng/kg/min at intervals 15 min on
the basis of tolerability and clinical
response (tolerability may limit
titrations to twice daily as inpatient or
twice weekly as outpatient)
Veletri is thermostable and does not
require cold packs
Flushing, headache,
nausea and vomiting,
diarrhea, jaw and
limb pain, rash,
hypotension, line-related
thrombosis, infection
May increase effects

of antiplatelet,
anticoagulant, or
antihypertensive
agents
Half-life:
35 min
Rapidly
hydrolyzed
in blood and
enzymatic
degradation
Treprostinil
Continuous IV or SC infusion
1.25 ng/kg/min and titrate by 1.25 ng/
kg/min per week for 4 wk; then 2.5
ng/kg/min per week on the basis of
tolerability and clinical response
Flushing, headache,
diarrhea, nausea and
vomiting, rash, jaw
pain, hypotension,
infusion-site pain
(SC), line-related
thrombosis, infection

of antiplatelet,
anticoagulant, or
antihypertensive
agents
Treprostinil may
require dose
adjustment for
CYP2C8 enzyme
inhibitors or inducers
Half-life: 4 hr
Metabolized in
liver, primarily
CYP2C8
Treprostinil
Inhalation
3 breaths (18 mcg) four times daily;
titrate by 3 breaths every 12 wk up
to target dose of 9 breaths (54 mcg)
four times daily
Cough, throat irritation

and pain, flushing,
headache, diarrhea,
nausea and vomiting, jaw
pain
Same as treprostinil
above
Same as
treprostinil above
Treprostinil
Oral
0.25 mg BID or 0.125 mg TID; titrate
by 0.25 mg or 0.5 mg BID or 0.125 mg
TID, not more than every 34 days on
the basis of tolerability and clinical
response
Administer with food. Swallow tablets
whole; do not cut or crush
Flushing, headache,
diarrhea, nausea and
vomiting, jaw and limb
pain, hypokalemia,
abdominal discomfort
Same as treprostinil
above
Same as
treprostinil above
Iloprost
Inhalation
2.55 mcg six to nine times per day
(minimum of 2 hr between doses)
Cough, flushing,
headache, nausea and
vomiting, jaw and muscle
pain, hypotension

of antiplatelet,
anticoagulant, or
Half-life: 20-30
min
Metabolized by
-oxidation
PK/PD = pharmacokinetics/pharmacodynamics; SC = subcutaneous(ly); TID = three times daily.
prostacyclin to receive approval in the United States in 2014.

Treprostinil is an osmotic sustained-release tablet that allows
for twice-daily oral administration. The phase III monotherapy trial that led to its approval included 349 patients with
WHO functional class IIIII with predominantly hereditable
PAH or IPAH. The average dose achieved was 3.4 mg twice
daily in the modified intention-to-treat population, which correlates with a parenteral dose of 1030 ng/kg/minute and an
inhaled dose of 54 mcg four times daily. The primary outcome
of the 6MWD at 12 weeks was statistically improved by 23 m
change in time to clinical worsening or other secondary outcomes. Tolerability was similar to that of iloprost, with cough,
headache, and flushing being the most problematic adverse
effects. Throat pain was reported, although this was not significantly different from placebo (McLaughlin 2010).
Oral Agents
Development of effective oral prostacyclin analogs has

been inhibited by issues with short half-lives, stability, tolerability, and oral bioavailability. Treprostinil was the first oral
69
use, data to support this practice have been limited until more
recently, as evidenced by vague guideline recommendations.
Combination therapy is considered the use of drugs from two
or more classes of agents approved for PAH including PDE-5
inhibitors, ERAs, prostanoids, and the sGC stimulators. This
is divided into initial combination therapy in patients who are
treatment naive and sequential combination therapy when a
lack of acceptable response to monotherapy prompts the use
of an additional agent. A summary of trials evaluating various
combination strategies is provided in Table 3-7.
Initial combination therapy has been evaluated in two small
observational studies, as well as in the BREATHE-2 trial and
the recently published AMBITION trial (a randomized, multicenter study of first-line ambrisentan and tadalafil in subjects
with PAH). Randomization to the combination of bosentan and
intravenous epoprostenol (target dose 1416 ng/kg/minute)
in BREATHE-2 failed to improve total pulmonary resistance at
16 weeks in patients with WHO functional class IIIIV compared with epoprostenol monotherapy, although the trial was
underpowered. There were trends toward improved hemodynamic parameters (cardiac index, PVR, mPAP, and mean right
atrial pressure) with combination therapy, but these also failed
to reach statistical significance (Humbert 2004). The same
combination improved 6MWD, WHO functional class, and
hemodynamics (PVR, right atrial pressure, cardiac index, and
mixed venous O2 saturation) at 4 months in a similar population compared with a matched cohort of patients initiated on
epoprostenol monotherapy. The combination therapy group
had improved PVR in addition to a trend toward improved survival (Kemp 2012).
The randomized, event-driven AMBITION evaluated the
effect of initial monotherapy with either tadalafil or ambrisentan to the combination of these agents in 500 treatment-naive
patients with WHO functional class IIIII PAH on time to first
clinical event, including death, hospitalization for worsening
PAH, disease progression (greater than 15% decrease from
baseline in 6MWD and WHO functional class IIIIV symptoms), and unsatisfactory clinical response. Combination
therapy was associated with a 50% risk reduction in the primary outcome compared with pooled monotherapy (HR 0.50;
95% CI, 0.350.72; p<0.001), which was consistent across
all prespecified subgroups (Galie 2015b). These results are
likely to change the approach to initial combination therapy in
patients with WHO functional class II or III symptoms.
The sole study evaluating initial triple combination therapy with intravenous epoprostenol, bosentan, and sildenafil
included 19 consecutive patients with newly diagnosed idiopathic or genetic PAH presenting with WHO functional class
IIIIV symptoms and impaired hemodynamics (cardiac index
less than 2.0 Lminute -1m -2 and/or mean right atrial pressure
greater than 20 mm Hg and/or PVR of 1000 dynessecondcm -5
or greater). This pilot observational study found that triple
therapy improved both clinical and hemodynamic outcomes
at 4 months, with 17 patients achieving WHO functional class
with oral treprostinil (p=0.0125). The most common adverse

events reported with treprostinil were those expected with
prostacyclin administration and included headache (69%),
nausea (39%), diarrhea (37%), jaw pain (25%), and vomiting
(24%), with a 10% discontinuation rate (Jing 2013). Trials evaluating the addition of oral treprostinil to ERA and/or PDE-5
inhibitor therapy failed to show any clinical benefit (Tapson
2013, 2012). Product labeling suggests dosing three times
daily to enhance tolerability. Until further data are available,
oral treprostinil should be reserved for patients with WHO
functional class IIIII symptoms as initial therapy or in those
who require transition off parenteral agents.
Selexipag
Selexipag is the first non-prostanoid to target the prostacyclin

pathway, acting as a selective prostacyclin receptor (IP receptor) agonist. After oral administration, it is rapidly hydrolyzed
to the active metabolite ACT-333679 and, unlike other agents
targeting this pathway, has a higher binding affinity for the IP
receptor than any other prostanoid receptor. This metabolic
process increases the half-life to 12 hours and may reduce
serum concentration fluctuations, reducing the GI adverse
effects that have plagued the oral prostanoids. Selectivity for
the IP receptor adds to the potential for improved tolerability by minimizing the activation of other prostanoid receptors
that may contribute to nausea and vomiting (Skoro-Sajer 2014;
Simonneau 2012; Mubarak 2010). In a phase II trial, selexipag
initiated at 200 mcg twice daily and titrated to a maximal dose
of 800 mcg twice daily significantly reduced PVR by 30.3% after
17 weeks (p=0.0045) in symptomatic patients with PAH receiving stable doses of ERA or PDE-5 inhibitors (Simonneau 2012).
The multicenter, double-blind, placebo-controlled phase III
GRIPHON trial evaluated the effects of selexipag on morbidity
and mortality in 1156 patients with PAH. Selexipag was titrated
to a maximum of 1600 mcg twice daily and was associated
with a 40% reduction in the risk of time to disease progression, hospitalization for PAH worsening, PAH worsening, or
death compared with placebo (HR 0.60; 99% CI, 0.460.78;
p<0.0001) over a mean of greater than 70 weeks of therapy.
Background treatment with an ERA and/or a PDE-5 inhibitor
was allowed; 47% of patient were receiving either class and
33% were receiving combination therapy at baseline, and the
benefit was consistent regardless of the use of background
therapy. Adverse effects were similar to those with prostanoids (McLaughlin 2015). It appears that this agent may
provide another oral alternative in the treatment of the PAH,
pending regulatory review.
COMBINATION THERAPY
Combining agents from the available classes of targeted
therapies for PAH, with each addressing a known pathophysiologic abnormality in the disease process, seems intuitive
and is routinely used in this population. Despite widespread
70
Table 3-7. Randomized Trials Evaluating Combination Therapy in PAH

Primary
Pertinent Observations
33,
FC IIIIV
TPR: -36.3% 4.3% vs.

-22% 6.2% (p=0.08)
Underpowered; 76% FC III; hemodynamics trended

toward improvement
None
500,
FC IIIII
Time to first clinical

failure: HR 0.50 (0.35
0.72, p<0.001)
Mean duration 517 days; result driven primarily by

hospitalization for worsening PAH; improvements
in N-terminal prohormone of BNP, 6MWD and
satisfactory clinical response at 24 wk
Inhaled iloprost (5 mcg

six to nine times daily)
Bosentan 4 mo
67,
FC IIIV
6MWD: +30 m vs. +4

m (p=0.001); placeboadjusted +26 m
(p=0.051)
94% FC III; FC improved with combination (34% vs.

6%, p=0.002); delayed TTCW and improved PVR
COMBI;
open-label;
12 wk
Inhaled iloprost (5 mcg

six times daily)
Bosentan > 3 mo
36,
FC III
6MWD: -9 100 m vs.

+1 27 m (p=0.65);
placebo-corrected
-10 m
Stopped after interim analysis for futility
PACES-1;
DB, PC;
16 wk
Sildenafil (80 mg TID)
Epoprostenol 3
mo, stable 4 wk
267,
FC IIV
6MWD: placeboadjusted +28.8

m (13.943.8 m,
p<0.001)
65% FC III, 25% FC II; improved hemodynamics,

TTCW, and QOL; 80% achieved target dose;
subgroup with baseline 6MWD < 325 m no benefit
TRIUMPH;
DB, PC;
12 wk
Inhaled treprostinil (9
breaths/54 mcg QID)
Bosentan or
sildenafil 3 mo
235,
FC IIIIV
6MWD: placebocorrected +20 m

(8.032.8, p=0.0004)
98% FC III; background sildenafil NS change in

6MWD, most benefit in baseline lowest quartile
6MWD; no difference in TTCW or FC
FREEDOM-C;
DB, PC;
16 wk
Oral treprostinil (Target

dose 16 mg BID, median
achieved dose 3 mg BID)
PDE-5 inhibitor
and/or ERA 30
days
350,
FC IIV
6MWD: median from

baseline +11 m (0.0
22.0, p=0.07)
76% FC III, 21% FC II; 45% on both PDE-5 inhibitor

and ERA; tolerability major issue, labeling
suggests TID dosing because AEs were dose
related; post hoc analysis suggested dose-related
response
PHIRST-1;
DB, PC;
16 wk
Tadalafil (40 mg dailya)
Bosentan 12 wkb
87,b
FC IIV
6MWD: placeboadjusted +23 m (-2 to

48 m)
63% FC III, 34% FC II; prespecified subgroup

was underpowered for add-on therapy separate
analysis; no difference in FC, TTCW, or
hemodynamics
PATENT-1;
DB, PC;
12 wk
Riociguat (2.5 mg TIDc)
ERA or nonparenteral
prostanoid 90
days
191,b
FC IIV
6MWD: LS mean +34

m (1156, p=0.08 for
interaction)
52% FC III, 44% FC II; patients required to be

symptomatic; prespecified subgroup, not designed
solely to evaluate combination therapy
Macitentan (10 mg dailyd)
PDE-5 inhibitor
or non-parenteral
prostanoid 3 mo
308b,
FC IIIV
Time to first PAHrelated event or

all-cause mortality:
HR 0.62 (0.430.89,
p=0.009)
52% FC II, 46% FC III; mean duration 85.3103.9

wk; prespecified subgroup, not designed solely
to evaluate combination therapy; result driven
primarily by worsening PAH; improvements in
6MWD, FC, and hemodynamics at 24 wk
Intervention
Background
BREATHE-2;
DB, PC;
16 wk
Epoprostenol (target
dose 1216 ng/kg/min)
bosentan (125 mg BID) 2
days later
None
AMBITION;
DB, PC;
event-driven
Ambrisentan (10 mg
daily) and tadalafil (40 mg
daily); either agent alone
or together
STEP;
DB, PC;
12 wk
Trial,
Design,
Duration
SERAPHIN;
DB, PC;
event-driven
Therapy
n, WHO
Functional
Class
Outcome
Tadalafil doses studied included 2.5, 5, 10, 20, and 40 mg; results shown are for FDA-approved dose of 40 mg.
Monotherapy was also evaluated; this represents the analyses for patients receiving background therapy only.
Riociguat doses included targets of 1.5 mg TID and 2.5 mg TID; results are shown for FDA-approved dose of 2.5 mg TID regardless
of background therapy.
d
Macitentan doses included 3 mg and 10 mg daily; results shown are for the FDA-approved dose of 10 mg.
6MWD = 6-minute walk distance; AE = adverse event; DB = double-blind; ERA = endothelin receptor antagonist; FC = functional class;
LS = least-squares; NS = not significant; NYHA = New York Heart Association; PC = placebo-controlled; PDE-5 = phosphodiesterase
type 5; PVR = pulmonary vascular resistance; QID = four times daily; QOL = quality of life; TPR = total pulmonary resistance; TTCW =
time to clinical worsening.
b
c
71
III. At the end of follow-up (mean 41.2 months), all patients

were alive, with one patient undergoing successful heart-lung
transplantation. Survival in this group was estimated at 100%
at 1, 2, and 3 years, which far exceeded the expected survival
calculated from registry data of 75%, 60%, and 49% at 1, 2,
and 3 years, respectively (Sitbon 2014). Although this was not
a randomized trial, it adds to the data regarding both initial
combination therapy and the use of triple therapy over a much
longer term. Further studies are needed before this becomes
a standard of practice.
Sequential combination therapy has been more thoroughly
evaluated, but clinical response to the initial agent has not
been documented routinely, and patients have generally been
required to be clinically stable before enrollment. All available
data are from trials that have compared sequential combination therapy with continued monotherapy in this stable patient
population. The trials have also exclusively added on to the
patients preexisting therapies and have not evaluated the
effects of changing baseline therapies compared with adding
on. The bulk of the current data evaluating sequential combination therapy is from analyses of phase III studies evaluating
new agents seeking approval for the treatment of PAH, which
were not designed as combination trials per se because they
allowed patients who were either treatment naive or receiving stable background therapy to be included (see Table 3-7).
Data on adding inhaled iloprost to bosentan therapy are
conflicting, whereas adding inhaled treprostinil to either
bosentan or sildenafil has shown benefit in patients with WHO
functional class III, as previously discussed (McLaughlin
2010; Hoeper 2006; McLaughlin 2006). Oral treprostinil when
added to background therapy with an ERA and/or a PDE-5
inhibitor failed to show improvement in 6MWD at 16 weeks
in 350 patients with predominantly WHO functional class II
III symptoms. Significant issues occurred with tolerability of
treprostinil, as previously mentioned (Tapson 2012). The only
trial evaluating the addition of an oral agent to a parenteral
prostacyclin included 267 patients in WHO functional class
IIV receiving intravenous epoprostenol. Patients predominantly had class II (25%) or class III (65%) symptoms, and
patients who were randomized to the group receiving combination therapy with the addition of sildenafil 80 mg three
times daily had improved placebo-adjusted 6MWD by 28.8 m
at 16 weeks (95% CI, 13.943.8 m, p<0.001). Improvements
in hemodynamics, time to clinical worsening, and quality of life also occurred. Unlike in most other trials, patients
with worse baseline 6MWD (less than 325 m) had no benefit
(Simonneau 2008). Of note, the sildenafil dose used exceeded
that approved by the FDA.
Adding tadalafil to background bosentan therapy from the
phase III trial that led to its approval was associated with a
6MWD improvement of 23 m at 12 weeks with the approved 40
mg dose in 87 patients with WHO functional class IIV symptoms; however, most patients were class II (63%) or class III
(34%) (Barst 2011).
The PATENT-1 and SERAPHIN trials with riociguat and

macitentan, respectively, also reported outcomes of patients
receiving background therapy separately. Riociguat at the
approved 2.5 mg three times daily regimen failed to significantly improve 6MWD (+34 m, p=0.08) in the prespecified
subgroup of 191 patients with WHO functional class IIV (44%
class II, 52% class III) when added to an ERA or non-parenteral
prostanoid (Ghofrani 2013). This PATENT-1 subgroup analysis
differs from the results of the SERAPHIN trial, where macitentan 10 mg daily significantly improved time to first PAH-related
event or death (HR 0.62; 95% CI, 0.430.89; p=0.009) in 308
patients with WHO functional class IIIV (21% class II, 76%
class III) receiving background PDE-5 inhibitor or non-parenteral prostanoid (Pulido 2013).
The first large, event-driven trial to evaluate sequential
combination therapy, COMPASS-2 is pending publication.
The COMPASS-2 study evaluated adding bosentan on time
to the first morbidity and mortality event in 334 symptomatic patients receiving sildenafil background therapy.
Presentations have reported that bosentan failed to show a
significant improvement, with an observed risk reduction of
17% (p=0.25); however, 6MWD was improved by 21.8 m at 16
weeks, and the N-terminal prohormone of BNP was lower over
20 months by 23.5% (McLaughlin 2014).
TREATMENT GUIDELINES
In 2013, the fifth WSPH was held in Nice, France. The recommendations of the task forces were published the same year.
Among these recommendations was an updated treatment
algorithm (Table 3-8). In 2014, the American College of Chest
Physicians (ACCP) published a guideline and expert panel
report with recommendations on pharmacologic treatment
for PAH in adults as well. The European Society of Cardiology
(ESC) and the European Respiratory Society (ERS) provided
the most recent publication of guidelines for the treatment
of PH. These guidelines were published in September 2015.
Overall, the ACCP guidelines are more specific with their recommendations regarding which agents to add for each WHO
functional class given the outcomes from the clinical trials.
Treatment recommendations from these guidelines are
similar, but several differences exist. All three guidelines are
consistent with recommendations regarding CCB therapy. In
patients who respond to vasodilatory testing, high-dose CCB
therapy should be considered, as discussed previously. In both
the WSPH and ACCP guidelines, oral monotherapy is recommended for WHO functional class II. For WHO functional class
III, WSPH guidelines suggest any agent (oral or parenteral).
However, the ACCP guidelines are more specific and propose
oral agents for WHO functional class III. If patients have rapid
disease progression or poor clinical prognosis, the guidelines
then recommend considering parenteral prostanoid therapy.
Because the ESC guidelines were updated after publication of
the AMBITION trial, the recommendations for WHO functional
72
Table 3-8. Initial Therapy with PAH-Approved Drugs According to Functional Class (Fifth World Symposium on Pulmonary
Hypertension)
Recommendation
Grade; Evidence
WHO-FC II
WHO-FC III
WHO-FC IV
I; A or B
Ambrisentan
Bosentan
Macitentan
Riociguat
Sildenafil
Tadalafil
Ambrisentan
Bosentan
Macitentan
Riociguat
Sildenafil
Tadalafil
Epoprostenol IV
Iloprost inhaled
Treprostinil SC, inhaled
Epoprostenol (IV)
IIa; C
Iloprost IVa
Treprostinil IV
Ambrisentan
Bosentan
Macitentan
Riociguat
Sildenafil
Tadalafil
Iloprost inhaled or IVa
Treprostinil (IV, SC, or inhaled)
IIb; C
Initial combination therapy no

specific agent recommendations
Initial combination therapy no specific agent

recommendations
Available only in New Zealand.
WHO-FC = World Health Organization Functional Class.

Information from: Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll
Cardiol 2013;62:D60-72.
PRACTICAL CONSIDERATIONS
class II-III (low or intermediate risk) are slightly different than

the other guidelines. The ESC guidelines recommend either
initial monotherapy (oral for WHO functional class II; oral or
parenteral for WHO functional class III) or initial oral combination therapy for this patient population. Ambrisentan and
tadalafil received the highest-level recommendation for initial oral combination therapy based on the results of the
AMBITION trial.
In WHO functional class IV, the ESC/ERS and WSPH
guidelines are again similar. Both recommend intravenous
epoprostenol first line for the potential survival benefit, but initial combination therapy can be considered as well. Sequential
combination therapy or triple combination therapy can be
considered for all WHO functional classes if clinical response
to initial therapy is inadequate. The ACCP guidelines recommend any parenteral therapy for WHO functional class IV. If a
patient is unable or unwilling to consider parenteral therapy,
an inhaled agent plus an ERA can be considered. These guidelines also recommend adding a second or third class of agent
if response is inadequate for WHO functional class III or IV
(Taichman 2014; Galie 2013, 2015a).
Before initiating therapy with any of the PAH-specific therapies, it is important to discuss the available options with the
patient and any caregivers according to the patients WHO
functional class and patient preferences. Patients should be
informed of the costs, adverse effects, REMS requirements,
dosing frequency, and preparation issues. End-organ function and drug-drug interactions must also be considered (see
Table 3-3, Table 3-4, Table 3-5, and Table 3-6). Obtaining insurance approval is also imperative, particularly for patients who
will require hospitalization for initiation, as with the parenteral
prostacyclins, as well as for patients who may initiate oral
therapies while hospitalized. Patient assistance programs are
available and should be considered if access or financial constraints prohibit therapeutic intervention. No head-to-head
trials comparing which agent is best for initial monotherapy
are currently available, but the aforementioned considerations should guide therapy. The possible exception to this
is in patients presenting with WHO functional class IV symptoms, in which case intravenous epoprostenol is generally
considered the treatment of choice according to the WSPH
73

pressure 122/55 (mean 81) mm Hg; pulmonary capillary
A 39-year-old woman is referred for progressive

dyspnea over 6 months and RV enlargement on echocardiography. She is unable to perform simple daily activities
without developing dyspnea and has occasional dyspnea
at rest. Physical examination reveals elevated jugular
venous pressure and no lower extremity edema. Low probability for pulmonary embolism on ventilation/perfusion
scan. Right and left heart catheterization is performed
with the following hemodynamics: pulmonary arterial
wedge pressure 13 mm Hg; RA 11 mm Hg; left ventricular

ejection fraction 70%; cardiac output 3.25; cardiac index
1.83; pulmonary vascular resistance 21 Wood units; normal coronary arteries; and no response to inhaled nitric
oxide. A 6MWD was performed, and she was able to walk
308 m. What is the best option for initial therapy for PAH
in this patient?
ANSWER
The first step is to determine the patients WHO functional class, given her symptoms. The patient has
occasional symptoms at rest and is unable to perform
simple activities of daily living without symptoms, placing her in functional class IV. For this patient, in light of
the severity of her disease on presentation and the few
patients enrolled in oral therapy trials, intravenous epoprostenol is considered the drug of choice according to
guideline recommendations from ESC/ERS and WSPH in
light of potential mortality benefit. Lower levels of inconsistent evidence would support the consideration from
upfront combination therapy in this patient, adding oral
bosentan for dual therapy or bosentan and sildenafil for
triple therapy. The data for these upfront combinations
are weak; thus, single therapy with intravenous epoprostenol is the best option. The patient would need to be aware
of the logistics and responsibilities associated with this

therapy and agree to treatment. It is imperative to obtain
insurance approval before planning hospital admission
for initiation of therapy because of the significant costs
associated with treatment. Therapy could be initiated at 2
ng/kg/minute with titration in 1- to 2-ng/kg/minute increments every 1224 hours until the patient reaches a dose
of 810 ng/kg/minute while hospitalized and is adequately
educated on the ambulatory infusion pump and admixture of the medication. More frequent dose adjustment
may lead to issues with tolerability, even though package labeling may indicate that more frequent titrations
are possible. Subsequent titration in 1- to 2-ng/kg/minute
increments may be continued in the outpatient setting at
weekly intervals.
1. Barst RJ, Rubin LJ, Wong WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for
primary pulmonary hypertension. N Engl J Med 1996;334:296-301.
2. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62(25
suppl):D60-72.
care; drug interaction avoidance; and adverse effect management. It is important to evaluate the needs of the institution,
the patient population cared for, and the available institutional resources to ensure safe, consistent, and sustainable
involvement. Formulary decisions must be made in a multidisciplinary manner and include review of safety, efficacy,
expected use, prescriber experience, and cost (Table 3-9).
Because of the low incidence of PAH and lack of consensus regarding agent selection and combination, the frequency
of encountering a patient with PAH receiving a given therapy
is likely to be sporadic outside PAH care centers. This is particularly important when considering the cost of maintaining
the inventory of these drugs and the potential for product
expiration. A consignment program is available for parenteral
treprostinil (Remodulin Hospital Access Program), allowing payment for only product that is used and not returned,
which can be hugely beneficial. These cost concerns must
be weighed carefully against the risks associated with abrupt
discontinuation when products are not available from the
as well as the ESC/ERS guidelines. The parenteral prostacyclins require special care in patient selection because of the
complexity with mixing cassettes/preparing syringes several
times per week, sterile technique, manipulation of the infusion
pump, requirement for a backup pump at all times in case of
malfunction, outpatient dose titration, and troubleshooting of
pump alarms. After initiating therapy, it is important to assess
clinical response and determine the need for sequential combination therapy. Each patient will require individualization
of a goal-directed approach according to baseline status
and personal goals. An evaluation of WHO functional class,
6MWD, BNP or N-terminal prohormone of BNP, cardiopulmonary exercise testing, echocardiography, and right heart
catheterization should be considered at baseline and at 3
months after alterations in therapy.
Pharmacists have the opportunity to be involved in inpatient formulary management; medication safety; regulatory
compliance; education of patients, caregivers, and other
health care professionals; medication access; transitions of
74
inpatient supply. The use of patients own medication or emer-
Pharmacist involvement in managing adverse effects is vital
gency acquisition through specialty pharmacies should be
to assist with dose titration of parenteral prostacyclins because
considered in these situations.
this is limited by patient tolerability. Appropriate starting doses
Ensuring compliance with regulatory requirements is
of 12 ng/kg/minute should be used with confirmation of patient
important for the REMS programs associated with the ERAs
tolerability before titration. Subsequent dose increases in 1- to
and riociguat. For a listing of the requirements, which differ
2-ng/kg/minute increments no more than twice daily as inpa-
with each agent, see Table 3-3. It is important to be aware of
tient or once or twice weekly as outpatient are reasonable. This
these requirements for both inpatient and outpatient use and
titration differs significantly from what is listed in the product
to encourage the use of order sets to assist with compliance.
labeling for these agents. However, this is what is done inpatient
These agents are available only through specialty pharma-
in clinical practice when initiating therapy, given that the labeled
cies in the outpatient setting. When considering formulary
titrations are often unrealistic because of tolerability issues.
addition of any of these agents, it is important to determine
Vasodilatory adverse effects are treated supportively, includ-
whether regulatory requirements can consistently be met.
ing analgesics for headache (avoiding NSAIDs in anticoagulated
Table 3-9. Cost Comparison of Agents Approved for Use in PAH

Drug
AWP Unit Price
30-Day Supply
Bosentan; 62.5- or 125-mg tablet
$164.40
$9864
Ambrisentan; 5- or 10-mg tablet
$294.76
$8843
Macitentan; 10-mg tablet
$287.40
$8622
Sildenafil; 20-mg tablet

Sildenafil citrate (generic, multiple); 20-mg tablet
$33.31
$19.00$20.23
$2998
$1710$1821
Tadalafil; 20-mg tablet
$45.54
$2732
Riociguat; 0.5-, 1-, 1.5-, 2-, or 2.5-mg tablet
$109.18
$9827
Treprostinil; 1-mg tablet
$46.80
$2808a
Iloprost; 10- or 20-mcg/mL ampule
$128.40
$770$1156b
Treprostinil; 2.9-mL ampule (0.6 mg/mL)
$201.72
$6052c
Epoprostenol (Flolan); 0.5- and 1.5-mg vial
0.5 mg: $22.43

1.5 mg: $54.17
$3984 d,e
Epoprostenol (Veletri); 0.5- and 1.5-mg vial
0.5 mg: $27.07

1.5 mg: $54.14
$3248d,f
Treprostinil; 1-, 2.5-, 5-, and 10-mg/mL (20-mL vial)
$73.70 per mg
IV: $4975d,g
IV (glycine): $5481d,g,h
SC: $5528d,i
Oral Agents
Inhaled Agents
Parenteral Agents
For the 1-mg BID regimen only.
For the dosing range of 2.5 mcg six times daily and to 5 mcg nine times daily; a new ampule must be used for each inhalation
session; additional costs for nebulizer device and cleaning supplies.
c
A new ampule must be used each day; additional costs for nebulizer device and cleaning supplies.
d
For a dose of 20 ng/kg/min in a 70-kg patient; costs will vary according to dose and weight; additional costs for infusion pump,
tubing, and other supplies.
e
Including glycine diluent using 25,000 ng/mL cassette changing every 24 hours.
f
Using 25,000-ng/mL cassette changing every 24 hours.
g
Using 45,000-ng/mL cassette changing every 48 hours.
h
If using glycine diluent.
i
Using 3 mL of 2.5-mg/mL concentration changing every 72 hours.
AWP = average wholesale price.
From: Red Book Online [Internet]. Greenwood Village, CO: Truven Health Analytics, May 13, 2015.
b
75
patients), lower room temperature and cool cloths for flushing,

and saline nasal sprays for congestion. Gastrointestinal adverse
effects can be controlled with antiemetics for nausea and often
require pretreatment before meals or planned dose increases.
Antimotility agents such as loperamide or diphenoxylate/atropine can be used to manage diarrhea. However, there are no
documented strategies to treat jaw pain. Subcutaneous treprostinil has the unique adverse effect of infusion-site pain and
erythema that can limit both titration and decision to continue
therapy, in which case transitioning to intravenous therapy may
be warranted. Because of the variety and severity of adverse
effects with this therapeutic class, it is important to have ongoing open dialogue with the patient to reinforce the importance of
therapy compliance and expectations.
Parenteral prostanoids are included on the Institute for Safe
Medication Practices list of high-alert drugs, given the complexity of both ordering and administering these agents. Some
of the possible errors include flushing of the dedicated line,
incorrect dose from concentration and/or calculation errors,
and pump programming errors that have resulted in significant
harm, including death (Kingman 2010). Abrupt discontinuation
of therapy can be life threatening, particularly with epoprostenol because of its shorter half-life. It is important to develop
policies and use interventions to prevent these errors on both
a departmental and an institutional level. Pharmacy-specific
initiatives can include implementation of calculation double
checks, dose confirmation with the outpatient provider and/or
specialty pharmacy supplier together with confirmation by the
patient/caregiver, use of unique labels to include all pertinent
details (patient name, cassette concentration, pump flow rate),
avoidance of storing backup cassettes on the nursing unit,
and use of different-colored cassettes for the various agents.
Nursing can further assist by implementing double checks
with dose and/or cassette changes and flags on lines to avoid
flushing. Institutional policies may also address the use of standardized order sets with the electronic health record (EHR), use
of static order-specific weights that are well documented in the
EHR, restriction of patient admission to dedicated nursing units
with appropriately trained staff, protocols for treating patients
undergoing diagnostic testing with incompatible pumps (i.e.,
MRI), and, at the very least, annual education and assessment
of all involved staff.
Because of the requirement for an indwelling catheter and
admixture outside the health care setting, managing infection
is another important consideration. Antimicrobial selection
and dosing and appropriate management of the access site
are crucial if an infection occurs. Guidelines for removing
central access and duration of antimicrobial therapy should
be followed (Mermel 2009). When central access is removed,
it is appropriate to infuse the intravenous agents through a
peripheral line temporarily while awaiting replacement. For
recurrent bacteremic episodes, it is important to reinforce
aseptic technique with drug preparation. This may also warrant hospitalization for transition to subcutaneous treprostinil
to allow for a line-free interval. A sample transition schedule

from epoprostenol is provided in Table 3-10; however, individualization may be required. When transitioning between routes
of treprostinil, no dose alteration is needed, but cross-titration
is still warranted. The time interval between dose adjustments
in this setting may be as frequent as every 68 hours, depending on patient tolerability. Before considering this transition it
is imperative to discuss the infusion site reactions associated
with subcutaneous administration with the patient as this
can be a barrier to transitioning to this route. The specialty
pharmacy supplier should also be involved with transitions to
assist in drug delivery and patient education with new infusion
pumps and other differences between agents. A transition
between intravenous and subcutaneous treprostinil would
require a change in the infusion pump to administer therapy,
but drug approval for insurance coverage would be of no concern because the same stock solution is used.
CONCLUSION
Pulmonary arterial hypertension is a complex disease
state with an expanding selection of targeted therapies to
choose from. The pharmacist must consider the unique
characteristics of each of these agents in the approach to
treating this patient population. These considerations must
be incorporated with the available data supporting use, studied combination therapies, regulatory requirements, and
patient tolerability. Cost and access to therapies are of vital
Table 3-10. Sample Transition from IV Epoprostenol
to SC Treprostinil
Stepa
Epoprostenol Dose
(IV)
Treprostinil Dose (SC)
Unchanged
10% starting
epoprostenol dose
80% starting dose
30% starting
epoprostenol dose
60% starting dose
50% starting
epoprostenol dose
40% starting dose
70% starting
epoprostenol dose
20% starting dose
90% starting
epoprostenol dose
5% starting dose
110% starting
epoprostenol dose
Off
110% starting
epoprostenol dose +
additional 5%10%
increments as needed
Titration can occur every 68 hours, depending on patient

tolerability.
76
importance, as is evaluation of drug-drug interactions. The

pharmacist should also be aware of the monitoring parameters to evaluate response to therapy to determine the need
for further intervention. Most data, until very recently, evaluated 6MWD as a primary outcome in short-term trials. There
has been a push more recently to evaluate these agents in
larger-scale trials with morbidity and mortality outcomes, as
evidenced by the SERAPHIN, AMBITION, and COMPASS-2 trials. These data can be incorporated into the decision-making
process for drug therapy selection. The pharmacist can play a
vital role in managing the adverse effects and complications
associated with the pharmacotherapy of PAH.
Barst RJ, Rubin LJ, Wong WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with
conventional therapy for primary pulmonary hypertension.
N Engl J Med 1996; 334:296-301.
Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension
(AMBITION). N Engl J Med 2015; 373:834-44.
Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol
2013; 62:D60-72.
Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS
Guidelines for the diagnosis and treatment of pulmonary
hypertension: The Joint Task Force for the Diagnosis and
Treatment of Pulmonary Hypertension of the European
Society of Cardiology (ESC) and the European Respiratory
Society (ERS): Endorsed by: Association for European
Paediatric and Congenital Cardiology (AEPC), International
Society for Heart and Lung Transplant (ISHLT). Eur Resp J
2015; 46:903-75.
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Pulmonary arterial hypertension has a variety of treat-
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79
44. R.C.s primary care team decides to initiate a PAH-specific
therapy. Which one of the following is best to recommend
for R.C.?
41. A woman recently received a diagnosis of idiopathic pulmonary arterial hypertension (IPAH) because of right
heart catheterization with a mean pulmonary arterial
pressure (mPAP) of 60 mm Hg. Other potential etiologies of pulmonary hypertension have been ruled out.
Her symptoms are consistent with WHO functional class
IV. Which one of the following drugs is a class I recommendation on the basis of survival benefit for this patient
according to WSPH and ESC/ERS guidelines?
A.
B.
C.
D.
A.
B.
C.
D.
45. After a discussion with R.C.s physician, it is decided to

initiate riociguat therapy. Which one of the following has
the greatest potential to affect riociguat dosing in R.C.?
Intravenous treprostinil.
Subcutaneous treprostinil.
Intravenous epoprostenol.
Oral riociguat.
A. Smoking.
B. Diltiazem CD 120 mg daily.
C. Lisinopril 10 mg daily.
D. Glyburide 10 mg daily.
42. A 35-year-old woman recently given a diagnosis of anorexigen-associated PAH presents with WHO functional class
II symptoms. Therapy is initiated with the endothelin
receptor antagonist (ERA) ambrisentan. Her other home
drugs include furosemide 40 mg daily, ferrous sulfate 325
mg daily, and metformin 1000 mg twice daily. Which one
of the following would be most important to review with
this patient before initiating therapy?
46. Six months later, R.C. returns to the clinic. He describes

WHO functional class III symptoms with a decline in his
6-minute walk distance (6MWD). The physician decides
to add additional therapy to riociguat. Which one of the
following is best to recommend for R.C.?
A.
B.
C.
D.
A. Monthly pregnancy testing and appropriate

contraceptive options.
B. Monthly liver function test (LFT) requirements.
C. Drug-drug interactions with current medications.
D. Dose adjustments required for renal dysfunction.
Bosentan 62.5 mg twice daily.

Sildenafil 20 mg three times daily.
Tadalafil 40 mg daily.
Macitentan 10 mg daily.
47. A 45-year-old woman who recently received a diagnosis of

IPAH presents to the clinic. She describes significant worsening of her symptoms and limitations in her ability to perform
activities of daily living. She notes that she is short of breath
at rest and that her O2 requirements have increased. Which
one of the following WHO functional classes best describes
this patients presenting symptoms?
43. A patient is transferred to your institution for possible

PAH. He has a 6-month history of fatigue, weakness, and
chest pain. A transthoracic echocardiogram suggests
normal right heart function but elevated systolic PAP. A
pulmonary function test shows no evidence of underlying
lung disease. A ventilation/perfusion lung scan is normal.
Which one of the following would most assist with a diagnosis of PAH in this patient?
A.
B.
C.
D.
A. High-resolution computed tomography.

B. Right heart catheterization.
C. ECG.
D. Chest radiography.
I.
II.
III.
IV.
48. Five years ago, a 35-year-old woman with a diagnosis

of PAH began combination therapy of bosentan 125 mg
twice daily and tadalafil 40 mg daily. Since her last visit,
her symptoms, which have significantly worsened, are
now consistent with WHO functional class IV. She is short
of breath at rest, and her O2 requirements have increased.
Her 6MWD has continued to decline to 250 m, and her
transesophageal echocardiogram has revealed new right
heart dysfunction. Which one of the following is best to
recommend for this patients PAH therapy?
R.C., a 40-year-old man, presents with symptoms consistent

with WHO functional class II. After completing appropriate
testing, he is determined to have PAH. R.C.s medical history
includes diabetes, depression, hyperlipidemia, and hypertension. He is an active smoker. His current home drugs include
glyburide 10 mg daily, simvastatin 40 mg daily, citalopram 20
mg daily, diltiazem CD 120 mg daily, and lisinopril 10 mg daily.
His vital signs include blood pressure 140/88 mm Hg and
heart rate 80 beats/minute.
Intravenous epoprostenol 2 ng/kg/minute.

Treprostinil inhalation 3 inhalations four times daily.
Bosentan 62.5 mg twice daily.
Sildenafil 20 mg three times daily.
A. Discontinue bosentan and tadalafil.

B. Continue current therapy and return to the clinic in 1
year.
80
51. In addition to removing his central venous catheter, which

one of the following would be the safest and timeliest to
transition to immediately as the first intervention for M.D.
while determining a long-term plan?
C. Discontinue tadalafil; initiate riociguat at 1 mg three

times daily.
D. Add epoprostenol intravenous therapy at 2 ng/kg/
minute.
A.
B.
C.
D.
N.H., a 26-year-old woman with PAH, presents to the clinic

today. In addition to PAH, she has a past medical history of
iron-deficiency anemia and depression. She had an appointment with her gynecologist 3 months ago and had a negative
serum pregnancy test at that time. Her current drugs include
furosemide 20 mg daily and sildenafil 20 mg three times daily.
Her symptoms initially improved with sildenafil, but they have
continued to progress to WHO functional class III symptoms
during the past 2 months. It is decided to add macitentan to
N.H.s current PAH therapy.
52. If the decision was made to consider transitioning M.D.

to subcutaneous treprostinil to allow for an interval without central access, which one of the following is best
to consider or discuss with M.D. before beginning this
transition?
A. Conversion to equivalent subcutaneous dose with a
10% dose increase.
B. Availability of appropriate infusion pump.
C. Insurance approval.
D. Discussion of expected adverse effects.
49. Which one of the following would be best to obtain before

N.H. starts macitentan?
A. Hemoglobin/hematocrit.
B. LFTs.
C. Pregnancy test.
D. Drug interaction screen.
53. M.D. is successfully transitioned to subcutaneous treprostinil, and his infection is cleared. Three months later,
he returns to the clinic with infusion-site pain that has
persisted since his transition. He is interested in transitioning back to intravenous therapy but does not want to
use the ice packs that were discussed when he initially
started therapy 7 years ago. Which one of the following
would be best to recommend for M.D.?
50. At her next clinic visit, N.H. reports that her symptoms
have improved. However, you discover that she recently
began taking St. Johns wort for depression and she has
noticed significant improvement in her depression symptoms since starting St. Johns wort. Which one of the
following is best to recommend for N.H.?
A. Continue subcutaneous treprostinil.

B. Transition back to intravenous treprostinil.
C. Transition to the Flolan intravenous epoprostenol
formulation.
D. Transition to the Veletri intravenous epoprostenol
formulation.
A. Immediately discontinue macitentan and initiate

ambrisentan.
B. Discontinue St. Johns wort; discuss alternative
therapies for depression.
C. Continue current therapy because the patients
symptoms have improved.
D. Increase the dose of macitentan to 20 mg daily.
54. A woman with PAH has WHO functional class IV symptoms with a baseline 6MWD of 200 m, right ventricular
(RV) enlargement on echocardiography, and elevated
BNP. She is initiated on intravenous epoprostenol. Three
months later, she comes to your clinic. Which one of the
following is the best treatment goal when reassessing
this patients clinical status, in light of her severe symptoms at baseline presentation?
M.D., a 51-year-old man with IPAH, has been receiving intravenous treprostinil for the past 7 years. Now he is admitted
to the hospital for management of recurrent bacteremia. M.D.
first had bacteremia 6 months before this admission. Since
then, he has had two recurrences at 1-month intervals. M.D.s
inpatient drugs include treprostinil 85 ng/kg/minute intravenously (dosing weight 108 kg), warfarin 5 mg by mouth daily,
levetiracetam 1500 mg by mouth twice daily, escitalopram
20 mg by mouth daily, hydromorphone 8 mg by mouth four
times daily, trimethoprim/sulfamethoxazole 160 mg/800 mg
by mouth three times daily, and levofloxacin 750 mg intravenously once daily. M.D. is otherwise stable, but blood and
urine cultures from the outside hospital before transfer grew
Serratia marcescens.
Intravenous epoprostenol.
Peripheral intravenous treprostinil.
Subcutaneous treprostinil.
Inhaled treprostinil.
A.
B.
C.
D.
WHO functional class I symptoms.

6MWD greater than 380 m.
Normalization of BNP.
Normalization of RV size.
55. Which one of the following patients is most likely to benefit from anticoagulation therapy, given the available
evidence?
A. A 34-year-old woman with PAH secondary to
scleroderma on hormonal contraception being
treated with intravenous treprostinil therapy.
81
A. Inhaled treprostinil added to a treatment-naive

patient.
B. Inhaled iloprost added to a patient receiving
background bosentan.
C. Inhaled treprostinil added to a patient receiving
background sildenafil.
D. Inhaled treprostinil added to a patient receiving
background bosentan.
B. A 54-year-old man with PAH secondary to anorexigen

use being treated with inhaled treprostinil.
C. A 34-year-old woman with heritable PAH on
hormonal contraception being treated with
intravenous epoprostenol.
D. A 45-year-old woman with IPAH being treated with
intravenous epoprostenol.
56. Which one of the following, when added to background
therapy with a PDE-5 inhibitor, is most likely to reduce the
morbidity and mortality associated with PAH?
A.
B.
C.
D.
Oral bosentan.
Oral macitentan.
Oral selexipag.
Inhaled treprostinil.
57. A 35-year-old woman with a new diagnosis of IPAH is

referred to you for disease management. Unresponsive to
vasoreactivity testing, she has dyspnea consistent with
WHO functional class II symptoms. She currently takes
no drugs. Which one of the following initial combination
therapies would best improve this patients symptoms
and reduce her likelihood of being hospitalized?
A. Inhaled iloprost and oral bosentan.
B. Oral ambrisentan and tadalafil.
C. Intravenous epoprostenol, oral bosentan, and oral
sildenafil.
D. Inhaled treprostinil and oral macitentan.
58. Which one of the following most accurately describes
the requirements for the REMS programs for bosentan,
ambrisentan, macitentan, and riociguat?
A. Medication guide requirements are the same for all
agents.
B. Pregnancy testing requirements are the same for all
agents.
C. Any hormonal contraception may be combined with a
barrier method.
D. Baseline LFT monitoring is required for the ERAs but
not for riociguat.
59. You are asked to evaluate the addition of riociguat and
macitentan to your hospitals formulary. Which one of
the following would most likely bar the addition of either
agent?
A. Contraindications with concomitant PDE-5 inhibitor
or nitrate.
B. Inability to enforce necessary regulatory
requirements.
C. Cost of stocking and administering the medications.
D. Nursing unfamiliarity with administration.
60. Given the patient populations studied in trials of inhaled
prostacyclin therapy, which one of the following would
have the greatest potential benefit in a patient with WHO
functional class III?
82
Learner Chapter Evaluation: Pulmonary Arterial Hypertension.


Strongly agree

Agree

Neutral

Disagree

Strongly disagree
51. Evaluate the role of anticoagulation in the treatment of
pulmonary arterial hypertension (PAH).
52.

Distinguish the differences in pharmacology, pharmacokinetics, drug-drug interactions, and adverse events
between endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase
stimulators, prostacyclins, and selexipag.
4 0. The content of the chapter met my educational needs.

5 3. Design a pharmacotherapy plan for a patient with PAH

using the various monotherapies or combination therapy
on the basis of current evidence and guidelines.
4 3. The content of the chapter was relevant to my practice

5 4. Develop an approach to manage complications associated with PAH-specific therapies.
4 4. The content of the chapter was objective and balanced.

4 5. The content of the chapter is free of bias, promotion, or


4 6. The content of the chapter was useful to me.

were effective.
Questions 5759 apply to the entire Cardiology I learning

module.
4 8. The active learning methods used in the chapter were

effective.
57. How long did it take you to read the instructional materials in this module?

were effective.
58. How long did it take you to read and answer the assessment questions in this module?
59. Please provide any additional comments you may have

regarding this module:
83
Cardiology II
CARDIOLOGY II
Series Editors:
John E. Murphy, Pharm.D., FCCP, FASHP
Professor of Pharmacy Practice and Science
Interim Dean for Academic Affairs and Assessment
University of Arizona College of Pharmacy
Tucson, Arizona
Mary Wun-Len Lee, Pharm.D., FCCP, BCPS
Vice President and Chief Academic Officer
Pharmacy and Optometry Education
Chicago College of Pharmacy
Downers Grove, Illinois
Faculty Panel Chair
Sarah A. Spinler, Pharm.D., FCCP, BCPS
Professor of Clinical Pharmacy
Authors
Laura A. Siemianowski, Pharm.D., BCPS, BCCCP
Clinical Pharmacy Specialist, Critical Care
Cooper University Health Care
Camden, New Jersey
Lucia Ros, Pharm.D., AAHIVP
Clinical Pharmacy Specialist, Infectious Diseases
Cooper University Health Care
Camden, New Jersey
Reviewers
Trent G. Towne, Pharm.D., BCPS (AQ-ID)
Associate Professor of Pharmacy Practice
Manchester University College of Pharmacy,
Natural and Health Sciences
Fort Wayne, Indiana
Nancy Shenouda, R.Ph., BCPS

Author
Douglas L. Jennings, Pharm.D., FCCP,
FAHA, AACC, BCPS, AQ-Cardiology
Clinical Pharmacy Manager Heart Transplant
and Mechanical Circulatory Support
New York Presbyterian Columbia University Medical Center
New York, New York
Reviewers
Judy W.M. Cheng, Pharm.D., MPH, FCCP, BCPS
MCPHS University
Brigham and Womens Hospital
Boston, Massachusetts
Jennifer H. Ting-Chan, Pharm.D., BCPS
Clinical Pharmacist
Huntington Hospital
Pasadena, California
Clinical Staff Pharmacist

Kingman Regional Medical Center
Kingman, Arizona
Oral Anticoagulants in VTE and AF

Authors
Nancy L. Shapiro, Pharm.D., FCCP, BCPS
Operations Coordinator, Antithrombosis Clinic
University of Illinois Hospital and Health Sciences System
Director, PGY2 Ambulatory Care Residency
University of Illinois College of Pharmacy
Chicago, Illinois
Shubha Bhat, Pharm.D., BCACP
Clinical Pharmacist, Antithrombosis Clinic
University of Illinois Hospital and Health Sciences System
Clinical Assistant Professor
University of Illinois College of Pharmacy
Chicago, Illinois
Reviewers
Thaddaus Hellwig, Pharm.D., BCPS
Associate Professor
South Dakota State University College of Pharmacy
Clinical Pharmacist
Sanford USD Medical Center
Sioux Falls, South Dakota
Allison M. Mann, Pharm.D., BCPS
Clinical Assistant Professor of Pharmacy Practice
University of Wyoming School of Pharmacy
Laramie, Wyoming
The American College of Clinical Pharmacy and the authors

thank the following individuals for their careful review of the
Cardiology II chapters:
Nicola G. Dahl, Pharm.D.
Medical Writer
Kanab, Utah
Ralph H. Raasch, Pharm.D., BCPS
Associate Professor of Pharmacy (retired)
Division of Practice Advancement and Clinical Education
Eshelman School of Pharmacy
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Jeffrey T. Sherer, Pharm.D., MPH, BCPS
Department of Clinical Sciences and Administration
University of Houston College of Pharmacy
Houston, Texas
Disclosure of Potential Conflicts of Interest

Consultancies: Nancy L. Shapiro (Portola)
Stock Ownership:
Royalties:
Grants: Nancy L. Shapiro (Janssen)
Honoraria:
Other:
Nothing to disclose: Shubha Bhat, Judy W.M. Cheng, Thaddaus Hellwig, Douglas L. Jennings, Allison M. Mann, Lucia Rose, Nancy
Shenouda, Laura A. Siemianowski, Jennifer H. Ting-Chan, Trent G. Towne
ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association
(APhA). BPS is totally separate and distinct from ACCP. The Board, through its specialty councils, is responsible for specialty
examination content, administration, scoring, and all other aspects of its certification programs. PSAP has been approved by BPS
for use in BCPS recertification. Information about the BPS recertification process is available at www.bpsweb.org/recertification/
general.cfm.
Other questions regarding recertification should be directed to:
Board of Pharmacy Specialties
2215 Constitution Avenue NW
Washington, DC 20037
(202) 429-7591
www.bpsweb.org
Continuing Pharmacy Education and

Recertification Instructions
Continuing Pharmacy Education Credit: The American College of Clinical Pharmacy is accredited by the Accreditation
Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE).
Target Audience: The target audience for PSAP 2016 Book 1 (Cardiology) is pharmacotherapy specialists and advanced-level clinical pharmacy generalists caring for patients with several important cardiovascular disease considerations.
Available CPE credits: Purchasers who successfully complete all posttests for PSAP 2016 Book 1 (Cardiology) can earn 13.5 contact hours of CPE credit. The universal activity numbers are as follows: Cardiology I 0217-0000-16-001-H01-P, 7.5 contact hours;
Cardiology II 0217-0000-16-002-H01-P, 6.0 contact hours. You may complete one or all available modules for credit. Tests may
not be submitted more than one time.
Posttest access: Go to www.accp.com and sign in with your e-mail address and password. Technical support is available from
8 a.m. to 5 p.m. (Central) weekdays by calling (913) 492-3311. PSAP products are listed under My Online Products on your My
Account page.
BCPS Recertification Credit: To receive BCPS recertification CPE credit, a PSAP posttest must be submitted within the 4-month
period after the books release. The first page of each print and online book lists the deadline to submit a required posttest for
BCPS recertification credit. Only completed tests are eligible for credit; no partial or incomplete tests will be processed. Tests
may not be submitted more than once. The passing point for BCPS recertification is based on expert analysis of the items in each
posttest module.
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release. The appropriate CPE credit will be awarded for test scores of 50% and greater.
Credit Assignment and Reporting: All required posttests that meet the 50% score standard will be awarded the appropriate ACPE
CPE credit within 3 days of test submission. For statements of CPE credit, visit www.mycpemonitor.net.
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earn BCPS recertification credits. These credits will be posted within 30 days after the BCPS test deadline. For statements of CPE
credit, visit www.mycpemonitor.net.
All BCPS recertification credits are forwarded by ACCP to the Board of Pharmacy Specialties (BPS). Questions regarding the
number of hours required for BCPS recertification should be directed to BPS at (202) 429-7591 or www.bpsweb.org. The ACCP
Recertification Dashboard is a free online tool that can track recertification credits as they are earned through ACCP and schedule
new opportunities for credits from upcoming ACCP professional development programs.
Posttest answers: The explained answers with rationale and supporting references will be posted 1 week after the BCPS test
deadline and will be available to anyone who has submitted a posttest or waived his or her right to receive credit (see below) from
a posttest. Go to www.accp.com and sign in with your e-mail address and password. Click the PSAP book on your My Account
page and you will see a link to the explained answers.
Test Waivers: To access the explained answers without submitting a posttest, sign in to your My Account page, select the PSAP
book, and click on the waiver link for that module. By completing the waiver form for a module, you waive the opportunity to
receive CPE credit for that module. After you submit a waiver, you will see a link to the PDF file that contains the answers for the
module you waived. Answers will be available starting 1 week after the BCPS test deadline.

By Douglas L. Jennings, Pharm.D., FCCP, FAHA, AACC, BCPS, AQ-Cardiology
Reviewed by Judy W.M. Cheng, Pharm.D., MPH, FCCP, BCPS; and Jennifer H. Ting-Chan, Pharm.D., BCPS
LEARNING OBJECTIVES
1.
Classify common heart valve disorders and distinguish when surgical intervention is indicated.
2.
Distinguish between traditional and transcatheter aortic valve replacement.
3.
Design appropriate pharmacologic thromboprophylactic regimens for patients after aortic valve replacement or patients
with mitral valve prostheses.
4. Evaluate the role of medical therapy for patients with symptomatic aortic stenosis.
5.
Justify adjunctive pharmacotherapy in patients with symptomatic mitral valve regurgitation.
ACC/AHA
ACCP
ACE
ARB
AS
AVR
COPD
LV
MR
MS
MVR
NYHA
STS
TAVR
VHD
VKA
American College of Cardiology/

American Heart Association
Physicians
Angiotensin-converting enzyme
Angiotensin receptor blocker
Aortic stenosis
Aortic valve repair
Chronic obstructive pulmonary
disease
Left ventricle
Mitral regurgitation
Mitral stenosis
Mitral valve replacement
New York Heart Association
Society of Thoracic Surgeons
Transcatheter aortic valve
replacement
Valvular heart disease
Vitamin K antagonist
INTRODUCTION
Heart valve disorders represent a prevalent constellation of pathologies, each one associated with significant potential for morbidity and
mortality. The epidemiology, natural history, and treatment options
for each heart valve condition vary according to the type of lesion
(e.g., regurgitant versus stenotic) and location of the lesion (e.g., aortic versus mitral). Many etiologies contribute to the development of
valvular heart disease (VHD), including congenital defects (bicuspid
aortic valve), infections (rheumatic fever and bacterial endocarditis),
and coronary artery disease (papillary muscle rupture). However,
senile calcification remains the most common culprit in most types
of VHD. Data from the Cardiovascular Health Study found that aortic
sclerosis (a precursor to aortic stenosis [AS]) was present in 20% of
patients aged 6574 years, in 35% of those aged 7584 years, and
48% of those 85 years or older (Carabello 2009).
Valvular heart disease is often identified by appreciation of a heart
murmur during cardiac auscultation; however, the condition may not
be diagnosed in patients without regular primary care screenings until
such patients are overtly symptomatic (i.e., with chest pain or shortness of breath). On discovery of a valvular lesion, a detailed history
and physical examination are warranted because many patients may
mask symptoms by gradually limiting their activities of daily living.
Imaging studies (e.g., transthoracic echocardiography, transesophageal echocardiography) are essential for confirming the diagnosis
and characterizing the effects of the valve lesion on cardiac geometry
and function. Additional testing (e.g., coronary angiography, cardiac
91
use of drug therapy is germane to successful management of

VHD, pharmacists have many opportunities to contribute to
the care of these patients.
magnetic resonance imagining) may be indicated according

to the presence of relevant comorbidities.
After completion of the diagnostic evaluation, staging
of the valvular lesion is needed to devise a treatment and
monitoring plan. The most recent VHD guidelines from the
American College of Cardiology/American Heart Association
(ACC/AHA) have created a staging system similar to the one
used for heart failure (Table 1-1). In general, patients in stage
A or B should receive risk factor modification and close monitoring, whereas those with more advanced disease should be
evaluated for possible surgical intervention. The overall goals
of surgery are to palliate symptoms, prolong survival, and
minimize the risk of VHD-related complications (e.g., ventricular dysfunction, pulmonary hypertension, atrial fibrillation
[AF]). Any surgical treatment modality carries the potential for
adverse consequences such as bleeding, stroke, and death;
therefore, all surgical candidates must also undergo a thorough preoperative risk assessment. The Society of Thoracic
Surgeons (STS) online risk calculator is a tool that can approximate the short-term risk associated with open-heart surgery.
Lifelong antithrombotic pharmacotherapy will be necessary for most patients after any type of valve replacement
surgery. Ancillary drug therapy (e.g., diuretics, vasodilators)
can benefit those with symptomatic VHD. Given that optimal
AORTIC STENOSIS
Aortic stenosis, which results from the slow accumulation of
calcium within the cusps of the aortic valve, has emerged as
the most common valvular disorder in developed countries.
Although age is the predominant contributor to the development
of AS, many traditional cardiac risk factors (e.g., hypertension,
hyperlipidemia, male sex) can also play roles. Patients without
overt symptoms can have good prognoses even in the setting
of severe valvular obstruction; however, the prognosis for those
with severe symptomatic disease (i.e., stage D) is quite dismal.
With an annual mortality rate of 25%, symptomatic AS requires
terminal-condition surgical intervention.
The classic clinical symptoms of ASin the forms of syncope, angina, and heart failureoccur when the left ventricle
(LV) can no longer overcome the excessive afterload imposed
by the malfunctioning aortic valve. Typically, clinical manifestations begin when the aortic valve area has decreased to less than
1 cm2. Cardiac auscultation of the patient with AS should reveal
a classic crescendodecrescendo murmur that peaks late in
systole and often radiates up to the neck. Additional physical
features of AS can include pulsus parvus et tardus (a diminished
and delayed rise in the carotid upstroke) and splitting of the S2.
Appreciation of any of those anomalous findings should prompt
or transesophageal echocardiography, which will provide the
necessary information (i.e., LV size and systolic function) for
determining prognosis and the timing of surgical intervention.

with the following:
General knowledge of cardiovascular anatomy and
physiology
Traditional Surgery
Common comorbid conditions associated with

development of valvular heart disease (e.g.,
hypertension)
The current ACC/AHA guidelines advocate for surgical aortic

valve replacement (AVR) in patients with AS who are in stage C2
with reduced ejection fraction (less than 50%) or who are in stage
D. (Both recommendations are class I, level-of-evidence A.) In
addition, according to specific echocardiographic criteria (class
IIa, levels-of-evidence B and C), several recommendations also
suggest intervention in selected patients in stage C1. Based on
those strong recommendations, more than 60,000 aortic valve
surgeries are performed in the United States each year (Du 2014).
Pharmacology of antithrombotic agents

The various cardiovascular medications used to
treat symptoms of valvular heart disease (e.g.,
vasodilators, diuretics, -blockers)
ADDITIONAL READINGS
Choice of Prosthesis
The decision between a mechanical and a bioprosthetic aortic prosthesis is complicated and must be made only after
thorough assessment of a patients clinical situation and lifestyle preferences. Many valves have been developed (Table
1-2), and details regarding their different structural nuances
and long-term clinical outcomes are beyond the scope of this
chapter. The ideal prosthetic heart valve should provide restoration of normal valve function and complete alleviation
of symptoms, be easy to implant with minimal postoperative
complications, last a lifetime, and require no long-term maintenance therapies. Unfortunately, currently available devices
Vahanian A, Alfieri O, Andreotti F, et al. Guidelines

on the management of valvular heart disease
(version 2012). Eur Heart J 2012;33:2451-96.
Whitlock RP, Sun JC, Fremes SE, et al.
Antithrombotic and thrombolytic therapy for
valvular disease: antithrombotic therapy and
prevention of thrombosis, 9th ed: American College
of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest
2012;141(Suppl):e576Se600S.
92
Table 1-1. General Staging for Heart Valve Diseases

Stage
Definition
Valve Structure
Symptoms
Risk factors present for

development of VHD
Normal
Absent
Progression
Mild to moderategrade lesion
Absent
C1
Asymptomatic Severe
Severe-grade lesion without evidence of ventricular

decompensation
Absent
C2
Asymptomatic severe
Severe-grade lesion with evidence of ventricular

decompensation (either left, right, or both)
Absent
Symptomatic severe
Severe-grade lesion with evidence of ventricular

decompensation (either left, right, or both)
Present
VHD = valvular heart disease

Information from Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular
heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am
Coll Cardiol 2014;63:e57e185.
fall short of those expectations. Bioprosthetic valves are vulnerable to structural deterioration with time, and mechanical
valves are hampered by the bleeding risk and the nuisance
associated with chronic anticoagulation (Figure 1-1).
Those major differences between valve types are reflected
in the most recent iteration of the ACC/AHA guidelines, which
advocate for a bioprosthesis in patients older than 70 years
and for a bileaflet mechanical valve in those aged less than
60 years (Figure 1-2). For patients aged 6070 years, the
guidelines defer to the discretion of the treating clinician.
A recent retrospective cohort of 4253 patients aged 5069
years who underwent primary isolated AVR demonstrated
similar rates for actuarial 15-year survival in the bioprosthesis group (60.6%) compared with the mechanical prosthesis
group (62.1%) (Chiang 2014). Even though the 15-year cumulative rate of reoperation was higher with bioprosthetic valves
(12.1 versus 6.9%; HR 0.52; 95% CI, 0.360.75), the cumulative incidence of major bleeding was higher in the mechanical
prosthesis group (13 versus 6.6%; HR 1.75; 95% CI, 1.272.43).
These data suggest that preference can be given to bioprosthetic AVR in most middle-aged patients.
Table 1-2. Examples of Available Heart Valves

Type
Model
Bioprosthetic
Porcine
Hancock I and II
Intact
CarpentierEdwards
Freestyle
Bicor
Bovine
CarpentierEdwards
Perimount
IonescuShiley
Mitroflow
Caged ball
StarrEdwards
Tilting disc
BjorkShiley
Medtronic Hall
Ultracor
Bileaflet
St. Jude
On-X
Carbomedics
EdwardsDuromedics
Baxter TEKNA
Mechanical
Drug Therapy for Thromboprophylaxis
Information from Rahimtoola SH. Choice of Prosthetic Heart
All patients with prosthetic heart valves will require lifelong

antithrombotic therapy to combat the inherent thrombotic risk
those devices pose. Thrombogenicity results from the hemobiologic incompatibility of the intravascular prosthetic material,
perivalvular zones of turbulent flow, and platelet activation
resulting from areas of high shear stress. Without thromboprophylactic pharmacotherapy, patients are susceptible to clotting
of the valve itself as well as embolic phenomena (e.g., stroke,
peripheral systemic embolism). In addition to patient-specific
factors like AF and hypercoagulable conditions, the main risk
determinants of valve-related thromboembolism are the type
and location of the prosthesis.
Classification
Valve in Adults. J Am Coll Cardiol 2010;55:41326.
Oral Anticoagulation and Antiplatelet Therapy
Bioprosthetic valves are significantly less thrombogenic than

their mechanical counterparts, and the rate for thromboembolism with an aortic bioprosthesis is around 1.9% per year
(Colli 2007). In accordance with that relatively forgiving risk
profile, most guidelines suggest that aspirin monotherapy
confers sufficient protection for patients after bioprosthetic
AVR (Table 1-3). The major disagreement between experts
93
Figure 1-1. Risks of major bleeding and reoperation from structural valve failure according to valve type and patient
age at implantation in aortic valve replacement patients.
Information from van Geldorp MWA, Jamieson WRE, Kappetein AP, et al. Patient outcome after aortic valve replacement with
mechanical or biological prosthesis. Weighing lifetime anticoagulant-related event risk against reoperation risk. J Thorac
Cardiovasc Surg 2009;137:881-6.
The rate of thromboembolism in patients with bileaflet

mechanical AVR who are prescribed a regimen of a VKA and
antiplatelet therapy is estimated to be 0.53% per patient-year
(Nishimara 2014). In the past, clinicians aimed for a target INR
of 3.04.5 in mechanical valve recipients. The current standard of care became established with the publication of data
from the AREVA group, which showed similar rates for thrombotic events, with reductions in bleeding by targeting INR
values of 2.03.0 (Acar 1996).
More recently, investigators explored even lower-target
INR ranges in patients with newer mechanical prosthesis.
The Prospective Randomized On-X Anticoagulation Clinical
Trial randomized 375 AVR recipients of the On-X mechanical valve to VKA therapy with an INR goal of 2.03.0 (control)
or 1.52.0 (intervention). All patients received aspirin 81 mg
daily, and those in the intervention group were maintained at
an INR goal of 2.03.0 for the first 3 postoperative months.
After a mean follow-up of 3.82 years, the intervention group
experienced significantly lower major (1.48% vs. 3.26% per
patient-year; p=0.047) and minor (1.32% vs. 3.41% per patientyear; p=0.021) bleeding events. Thromboembolic rates were
low and did not differ significantly between groups (2.67% vs.
surrounds the use of a vitamin K antagonist (VKA) for the

first 36 months after valve implantation. Although that regimen seems logical given the heightened thrombotic risk in
the immediate postoperative period while the new valve is
endothelializing, data from small randomized trials have not
shown any benefit from short-term postoperative therapy with
a VKA. However, a more recent retrospective analysis from a
Danish registry of 4075 patients found an estimated rate of
7 strokes per 100 person-years in patients not treated with
VKA versus 2.69 in those receiving such therapy (HR, 2.46;
95% CI, 1.095.55) (Mrie 2012). The authors also report an
associated reduction in cardiovascular death with VKA therapy. The findings are noteworthy, but they are limited by the
omission of aspirin (the current standard of care) in the control patients, which biases the results in favor of the warfarin
group. Furthermore, rates of bleeding were actually lower
in the VKA-treated patients, which suggests residual confounding in the analysis. Therefore, although these data are
provocative, additional studies are required before routine use
of short-term VKA therapy should be considered in patients
undergoing bioprosthetic AVR.
94
1.59%; 95% CI, 0.813.49). Those preliminary data are encouraging and suggest that newer valve technology may permit
lower-intensity anticoagulation, but at present, clinicians
should not routinely deviate from the current standard regimen for patients with mechanical prostheses.
Even though an INR target of 2.03.0 remains the standard for most patients after mechanical AVR, the ACC/AHA
guidelines provide consideration for more-aggressive anticoagulation in patients with other risk factors for thromboembolism
(see Table 1-3). The American College of Chest Physicians
(ACCP) guidelines acknowledge that the presence of those
comorbidities does enhance thrombotic risk; however, the
guidelines also find no data to support the notion that higher
INR target values are effective in abating that harm. Therefore,
those experts do not recommend routinely targeting higher
INR values in patients with additional risk factors. In the face
of those discordant recommendations, clinicians must make
individual decisions regarding INR intensity based on their individual risk assessments for bleeding and thrombosis.
In addition to VKA therapy, all patients who have undergone mechanical AVR should receive concomitant daily
aspirin. This regimen is strongly endorsed by both the ACC/
AHA (75100 mg/day) and ACCP guidelines (50100 mg/day)
(Nishimura 2014, Whitlock 2012). The addition of aspirin 100
mg daily to oral VKA therapy decreases the annual incidence
of major embolism or death (1.9% vs. 8.5%; p<0.001), stroke
(1.3% vs. 4.2%; p<0.027), and overall mortality (2.8% vs. 7.4%;
p<0.01). Although those benefits do come at the expense of
a slight increase in minor bleeding rates, all patients with
mechanical heart valves should receive aspirin in addition to
VKA unless a strong contraindication to such therapy exists.
Use of Parenteral Anticoagulation Bridging
Bioprosthetic valves in the aortic position do not carry sufficient thromboembolic risk to require administration of a
parenteral anticoagulant. Patients with mechanical aortic
valves, however, may need periprocedural bridging depending on the clinical scenario. In general, procedures in which
Valve Replacement
Age > 70 years
Age < 60 years
Short life expectancy or CI to OAC
Atrial fibrillation or previous VTE
No
Short life expectancy or CI to OAC
Yes
No
Yes
High bleeding risk or

CI to OAC
No
Bioprosthetic valve
Yes
Mechanical valve
Bioprosthetic valve
Figure 1-2. General approach to prosthetic valve selection.

VTE = venous thromboembolism; CI = contraindication; OAC = oral anticoagulant
Coll Cardiol 2014;63:e57-185.
95
Transcatheter Aortic Valve Replacement
bleeding can be controlled easily (e.g., cataract removal,

dental extraction) should be performed with uninterrupted
VKA therapy. The ACC/AHA guidelines discourage the use
of parenteral bridging during temporary interruptions of
VKA therapy, provided the patient has neither an older-generation valve (e.g., StarrEdwards) nor any additional risk
factors for thromboembolism (i.e., atrial fibrillation). If those
risk factors are present, then parenteral bridging with either
intravenous unfractionated heparin (UFH) or subcutaneous
low-molecular-weight heparin (LMWH) is advised (class I, level-of-evidence C).
The ACCP guidelines recommend parenteral bridging
with either subcutaneous UFH (prophylactic dose) or LMWH
(either prophylactic or therapeutic dose) during warfarin initiation after mechanical AVR surgery (level 2C). The nonspecific
nature of that recommendation is based on the very limited evidence available on the topic. One of the largest observational
studies compared patients who received VKA monotherapy
(n=245) with patients who also received enoxaparin 1 mg/kg
every 12 hours starting 6 hours after surgery (n=293) (Talwar
2004). The incidence of prosthetic valve thrombosis was significantly lower in patients who received enoxaparin (6.1% vs.
2.0%, p<0.01), and there was no significant difference in bleeding. Despite those positive findings, this was a nonrandomized
analysis with a relatively small sample size; therefore, a global
assessment that includes both surgical bleeding and thrombotic risk should be implemented on a case-by-case basis
when considering postoperative bridging in patients receiving
mechanical aortic valves.
Traditional AVR can markedly improve symptoms and extend

life in those with severe AS, but many such patients are not
candidates for open-heart surgery because of the unacceptably high risk of peri- and postoperative morbidity and
mortality. Transcatheter aortic valve replacement (TAVR) has
emerged as a viable treatment alternative for patients with
unacceptable surgical risk. In the pivotal PARTNER A trial,
TAVR was compared with traditional surgical AVR in patients
with severe symptomatic AS. That trial found similar rates of
1-year mortality for TAVR versus traditional surgery (24.2% vs.
26.8%; HR, 0.93; 95% CI, 0.711.22, p=0.001 for noninferiority). Although there was an increased risk of stroke at 1 year
with TAVR (8.3% vs. 4.3%; p=0.04), it was offset by reduced
incidence of bleeding (14.7% vs. 25.7%; p<0.01). Two-year outcomes from that cohort demonstrated similar mortality and
stroke risk between TAVR and traditional AVR.
In the PARTNER B trial, TAVR was compared with medical
therapy in patients who were deemed inoperable because of
unacceptable risk profiles (Leon 2010). Though the overall surgical risk was high in this cohort (STS score, 11.6% 6.0%),
many patients had low STS scores but specific anatomic or
clinical factors that contributed to the surgeons assessment
that they were not suitable candidates for surgery. Those factors included a porcelain aorta (15.1%), a chest wall deformity
or deleterious effects of prior chest wall irradiation (13.1%),
chronic obstructive pulmonary disease (COPD) requiring
supplemental oxygen (23.5%), and frailty, as defined according to prespecified criteria (23.1%). At 1 year, the rate of death
Table 1-3. Recommended Antithrombotic Therapy after Aortic Valve Replacement
Valve Type and Location
ACCP Guidelines
ACC/AHA
Bioprosthetic AVR
ASA 50100 mg daily for at least 3 months (2C)a
ASA 75100 mg daily (IIb, B)

Consider warfarin INR goal 2-3 for
first 3 months (IIb, B)
Mechanical AVR
Warfarin INR goal 23 (1B)c
Warfarin INR goal 23 if low risk (IB)c

Warfarin INR goal 2.53.5 if high risk (IB)b,c
Aortic valve repair
ASA 50100 mg daily (2C)
Not addressed
For patients in normal sinus rhythm with no other indications for warfarin.
High-risk includes those with atrial fibrillation, previous thromboembolism, or left-ventricular dysfunction, hypercoagulable
condition or with either StarrEdwards valves or mechanical disc valves (other than Medtronic Hall prostheses).
c
Aspirin should be added to warfarin for all patients with mechanical heart values unless the bleeding risk is unacceptably high.
ACC = American College of Cardiology; ACCP = American College of Chest Physicians; AHA = American Heart Association; ASA =
aspirin; AVR = aortic valve replacement; MVR = mitral valve replacement
Information from Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and Thrombolytic Therapy for Valvular Disease.
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012;141(Suppl):e576Se600S; Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the
management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57e185.
b
96
PARTNER I, and it adds a 29-mm size to the current armamentarium. A recent randomized trial conducted a head-to-head
comparison between the SAPIEN XT and the CoreValve in 240
patients with severe AS and high surgical risk (Abdel-Wahab
2014). Rates of mortality and major bleeding between the
two devices were similar; however, procedural success was
higher in the SAPIEN XT groupmostly because of lower rates
of residual moderate to severe aortic regurgitation. Stroke
occurred in seven patients (5.8%) in the balloon-expandable
valve group (three major and four minor strokes) and three
patients (2.6%) in the self-expandable valve group (all major
strokes, RR, 2.26; 95% CI, 0.608.52). Also, more patients in
the CoreValve group required permanent pacemaker placement (37.6 vs.17.3%; p=0.001).
from any cause was 30.7% with TAVR compared with 50.7%
with standard therapy (HR 0.55; 95% CI, 0.400.74; p<0.001).
Those benefits persisted with time, and at 2 years, the rate
of rehospitalization was 35% in the TAVR group and 72.5% in
the standard-therapy group (p<0.001). The rate of stroke was
higher after TAVR than with medical therapy (13.8% vs. 5.5%;
p=0.01), which was driven in the first 30 days by the occurrence
of more ischemic events in the TAVR group (6.7% vs. 1.7%,
p=0.02) and beyond 30 days by the occurrence of more hemorrhagic strokes in the TAVR group (2.2% vs. 0.6%, p=0.16).
Available Prostheses
The PARTNER I trials (both the A and B cohorts) implanted

the SAPIEN heart valve system (Edwards Lifesciences, Irvine,
CA), which consists of a balloon-expandable, stainless-steel
stent frame housing a trileaflet bovine pericardial valve within
a deflectable delivery catheter (Figure 1-3). The system is
inserted under general anesthesia either by way of a percutaneous transfemoral arterial approach or through direct
transapical puncture of the left ventricle by a limited anterior
thoracotomy. The CoreValve (Medtronic Inc., Minneapolis,
MN), an alternative transcatheter bioprosthesis comprising a
self-expanding nitinol frame and trileaflet porcine pericardial
valve, has approval from the FDA based on favorable data in
critical patients with AS and high operative risk (Adams 2014).
After a preliminary review of data from the ongoing
PARTNER II study, the second-generation SAPIEN XT valve
(Edwards Lifesciences) was approved in June 2014. This
device has a lower profile than the successor valve used in
Place in Therapy
Since completion of the PARTNER trial, data from several

large registries have supported the benefits of TAVR. Most
recently, the Centers for Medicare & Medicaid Services published database data that consisted of 12,182 patients from
299 centers in the United States (Holmes 2015). This registry confirms the positive findings from the above clinical
trials and reported 1-year rates of 23.7 and 4.1%, respectively,
for mortality and stroke. Although long-term (greater-than5-year) follow-up data are not yet available, the ACC/AHA
guidelines recommend TAVR for patients who are candidates
for AVR with prohibitive surgical risk (class I, level of evidence
B) and for those with high surgical risk (class IIa, level of evidence B). Transcatheter aortic valve replacement should not
Figure 1-3. Currently available transcatheter heart valves.

A, The Edwards SAPIEN balloon-expandable valve (Edwards Lifesciences, Irvine, CAalifornia) incorporates a stainless steel frame,
bovine pericardial leaflets, and a fabric sealing cuff. B, The SAPIEN XT (Edwards Lifesciences) uses a cobalt chromium alloy frame
and is compatible with lower profile delivery catheters. C, The Medtronic CoreValve (Medtronic, Minneapolis, MNinnesota)
incorporates a self-expandable frame, porcine pericardial leaflets, and a pericardial seal.
Reprinted with permission from J Am Coll Cardiol 2012;60:48392.
97
warfarin for 1 month (Amat-Santos 2012). Despite the use of

anticoagulation therapy, rates of stroke and systemic embolism remained higher in the AF patients than in those without
AF (13.6% vs 3.2%, OR 4.79; 95% CI, 1.1420.15; p=0.021).
The role of concomitant antiplatelet therapy in new-onset AF
after TAVR is also murky. In Amat-Santoss previous paper,
most patients received dual therapy with warfarin and aspirin. Similarly, in the U.S. CoreValve trial, those with indications
for anticoagulation were treated with warfarin and aspirin (i.e.,
no clopidogrel). Pending publication of additional data, those
caring for TAVR patients who develop indications for oral anticoagulation or who have indications before the procedure
must make decisions about anticoagulation and antiplatelet
therapy according to each patients individual risks for both
bleeding and stroke.
be pursued in patients with limited life expectancy caused by

comorbidities such as advanced age (greater than 95 years),
end-stage renal disease, severe COPD, or STS scores greater
than 15%. Finally, very recent evidence suggests that TAVR
may be an acceptable alternative in patients with lower surgical risk, but its use in such patients cannot be endorsed at this
time (Thyregod 2015).
Although TAVR is a life-prolonging therapy for those with

severe AS, thromboembolic complicationsparticularly
strokepose significant clinical challenges. The risk for
stroke arises not only from potential clot formation on the
prosthetic material but also from mechanical trauma to the
calcified native valvewith subsequent debris embolization
during the procedure. As discussed previously, data from the
PARTNER trial reveal that the incidence of ischemic stroke
after TAVR procedures is most pronounced in the first 30
postoperative days.
Because these valves are bioprosthetic, there is no need
for anticoagulation therapy after implantation. Rather, antithrombotic therapy often involves a regimen of aggressive
antiplatelet therapy. In the PARTNER trial, patients received
6 months of dual antiplatelet therapy with aspirin 75100 mg
daily and clopidogrel, followed by lifelong aspirin therapy. In
the CoreValve study, dual antiplatelet therapy with aspirinat
least 81 mg dailyand clopidogrel was recommended for 3
months after the procedure, followed by aspirin or clopidogrel
monotherapy indefinitely (Adams 2014). The guidelines of the
ACC/AHA suggest that clopidogrelin addition to aspirin
may be reasonable for the first 6 months after TAVR (class
IIb, level-of-evidence C), the most recent guidelines from the
ACCP recommend 3 months of dual antiplatelet therapy after
a TAVR procedure (level 2C recommendation).
Adding further uncertainty to the issue, randomized trials
that explore the potential risks and benefits of adding clopidogrel post-TAVR are lacking. One small study randomized
patients implanted with the CoreValve to 3 months of clopidogrel plus aspirin 100 mg daily or aspirin alone. No significant
differences in the rates of major adverse cardiac events
were noted between the two groups at both 30 days (13%
vs. 15%, p=0.71) and 6 months (18% vs. 15%; p=0.85) (Ussia
2011). Rates of ischemic stroke were also similar between the
dual-therapy and aspirin-only groups. Because of this trials
small sample size, additional studies are needed to determine
the role of clopidogrel for prevention of ischemic stroke in
patients undergoing TAVR.
New-onset AF can afflict as many as 30% of those undergoing TAVR procedures, which is particularly concerning given
the risk of ischemic stroke in these patients (Amat-Santos
2012). Unfortunately, data describing the effectiveness of oral
anticoagulation in the TAVR population are very limited. In
one published cohort of 138 patients, 44 developed postoperative AF, of whom 37 received intravenous heparin along with
Medical Management
Severe symptomatic aortic stenosis is a lethal outflow obstruction that can only be managed with mechanical relief through
valve repair or replacement. No medical treatment is effective
for slowing disease progression in patients with early disease
or for prolonging survival in advanced-stage patients. Despite
the role of vascular inflammation and hyperlipidemia in the
pathophysiology of AS, many randomized trials in this population have demonstrated that statin therapy does not attenuate
disease progression or improve clinical outcomes. As such,
the ACC/AHA guidelines advocate against the routine use of
statin therapy in patients with calcific AS unless another compelling indication exists (e.g., coronary artery disease) (class
III, level of evidence A).
As the aortic valve narrows and the area of the outflow
tract diminishes, pressure overload worsens within the LV.
Preservation of cardiac output thus depends on compensatory left-ventricular hypertrophy. By increasing left-ventricular
afterload, uncontrolled hypertension can work in concert with
valve obstruction to exacerbate that physiology of pressure-overload hypertrophy. Uncontrolled hypertension is also
a risk factor for adverse clinical events in these patients. In
1616 patients with asymptomatic AS in the SEAS (Simvastatin
Ezetimibe in Aortic Stenosis) study, hypertension was associated with a 56% higher rate of ischemic cardiovascular events
and a 2-fold increased mortality rate (both p<0.01). The ACC/
AHA guidelines thus provide a strong recommendation (class
I, level of evidence B) for treatment of hypertension in those at
risk of developing AS (i.e., stage A) or those with asymptomatic disease (i.e., stages B and C).
Vasodilators are attractive options for improving the transvalvular gradient and palliating the symptoms of severe
AS. Unfortunately, those agents represent a potential double-edged sword in the AS physiology setting, because any
sudden decrease in systemic vascular resistance could result
in an acute decline in cardiac output across the obstructed
aortic valve. Because of those theoretical concerns, angiotensin-converting enzyme (ACEs) inhibitors and angiotensin
98
Primary MR is characterized by damage to the mitral apparatus, whereas secondary MR occurs when alterations in
cardiac geometrysuch as a dilated cardiomyopathyimpair
the function of a structurally intact valve. Mitral valve prolapse is the most common cause of primary MR in developed
countries; it results from chronic degenerative (myxomatous)
changes in the papillary muscles. Like MS, severe MR can produce debilitating symptoms such as exertional dyspnea and
fatigue, as well as increases in left atrial pressure, pulmonary
artery hypertension, and AF.
receptor blockers (ARBs) have historically been contraindicated in the clinical AS setting. However, because the presence
of heart failure foretells a dim prognosis in the setting of AS,
the known benefits of ACE inhibitors and ARBs may supersede that possible contraindication.
Limited data supporting that notion come from a registry of
2117 patients with mostly mild to moderate AS, of whom 699
received ACE inhibitors or ARBs (Nadir 2011). During a mean
follow-up of 4.2 years, patients treated with those agents
had significantly lower all-cause mortality (HR, 0.76; 95% CI,
0.620.92; p<0.0001) and fewer CV events (HR 0.77; 95% CI,
0.650.92; p<0.0001). Based on those data, it would seem
prudent to not withhold ACE inhibitor therapy based simply
on the presence of AS. Furthermore, this study suggests it is
reasonable to give a trial of these agents in those with mild
to moderate valvular disease who are not yet candidates for
surgery. Finally, given the known salutatory effects of these
drugs in patients with heart failure, ACE inhibitors should
also be considered in patients with AS and reduced ejection
fractions.
In addition to ACE inhibitors, ancillary pharmacotherapy
may involve diuretics for volume overload or -blockers for
concomitant coronary artery disease. But because a rapid
decrease in preload may cause hypotension, diuresis must
be done conservatively if the patients left ventricular chamber is reduced due to hypertrophy. Similarly, -blocker therapy
must also be done cautiously, because negative inotropy in
the face of an overloaded LV could be harmful. It is therefore
imperative to always start with low doses of any ancillary drug
therapy in the setting of significant AS, up-titrating only if the
patient remains clinically stable.
Traditional Surgery
The current ACC/AHA guidelines provide strong recommendations (class I, level of evidence B) for surgical mitral valve
replacement (MVR) in patients with primary MR and severe
symptoms (stage D); surgery should also be considered in
those with MR who also have evidence of left-ventricular
dysfunction but no symptoms (stage C2). If possible, mitral
valve repair is preferred over MVR, because preservation
of the native valve apparatus can reduce mortality, improve
left-ventricular function, and abrogate the need for long-term
anticoagulation. For those with secondary MR, surgery is
indicated only when patients are persistently symptomatic
despite guideline-directed medical therapy for the underlying
cardiomyopathy (class IIb, level of evidence B).
Although MVR is clearly warranted in those with advanced
rheumatic MS, the indication for surgical intervention in those
with senile calcific disease is much less clear. The number of patients with nonrheumatic MS is so small that little
information is available concerning the natural history of the
disorder. Furthermore, the presence of severe mitral annular
calcification poses a specific surgical challenge because calcification and the narrowing of the orifice can cause problems
with secure attachment of the prosthetic valve. Given those
limitations, the ACC/AHA guidelines make no specific recommendations for MVR in the setting of nonrheumatic MS. In
general, intervention should be delayed until symptoms are
refractory to medical therapy.
MITRAL VALVE DISEASE

In the developed world, mitral valve disorders occur far
less often than aortic stenosis. For instance, roughly 80%
of mitral stenosis can be attributed to rheumatic heart disease (common in developing countries), whereas only 3% of
mitral stenosis results from senile calcification of the mitral
annulus (Horstkotte 1991). Although a relatively uncommon
VHD, mechanical obstruction of the mitral valve can lead to
increased pressure within the left atrium, pulmonary vasculature, and right side of the heart. Unlike with AS, the LV is
unaffected in the setting of isolated MS. Barring surgical correction, patients with MS can eventually develop disabling
symptoms such as dyspnea, hemoptysis, thromboembolism,
AF, and right-side heart failure.
Mitral regurgitation (MR) can arise from abnormalities of
any part of the valve apparatus, including the leaflets, annulus,
chordae tendineae, and papillary muscles. Trivial or physiologic MR is detectable with sensitive Doppler techniques in
up to 70% of healthy adults, whereas moderate or severe disease is far less common and can be found in roughly 1.9%
and 0.2%, respectively, of the U.S. population (Jones 2001).
Choice of Prosthesis
Factors influencing the choice between a bioprosthetic or

a mechanical MVR are very similar to those previously discussed with regard to AVR (see Figure 1-2). There is much
less information describing structural valve deterioration
after MVR than information describing structural valve deterioration after AVR; however, the available data suggest
that prosthetic valves in the mitral position are more prone
to failure. In general, structural valve deterioration begins
at about 5 years after MVR and at about 8 years after AVR
(Hammermeister 2000). Likewise, survival after MVR is typically lower when compared with AVR. For instance, one study
showed that among patients who had valve surgery at age
6170 years, the probability of being alive at 15 years after AVR
99
was 30.9% versus 16.1% after MVR (Jamieson 2000). Despite

those differences in outcomes, the ACC/AHA guidelines provide identical recommendations for selection of bioprosthetic
and mechanical valves in both MVR and AVR patient populations (see Figure 1-2).
protection given the low long-term thrombogenic risk of bioprosthetic valves.

According to current guidelines, implantation of a mechanical mitral prosthesis mandates high-intensity anticoagulation
with a VKA (see Table 1-4). Despite those rather robust recommendations, the evidence in support of the regimen is sparse.
In the GELIA study of patients with mechanical mitral prostheses, patients were randomized into three groups: stratum A
targeted an INR of 3.04.5, stratum B targeted an INR of 2.5
4.0, and stratum C targeted an INR of 2.03.5 (Hering 2005).
Rates of thromboembolism were low across the groups,
occurring in only 5 and 12 patients in strata A and C, respectively (p>0.05). Bleeding rates, however, increased in stratum
A compared with stratum C (205 vs, 151; p=0.008). Subgroup
analysis from another study suggests that the target range of
3.03.9 was superior to a target of 2.02.9 for patients with
mechanical MVR (Cannegieter 1995). While intriguing, these
data must be viewed strictly as hypothesis generating given
the design of the study.
Data delineating the optimal anticoagulation regimen for
patients with both mitral and aortic mechanical valves are
extremely limited. However, the GELIA trial reported an annual
incidence of thromboembolism of 0.5%, 0.9%, and 1.2%
among those with isolated AVR, isolated MVR, and dual valve
replacement, respectively. In accordance with that elevated
risk, more-aggressive anticoagulation (INR target 2.53.5)
in this group seems justified. Finally, similar to those with
mechanical aortic valves, all patients with mechanical MVR
should receive concomitant aspirin daily unless a strong contraindication for such therapy is present.
Mitral prosthetic heart valves are more thrombogenic than

those in the aortic position because of the differing hemodynamic and flow characteristics across the valve. Without
long-term anticoagulation, a mechanical mitral valve can
carry an annual risk of thromboembolism as high as 20%. As
such, VKA therapy is required for all patients after MVR.
Oral Anticoagulation and Antiplatelet Therapy
The risk of a stroke from a mitral bioprosthetic valve in the first

30 days postoperatively has been reported to be as high as
40 events per 100 patient-years (Heras 1995). Unfortunately,
randomized data comparing VKA with antiplatelet therapy
early after mitral valve bioprosthesis are lacking. One small,
nonrandomized cohort suggested a trend for lower rates of
thromboembolism with oral VKA therapy after bioprosthetic
MVR (Heras 1995). However, other data have shown that
even with routine anticoagulation early after valve surgery,
the incidence of ischemic stroke within the first 30 postoperative days was higher after a biological prosthesis (4.6%)
than after mitral valve repair (1.5%; p<0.0001) (Nishimura
2014). Despite that relatively weak evidence, the guidelines of
both the ACCP and the ACC/AHA advocate for 3 months of
VKA after implantation of a bioprosthetic mitral valve (Table
1-4). After 3 months, aspirin monotherapy offers adequate
Table 1-4. Recommended Antithrombotic Therapy after Mitral Valve Replacement
Valve Type and Location
ACCP Guidelines
ACC/AHA
Bioprosthetic MVR
Warfarin INR goal 23 for 3 months (2C), then

ASA 50-100 mg daily (2C)
Consider warfarin INR goal 23 for first 3

months if low risk (IIa, C)
Mechanical MVR
Warfarin INR goal 2.53.5 (2C)a
Warfarin INR goal 2.53.5 (I, B)a
Mechanical AVR + mechanical MVR Warfarin INR goal 2.53.5 (2C)a
Not addressed
Mitral valve repair with prosthetic

ring placement
Consider warfarin INR goal 23 for first 3

months if low risk (IIa, C)
ASA 50100 mg daily therapy for at least 3

months (2C)b
Aspirin should be added to warfarin in all patients with mechanical heart values unless the bleeding risk is unacceptably high.
For patients in normal sinus rhythm with no other indications for warfarin.
ACC = American College of Cardiology; AHA = American Heart Association; AVR = aortic valve replacement; MVR = mitral valve
replacement.
Information from Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and Thrombolytic Therapy for Valvular Disease.
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012;141(Suppl):e576Se600S; Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the
management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57e185.
100
Use of Parenteral Anticoagulation Bridging
intervention. Drug therapy plays a complementary role for

such patients, especially those with left-ventricular dysfunction or overt heart failure symptoms. The premise for
vasodilators in acute MR is to reduce the impedance of aortic flow, thereby preferentially guiding flow away from the left
atrial regurgitant pathway, which decreases MR while simultaneously increasing forward output. Conversely, chronic MR
is a different hemodynamic entity, and vasodilators benefit
only those with secondary MR and concurrent left-ventricular dysfunction. Results from a small number of trials have
shown that asymptomatic patients with primary valve disease
appear to exhibit little or no hemodynamic improvement from
ACE inhibitors, ARBs, or hydralazine. That finding is reflected
in the ACC/AHA guidelines, which recommend against vasodilator therapy in normotensive asymptomatic patients with
chronic primary MR and normal systolic function (class III,
level-of-evidence B).
Because of the unacceptably high risk of thromboembolism,

patients with mechanical MVR should receive parenteral
bridging during periods of subtherapeutic anticoagulation.
That recommendation is supported by the guidelines of both
the ACC/AHA (class I, level-of-evidence C) and the ACCP
(grade 2C). Unfortunately, neither document specifies firm
guidance regarding choice of agent (i.e., UFH vs. LMWH) or
dosing regimen in patients with mechanical MVR. Therefore,
providers should individualize regimens according to the setting (e.g., inpatient vs. outpatient) and the clinical situation
(e.g., presence of renal failure). Bridging for patients with bioprosthetic mitral valves is generally not required.
Transcatheter Mitral Valve Repair
Traditional MVR is the gold standard treatment modality for

severe, symptomatic MR. However, many patients may not be
candidates for such therapy because of their unacceptable
surgical risk profiles. A novel percutaneous device has been
developed to treat MR by approximating the two leaflets of the
valve (MitraClip, Abbott, Menlo Park, CA). Reduction in MR
severity may parenthetically improve left-ventricular function,
which can lead to symptom relief and functional improvement
in patients with inoperable disease (Lim 2014). The device
recently gained FDA approval, and the ACC/AHA guidelines
suggest that transcatheter mitral valve repair can be considered in patients with nonoperable stage D disease (class IIb,
level-of-evidence B). The manufacturer currently does not
provide details regarding thromboprophylactic agents; however, patients enrolled in the pivotal randomized trial for this
device received aspirin 325 mg daily for at least 6 months and
clopidogrel for 30 days (Mauri 2013).
ANTITHROMBOTIC POTPOURRI
Failure of Primary Prevention
Cumulative data show that anticoagulation with a VKA is protective against valve thrombosis (HR 0.11; 95% CI, 0.070.2)
and thromboembolic events (HR 0.21; 95% CI, 0.160.27) in
patients with mechanical heart prostheses (Nishimura 2014).
Regrettably, residual thrombotic risk persists even in the
setting of high-quality anticoagulation, with annual rates of
1%2% for mechanical valves versus 0.7% with bioprosthesis.
Data defining the optimal strategy for intensifying anticoagulation in patients with prosthetic valves who develop
thromboembolic complications are lacking. Despite that
absence of evidence, though, the ACC/AHA guidelines provide practical recommendations according to a patients level
of anticoagulation at the time of the event. Before escalation
of anticoagulation intensity, potential contributing factors
such as subtherapeutic INR values or nonadherence should
be investigated. If periods of subtherapeutic INR values are
identified, aggressive counseling regarding strict medication
and dietary adherence should be implemented, and patients
should be considered for referral to a specialty anticoagulation clinic if not already enrolled.
Medical Management
The onset of symptoms requiring medical therapy is an

indication for intervention in patients with severe MS.
Pharmacotherapy is thus supplementary for those patients
and should be used primarily to optimize hemodynamic
function before surgery. Careful use of loop diuretics can be
helpful in relieving dyspnea through pulmonary decongestion. Overdiuresis in the setting of a stenotic mitral valve must
be avoided because it could facilitate a precipitous drop in
left-ventricular preload. -Blockers can decrease heart rate
and cardiac output at rest, causing decreases in the transmitral gradient, pulmonary capillary wedge pressure, and mean
pulmonary pressure in patients with MS. Those physiologic
improvements notwithstanding, the available evidence has
failed to demonstrate any improvement in exercise tolerance
with -blockade in MS. As such, the ACC/AHA guidelines offer
a weak recommendation to consider these agents in patients
with MS and who have symptoms associated with exercise
(class IIb, level-of-evidence B).
Like MS, symptomatic primary MR is a mechanical problem that can be corrected only with surgery or percutaneous
Treatment of Valve Thrombosis
Prosthetic valve thrombosis has an incidence of 0.1% to 5.7%

per patient-year. Despite such relative infrequency, valve
thrombosis can lead to catastrophic outcomes such as acute
cardiogenic shock and death. Patients with suspected valve
thrombosis should undergo prompt diagnostic testing, including physical examination and echocardiographic assessment.
A thorough clinical evaluation is the first step, including auscultation for diminished or abolished clicks together with
new systolic or diastolic murmurs. Transesophageal echocardiography is essential in excluding alternative diagnoses
(i.e., pannus ingrowth), in quantifying the degree of valvular
101
dysfunction, and in estimating the size of the thrombus. The

last measurement is of particular significance, because for
patients with a large thrombus (>1.0 cm diameter or 0.8 cm2 in
area), each 1.0-cm2 increase in size means a 2.4fold higher
rate of complications (i.e., cardioembolic stroke or bleeding)
with fibrinolysis therapy (Tong 2014).
In addition to thrombus size, the presence of New York
Heart Association (NYHA) class IIIIV symptoms also presages poor outcomes with fibrinolytic therapy. Unfortunately,
perioperative mortality also increases directly with NYHA
class, from 4.7% in patients in class I through III to 17.5%
in patients in class IV (Deviri 1991). Treatment decisions
regarding surgery versus fibrinolytic therapy must therefore be determined according to a comprehensive evaluation
of clinical and echocardiographic features (Figure 1-4). The
guidelines of both the ACC/AHA and ACCP favor emergent
surgery over pharmacotherapy in patients with hemodynamic
compromise, severe symptoms, or large thrombi. Otherwise, a
trial of heparin therapy with judicious monitoring is a practical
strategy, especially with very small thrombi. Those with persistent thrombi after several days of intravenous UFH should
be administered fibrinolysis with recombinant tissue plasminogen activator. Published reports of dosing protocols are
limited; one group reported use of both a high-dose regimen
(10-mg bolus dose followed by an intravenous infusion of 90
mg over 2 hours) and a low-dose regimen (20-mg bolus followed by an intravenous infusion of 10 mg/hour for 3 hours)
(Roudaut 2003). Outcome measures for the tissue plasminogen activator arms were presented as one aggregate group;
hence, the decision for which regimen to use must be made
by the treating clinician and should be driven by the presence
of additional risk factors for hemorrhage.

A 45-year-old woman with a history of mitral valve
prolapse and severe mitral regurgitation status post
mechanical mitral valve replacement is admitted with
a cardioembolic stroke. At the time of her stroke, she
was taking aspirin 81 mg daily and warfarin with an
INR target of 2.53.5. Her INR was 2.9 on presentation. She has no other pertinent medical history.
Fortunately, she suffers only mild residual left-sided
weakness, and she is progressing well through therapy. On discharge, the physician requests assistance
with subsequent anticoagulation management. What
strategy would best prevent further thromboembolic
complications in this patient?
ANSWER
Unfortunately there are limited data available to guide

clinicians who face this specific scenario. The current
guidelines offer suggestions for intensification of anticoagulation in patients with prosthetic heart valves who
suffer a thromboembolic complication:
Warfarin, INR 2.03.0: warfarin dose increased to achieve
INR of 2.53.5
Warfarin, INR 2.53.5: warfarin dose may have to be increased to achieve INR of 3.54.5
Not taking aspirin: aspirin 75100 mg per day should be
initiated
Warfarin plus aspirin 75100 mg per day: aspirin dose may
also have to be increased to 325 mg per day if the higher
dose of warfarin is not achieving the desired clinical result
Aspirin alone: aspirin dose may have to be increased to 325
mg per day, and/or warfarin added.
Fortunately for this patient, she has a relatively

low bleeding risk given her age and lack of comorbid
conditions. She therefore may tolerate intensified anticoagulation. The pharmacist managing this patient
could consider increasing her INR target to 3.04.0 or
3.54.5. Alternatively, the patients aspirin dose could
be increased to 325 mg daily. The decision would ultimately be guided by the patients wishes. If a decision is
made to intensify therapy, the patient should be monitored extremely closely for signs of bleeding.
Anticoagulation Reversal
The incidence of anticoagulation-related bleeding in patients

with mechanical prosthetic heart valves is around 1%2% per
year. This clinical scenario is particularly precarious, because
anticoagulation reversal in the mechanical prosthesis setting
could potentially precipitate a thromboembolic complication.
In light of that intrinsic risk, decisions regarding the use of
vitamin K or fresh frozen plasma must consider the urgency
with which normal coagulation must be restored. In the face
of uncontrolled or life-threatening bleeding, the ACC/AHA
guidelines suggest that administration of fresh frozen plasma
or prothrombin complex concentrate may be justified (class
IIa, level-of-evidence B)with the caveat that the risk of subsequent thrombosis with those products has not been defined
in the prosthetic heart valve patient population. As with nonprosthetic heart valve patients, supratherapeutic INR values
(<9) without overt bleeding can be managed safely by withholding warfarin for a time. Markedly elevated INR values
(>10) may prompt consideration for low-dose oral vitamin K
depending on the patients hemorrhage.
1. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/

ACC guideline for the management of patients with valvular
heart disease: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol 2014;63:e57e185.
2. Witlock RP, et al. Antithrombotic and Thrombolytic
Therapy for Valvular Disease. Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest
2012;141(Suppl):e576Se600S.
102
Suspected Prosthetic Valve Thrombosis
TTE to confirm diagnosis (I, LOE B)
Left-sided prosthetic
Right-sided prosthetic
valve thrombosis
valve thrombosis
TEE for sizing of thrombus (I, LOE B)
NYHA class III-IV
Mobile or large
symptoms
(0.8 cm2 thrombus)
NYHA class I-II symptoms and small

thrombus (<0.8 cm2)
Emergent surgery
Emergent surgery (IIa,
Fibrinolytic therapy if persistent valve thrombo-
(I, LOE B)
LOE C)
sis after IV heparin therapy

(IIa, LOE B)
Figure 1-4. Evaluation and management of suspected prosthetic valve thrombosis.

TTE = transthoracic echocardiography; TEE = transesophageal echocardiography; NYHA = New York Heart Association; LOE = level
of evidence.
Coll Cardiol 2014;63:e57e185.
Use of Target-Specific Oral Anticoagulants
(7 patients vs. 2) with dabigatran versus warfarin. All major

bleeding events were pericardial and occurred within 2 weeks
of the index valve implant. The authors of this paper posit
that those adverse findings may be explained by the dabigatran trough levels used in the trial, which could have been
insufficient to suppress thrombin generation through contact
factor activation (i.e., from the mechanical prosthesis). In light
of those data, the ACC/AHA guidelines recommend against
anticoagulant therapy with any of the TSOACs in patients with
mechanical valve prostheses (class III, level-of-evidence B).
The high incidence of coexistent AF in patients with bioprosthetic heart valves has generated interest in using TSOACs in
that population. Nevertheless, because those patients were
excluded from the major AF clinical trials, the TSOACs cannot be endorsed in patients with bioprosthetic heart valves.
Recently presented preliminary data signaled safety issues
with rivaroxaban and apixaban anticoagulation in patients
The target-specific oral anticoagulants (TSOACs)which are

dabigatran, rivaroxaban, apixaban, and edoxabanoffer distinct pharmacologic advantages over warfarin-based therapy.
Their favorable pharmacokinetics, the absence of cumbersome
drug-drug and drug-food interactions, and the straightforward
dosing make them appealing options for those on lifelong anticoagulation. Regrettably, the only in vivo study evaluating the
safety and efficacy of a TSOAC in patients with mechanical
heart valves reported discouraging results.
In the RE-ALIGN trial, 252 patients were randomized in a
2:1 fashion to either dabigatran or warfarin (Eikelboom 2013).
The dose of dabigatran was individualized according to the
patients trough levels (goal greater than 50 ng/mL); the warfarin dose was individualized according to the patients type
of prosthesis. The trial was terminated early because of
excess rates of stroke (9 patients vs. 0) and major bleeding
103
with AF and bioprosthetic valves; however, that information

must be vetted through peer review before any conclusions
can be made (Di Biase 2015).
accidentally resumed by the patient. However, a patient with

a new mechanical heart valve may decide to stop taking aspirin after starting warfarin, mistaking one as a replacement for
the other. Effective counseling can empower patients to take
CONCLUSION
a central role in preventing potentially catastrophic complications of valve replacement surgery (i.e., bleeding or stroke),
Clinical pharmacists are integral members of the multidisciplinary team responsible for managing patients after valve
replacement surgery. Drug therapy regimens after cardiac surgery can be complex, and for each type of procedure, clinicians
must be fully versed in the fundamental pharmacotherapy concepts outlined in this chapter. In addition, pharmacotherapists
have to be familiar with the essential elements of the various
types of valve replacement procedures and possess a full
understanding of the drug therapy ramifications that accompany different surgeries (e.g., aortic valve replacement vs.
TAVR). The clinical pharmacist is well equipped to engage the
health care team and ensure that the requisite thromboprophylactic therapies are properly prescribed.
Equally important is the role of the pharmacist in providing
key education and follow-up monitoring of patients after valve
surgery. The pharmacist must emphasize to each patient
that surgery is not a cure and that medication adherence is
vital in the prevention of both thrombotic and bleeding complications. Accurate medication reconciliation, especially
regarding drugs that may interfere with anticoagulants, is
also central to the pharmacists role. Drugs used for symptom control (e.g., furosemide, hydralazine) may no longer
be required after successful valve replacement but could be
which could result in a loss of efficacy and undermine any

gains from the initial procedure.
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of balloon-expandable vs self-expandable valves in
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3. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter
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4. Amat-Santos IJ, Rods-Cabau J, Urena M, et al. Incidence,
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oral anticoagulant therapy in patients with mechanical
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Practice Points
6. Carabello BA Paulus WJ. Aortic stenosis. Lancet

2009;373:956-66.
In determining the optimal treatment for a patient

after valve replacement surgery, the clinician has several considerations:
7. Chiang YP, Chikwe J, Moskowitz AJ, et al. Survival and

long-term outcomes following bioprosthetic vs mechanical aortic valve replacement in patients aged 50 to 69
years. JAMA 2014;312:1323-9.
Bioprosthetic AVR patients can usually be managed with

aspirin as monotherapy.
Patients with mechanical AVR should be treated with warfarin to an INR goal of 2.03.0.
Placement of a TAVR valve should warrant indefinite aspirin therapy along with 36 months of clopidogrel.
ACE or ARB therapy may be beneficial in AS patients, especially those with left-ventricular dysfunction.
Aspirin should be added to the regimen of all patients
with mechanical heart valves unless their bleeding risk is
unacceptably high.
Mechanical MVR should prompt more-intensive anticoagulation, with INR targets of 2.53.5.
Routine use of vasodilator therapy in chronic, asymptomatic MR is not recommended unless the ejection fraction is
reduced.
Anticoagulation reversal in the setting of a mechanical
heart valve can be considered depending on the clinical
scenario.
TSOACs should not be used in patients with prosthetic
8. Colli A, Mestres CA, Castella M, et al. Comparing warfarin

to aspirin (WoA) after aortic valve replacement with the
St. Jude Medical Epic heart valve bioprosthesis: results of
the WoA Epic pilot trial. J Heart Valve Dis 2007;16:667-71.
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mechanical heart valve prostheses: clinical aspects and
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aortic valve replacement with mechanical prosthetic
vs bioprosthetic valves among medicare beneficiaries:
a population-based cohort study. JAMA Intern Med
2014;174:1788-95.
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104
12. Eikelboom JW, Connolly SJ, Brueckmann M, et al.

Dabigatran versus warfarin in patients with mechanical
heart valves. N Engl J Med 2013;369:1206-14.
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of Cardiology/American Heart Association Task Force on
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26. Puskas J, Gerdisch M, Nichols D, et al. Reduced anticoagulation after mechanical aortic valve replacement: interim
results from the prospective randomized on-X valve anticoagulation clinical trial randomized Food and Drug
Administration investigational device exemption trial. J
Thorac Cardiovasc Surg 2014;147:1202-10.
13. Hammermeister KE, Sethi GK, Henderson WC, et al.

Outcomes 15 years after valve replacement with a
mechanical versus bioprosthetic valve: final report of
the Veterans Affairs randomized trial. J Am Coll Cardiol
2000;36:1152-8.
14. Heras M, Chesebro JH, Fuster V, et al. High risk of
thromboemboli early after bioprosthetic cardiac valve
replacement. J Am Coll Cardiol 1995;25:1111-9.
27. Roudaut R, Lafitte S, Roudaut MF, et al. Fibrinolysis of

mechanical prosthetic valve thrombosis: a single-center
study of 127cases. J Am Coll Cardiol 2003;41:653-658.
15. Hering D, Piper C, Bergemann R, et al. Thromboembolic

and bleeding complications following St. Jude Medical
valve replacement: results of the German Experience
With Low-Intensity Anticoagulation Study. Chest
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28. Rieck E, Cramariuc D, Boman K, et al. Hypertension in

aortic stenosis: implications for left ventricular structure
and cardiovascular events. Hypertension. 2012;60:90-7.
29. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus
surgical aortic-valve replacement in high-risk patients. N
Engl J Med 2011;364:2187-98.
16. Holmes DR Jr, Brennan JM, Rumsfeld JS, et al. Clinical

outcomes at 1 year following transcatheter aortic valve
replacement. JAMA 2015;313:1019-28.
30. Talwar S, Kapoor CK, Velayoudam D, et al. Anticoagulation protocol and early prosthetic valve
thrombosis. Indian Heart J 2004;56:225-8.
17. Horstkotte D, Niehues R, Strauer BE, et al.

Pathomorphological aspects, aetiology and natural
history of acquired mitral valve stenosis. Eur Heart J.
1991;12 Suppl B:55.
31. Tong AT, Roudaut R, Ozkan M, et al. Transesophageal

echocardiography improves risk assessment of thrombolysis of prosthetic valve thrombosis: results of the
international PRO-TEE registry. J Am Coll Cardiol
2004;43:77-84.
18. Jamieson WRE, Miyagshima RT, Burr LH, Lichtenstein

SV, Fradet GJ, Janusz MT. Carpentier-Edwards porcine
bioprosthesis: clinical performance assessed by actual
analysis. J Heart Valv Dis 2000;9:530-5.
32. Thyregod HG, Steinbrchel DA, Ihlemann N, et al.

Transcatheter versus surgical aortic valve replacement in
patients with severe aortic valve stenosis: 1-year results
from the all-comers (NOTION) randomized clinical trial. J
Am Coll Cardiol 2015;65:2184-94.
19. Jones EC, Devereux RB, Roman MJ, et al. Prevalence

and correlates of mitral regurgitation in a population-based sample (the Strong Heart Study). Am J Cardiol
2001;87:298.
33. Ussia GP, Scarabelli M, Mul M, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing
transcatheter aortic valve implantation. Am J Cardiol
2011;108:1772-6.
20. Leon MB, Smith CR, Mack M, et al. Transcatheter

aortic-valve implantation for aortic stenosis in
patients who cannot undergo surgery. N Engl J Med
2010;363:1597-607.
34. Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic

and Thrombolytic Therapy for Valvular Disease.
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest
2012;141(Suppl):e576S-e600S.
21. Lim DS, Reynolds MR, Feldman T, et al. Improved functional status and quality of life in prohibitive surgical
risk patients with degenerative mitral regurgitation
after transcatheter mitral valve repair. J Am Coll Cardiol
2014;64:182-92.
22. Mauri L, Foster E, Glower DD, et al. 4-year results of a
randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol
2013;62:317-28.
23. Mrie C, Kber L, Skov Olsen P, et al. Association of warfarin therapy duration after bioprosthetic aortic valve
replacement with risk of mortality, thromboembolic complications, and bleeding. JAMA 2012;308:2118-25.
24. Nadir MA, Wei L, Elder DH, et al. Impact of ReninAngiotensin System Blockade Therapy on Outcome in
Aortic Stenosis. J Am Coll Cardiol 2011;58:570-6.
25. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/
ACC guideline for the management of patients with
105
A. Discontinue aspirin and maintain her current INR
goal range.
B. Discontinue both aspirin and warfarin.
C. Discontinue warfarin but continue with aspirin 325
mg daily.
D. Decrease INR goal to 1.5-2.0 and continue with
aspirin 81 mg daily.
1. Which one of the following patients would be the best

candidate for a mechanical aortic valve replacement for
severe symptomatic aortic stenosis (AS)?
A. A 72-year-old man with a history of hypertension,
diabetes, and smoking
B. A 64-year-old woman with atrial fibrillation who takes
apixaban because of a history of labile INR values on
warfarin therapy
C. A 42-year-old man with a bicuspid aortic valve
D. A 34-year-old woman with a history of intravenous
drug use, recurrent endocarditis, and end-stage renal
disease on hemodialysis
6.
A. An 85-year-old man with severe COPD, and stage 4

chronic kidney disease
B. A 74-year-old woman with hypertension, gout, and a
high-risk Society of Thoracic Surgeons (STS) score
C. A 76-year-old man with history of stable angina,
hyperlipidemia, and a low-risk STS score
D. A 72-year-old woman with hypertension, a porcelain
aorta, and a high-risk STS score
J.T. is a 68-year-old man with a history of hypertension, diabetes, gout, and peptic ulcer disease. He undergoes an aortic valve
repair (AVR) with a St. Jude mechanical valve for severe AS. His
early postoperative course is uneventful, and on postoperative
day 2, plans are being made to initiate warfarin therapy.
7. A 78-year-old man has a history of hypertension, hyperlipidemia, coronary artery disease, peptic ulcer disease,
and severe symptomatic AS. He undergoes a successful TAVR procedure with a SAPIEN XT valve. He also
has an everolimus-eluting stent placed in his right coronary artery for relief of angina symptoms. Which of the
following antithrombotic regimens would be best to recommend for this patient?
2. Which one of the following is the best goal INR range for
J.T.?
A.
B.
C.
D.
3.
2.03.0
2.53.5 for 3 months, then decrease to 2.03.0
2.53.5
2.03.0 for 3 months, then decrease to 1.52.0
On postoperative day 4, J.T. develops two episodes of

postoperative atrial fibrillation. Which one of the following is now the best goal INR for J.T.?
A.
B.
C.
D.
A. 2.5-3.5
B. 2.5-3.5 for 3 months, then 2.0-3.0
C. 2.0-3.0
D. 2.0-3.0 for 3 months, then decrease to 1.5-2.0
5.
Add aspirin 81 mg daily.

Add aspirin 325 mg daily.
Increase warfarin dose.
Discontinue warfarin and add aspirin.
A.
B.
C.
D.
About 3 years ago, a 72-year-old woman underwent an AVR

surgery (On-X mechanical valve) for critical AS. Her current
antithrombotic regimen is warfarin (INR goal 2.0-3.0) and
aspirin 81 mg daily. Over the last 4 months, she has presented to hospital twice with recurrent GI bleeding. Her INR
values are consistently within her goal range. Which one of
the following is best to recommend for this patient?
Aspirin indefinitely with clopidogrel for 3 months

Aspirin indefinitely with clopidogrel indefinitely
8. A 68-year-old woman has a history of hypertension, mild

COPD, gout, and newly diagnosed mild-to-moderate AS.
At present she has no symptoms of fainting, chest pain,
dyspnea, or leg swelling. Her vital signs reveal a heart
rate of 78 beats/minute and a blood pressure of 150/81
mm Hg. Her laboratory results are unremarkable. She
currently takes tiotropium one inhalation daily and hydrochlorothiazide 25 mg daily. Which one of the following is
best to recommend for this patient?
4. J.T. is eventually discharged. Two months later, he presents for follow-up in clinic. His INR is 2.8, and he currently
takes warfarin, metoprolol, and metformin. Which of the
following is best to recommend for reducing J.T.s risk of
thromboembolism?
A.
B.
C.
D.
Which one of the following patients with severe symptomatic AS would be the best candidate for consideration of a
TAVR procedure?
Initiate simvastatin 40 mg daily.

Initiate lisinopril 5 mg daily.
Initiate metoprolol 25 mg twice daily.
Continue the present drug therapy regimen.
9. A 64-year-old man undergoes bioprosthetic mitral valve

repair for mitral valve prolapse. His only other medical history is a deep vein thrombosis (11 years ago), for
which he received 6 months of warfarin. His postoperative course is uncomplicated and his physician would like
106
13. The physician calls your pharmacy requesting assistance

with dosage of tPA. Which one of the following is best to
recommend for A.D.?
to initiate antithrombotic therapy. Which one of the following is best to recommend for this patient?
A.
B.
C.
D.
Aspirin 81 mg daily
Warfarin goal INR of 2.03.0 for 3 months
A. tPA 10-mg bolus dose followed by an intravenous

infusion of 90 mg over 2 hours.
B. tPA 20-mg bolus followed by an intravenous infusion
of 10 mg/hour for 3 hours.
C. tPA not indicated, proceed to emergent surgery.
D. tPA not indicated, first administer intravenous
heparin.
10. A 58-year-old woman has a history of hyperlipidemia, coronary artery disease, systolic heart failure, GI bleeding,
and moderate-to-severe chronic secondary mitral regurgitation. She is undergoing coronary bypass grafting for
her coronary disease, and the decision is made to repair
her mitral valve with a prosthetic ring. Which one of the
following antithrombotic regimens is best to recommend
for this patient?
A.
B.
C.
D.
14. A.D. responds favorably to treatment and is ready for

discharge. Which one of the following strategies for secondary prevention is most appropriate for A.D.?
A. Education regarding adherence to dietary and
medication regimen for warfarin.
B. Increase target INR value to 2.53.5.
C. Increase aspirin dose to 325 mg daily.
D. Addition of clopidogrel 75 mg daily.
Warfarin goal INR 2.0-3.0 for 3 months

Warfarin goal INR 2.5-3.5 for 3 months
Warfarin goal INR 2.0-3.0 indefinitely
Aspirin 81 mg daily
11. A 48-year-old Indian man presents with severe mitral

stenosis secondary to rheumatic fever as a child. He
undergoes successful mechanical mitral valve surgery,
and the medical team would like to begin anticoagulation
therapy. The patients renal function is normal. Which one
of the following regimens would be most appropriate for
this patient?
15. A 58-year-old man with a history of mechanical mitral

valve replacement is admitted with chest pain. He
receives a diagnosis of unstable angina and is stabilized
with medical therapy. The team would like to proceed with
diagnostic angiography. The patients INR is 2.8, and the
physician orders 4 units of fresh frozen plasma before the
procedure. Which one of the following is best to recommend for this patient?
A. Enoxaparin 1 mg/kg twice daily with warfarin goal

INR 2.0-3.0
B. Warfarin goal INR 2.5-3.5
C. Enoxaparin 1 mg/kg twice daily with warfarin goal
INR 2.5-3.5
D. Warfarin goal INR 2.0-3.0
A. Process the order as written.

B. Change the order to vitamin K 10 mg intravenously as
one dose.
C. Discontinue the order and withhold warfarin until the
INR value is acceptable.
D. Add vitamin K 5 mg orally as one dose to the fresh
frozen plasma.
12. Which of the following patient factors would be most

likely to preclude vasodilator therapy in the setting of
mitral regurgitation?
16. A 68-year-old woman with a history of hypertension,

asthma, and atrial fibrillation is admitted for elective bioprosthetic mitral valve replacement. Pre-operatively, the
patient was taking rivaroxaban for primary stroke prevention. The patients surgery is uneventful, and as discharge
approaches the team would like to resume the patients
rivaroxaban. Which one of the following is best to recommend for this patient?
A. Concurrent left-ventricular dysfunction, symptoms of

dyspnea, blood pressure 120/65 mm Hg
B. Normal left-ventricular function, symptoms of
dyspnea, blood pressure 120/65 mm Hg
C. Normal left-ventricular function, no symptoms, blood
pressure 120/65 mm Hg
D. Normal left-ventricular function, no symptoms, blood
pressure 150/85
A.
B.
C.
D.
A.D. is a 65-year-old man with a history of a mechanical

aortic valve repair surgery (7 years ago). He presents with
progressive shortness of breath over the last 5 days, which is
characterized as NYHA class II. The patient takes aspirin 81
mg daily and warfarin for thromboprophylaxis, and his INR is
1.6 (goal 2.03.0). Further workup reveals a thrombus on the
prosthetic valve measuring 0.6 cm2.
Transition to warfarin.
Resume rivaroxaban.
Transition to dabigatran.
Transition to apixaban.
17. A new oral direct thrombin inhibitor (pradapixaban) is

under development for use in patients with mechanical
heart valves. During a randomized, phase III non-inferiority study comparing it with warfarin, the incidence of the
primary efficacy end point was 1.50% with warfarin and
1.18% with pradapixaban (HR 0.79; 97.5% CI, 0.630.99;
107
p<0.001). According to these results, which of the following best summarizes this new drug?
A.
B.
C.
D.
It is superior to warfarin.
It is inferior to warfarin.
It is non-inferior to warfarin.
It is equivalent to warfarin.
18. A 75-year-old woman undergoes routine elective AVR

surgery with a bioprosthetic valve. Which one of the following thromboprophylactic regimens would be most
appropriate for this patient?
A. Warfarin goal INR 2.03.0 for 3 months, then aspirin
81 mg daily
B. Warfarin goal INR 2.03.0 indefinitely
C. Warfarin goal INR 2.03.0 plus aspirin 81 mg daily
indefinitely
D. Aspirin 81 mg daily indefinitely
19. A 78-year-old man has a history of hypertension, diabetes, atrial fibrillation, spinal stenosis, and aortic stenosis
status post mechanical aortic valve replacement 9 years
ago. Now he is scheduled for elective spinal surgery. The
patients estimated CrCl is 70 mL/minute. His physician
would like to withhold warfarin therapy before the surgery
and requests your assistance with determining a peri-operative bridging regimen. Which one of the following, in
addition to holding warfarin for 5 days before surgery, is
A.
B.
C.
D.
Admit to surgery without bridging.

Initiate enoxaparin bridging in the outpatient setting.
Admit to hospital for unfractionated heparin bridging.
Admit to hospital for enoxaparin bridging.
20. A 65-year-old man with severe mitral regurgitation and

aortic stenosis undergoes simultaneous mitral and aortic
valve replacement (both mechanical). His postoperative
course is unremarkable, and the medical team would
like your recommendations regarding his thromboprophylactic regimen. Which one of the following is best to
recommend for this patient?
A.
B.
C.
D.
Warfarin goal INR 3.0-4.0 with aspirin 81 mg daily

Warfarin goal INR 2.5-3.5
108
Learner Chapter Evaluation: Valvular Heart Disease.


12. Classify common heart valve disorders and distinguish

when surgical intervention is indicated.
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
13. Distinguish between traditional and transcatheter aortic

valve replacement.
14. Design appropriate pharmacologic thromboprophylactic
regimens for patients after aortic valve replacement or
patients with mitral valve prostheses.
15. Evaluate the role of medical therapy for patients with

symptomatic aortic stenosis

16. Justify adjunctive pharmacotherapy in patients with
symptomatic mitral valve regurgitation





were effective.
effective.
were effective.
109
By Laura A. Siemianowski, Pharm.D., BCPS, BCCCP; and Lucia Ros, Pharm.D., AAHIVP
Reviewed by Trent G. Towne, Pharm.D., BCPS (AQ-ID); and Nancy Shenouda, RPh, BCPS
LEARNING OBJECTIVES
1. Design an empiric treatment regimen for the patient with suspected infective endocarditis using patient-specific factors
and the most likely bacteria.
2. Apply pharmacokinetic and pharmacodynamic principles to develop a definitive antimicrobial regimen for the treatment
of infective endocarditis according to patient- and pathogen-specific factors.
3. Justify the role of alternative antimicrobials in the management of infective endocarditis based on recently published
evidence.
4. Design strategies for preventing and managing adverse drug reactions for antimicrobials commonly used for the treatment of infective endocarditis.
5. Analyze the role of different antimicrobials in the management of infective endocarditis in patients transitioning care to
the outpatient setting.
6. Determine which high-risk patient populations warrant antibiotic prophylaxis for endocarditis during certain medical
procedures.
HLAR
High-level aminoglycoside
resistance
IE
Infective endocarditis
IVDU
Intravenous drug usage
MIC
Minimum inhibitory concentration
MRSA Methicillin-resistant
Staphylococcus aureus
MSSA Methicillin-susceptible
Staphylococcus aureus
NVE
Native valve endocarditis
OPAT
Outpatient parenteral antibiotic
therapy
PVE
Prosthetic valve endocarditis
VGS
Viridans group streptococci
VRE
Vancomycin-resistant enterococci
INTRODUCTION
Infective endocarditis (IE) is an infection of the endocardial surface
of the heart, generally involving at least one heart valve. In the United
States, the incidence of IE is about 10 to 15 per 100,000 persons. The
incidence of IE is steadily increasing because of changes in risk factors
over the years, such as increasing use of intracardiac devices and prosthetic valves, hemodialysis, and the aging population (Slipczuk 2013).
Gram-positive organisms including viridans group streptococci (VGS),
Staphylococcus aureus, and Enterococcus spp. remain the most common causative pathogens. Epidemiologic changes with regard to these
bacteria and their associated resistance have occurred over the years.
This chapter focuses mainly on VGS, S. aureus, and Enterococcus spp;
however, other gram-positive bacteria, gram-negative bacteria, and
fungi are potential causes of IE, although they are much less common
(Baddour 2015). Marked improvements to laboratory methods for identifying bacteria have made culture-negative IE increasingly less common
a great benefit from the management perspective (Slipczuk 2013).
In general, the incidence of IE is significantly higher in certain
patient populations such as those with valvular heart disease, prosthetic valves, or intravenous drug usage (IVDU). Other conditions
predisposing a patient to the development of IE include hemodialysis
dependency, persistent S. aureus bacteremia (i.e., for greater than 34
days), and poor source control of another infection (Holland 2014). Of all
cases of IE, about 80% are caused by staphylococci and streptococci,
111
with staphylococci being the most common cause. Although

the cost burden varies with the need for surgery, many patients
are subject to prolonged hospitalization and long-term antimicrobial therapy, making the management of this disease quite
complicated. Despite diagnostic and surgical advances, overall
mortality rates (about 20%) have remained relatively constant
over the past few decades (Slipczuk 2013). However, mortality
rates of patients with left-sided IE tend to be higher than those
with isolated right-sided IE (Kamaledeen 2012).
(e.g., positive blood cultures, confirmatory echocardiographic

findings) are not present, diagnosis can be complicated and
potentially delayed. Patients may present with nonspecific
symptoms such as fever, chills, fatigue, malaise, and weight
loss; therefore, a high index of suspicion is often required to
make a clinical diagnosis. In most cases, having a definitive
diagnosis of IE is ideal because management considerations
such as the need for cardiac surgery and treatment durations
can be different than for bacteremia alone.
Because of the prolonged antibiotic therapy required, avoidance of long-term treatment with broad-spectrum antibiotics is
recommended in order to minimize risk of toxicity and secondary effects such as selection pressure on other bacteria and
superinfection. Obtaining blood cultures before initiating antibiotic therapy is crucial so that appropriate de-escalation can
be performed after the pathogen is identified and susceptibilities are defined. Because of the risk of adverse outcomes with
delayed therapy, broad-spectrum antibiotics that target the
most common pathogens should be initiated promptly after
blood cultures are drawn and while susceptibilities are pending.
Pharmacologic treatment of IE employs high-dose, bactericidal, intravenously administered antimicrobials with
the need for careful consideration of the selected antibiotic
pharmacokinetic and pharmacodynamic properties when
designing dose regimens. The goals of therapy are to quickly
eradicate the causative organism, to reduce the risk of cardiac and embolic complications, and to improve mortality
outcomes. Additional patient- and treatment-specific goals
include resolution of clinical signs and symptoms; avoidance
of treatment-related adverse effects and toxicities, as well as
readmission; and compliance with the long-term treatment
and monitoring plan.
Although indications for surgery are beyond the scope of
this chapter, the decision to perform cardiac surgery should
be made on a case-by-case basis when the benefit outweighs
the risk. One study was not able to show a mortality benefit for
early valve surgery (within 60 days) in prosthetic valve endocarditis (PVE) caused by S. aureus. Of note, certain patient
populations (e.g., patients with active IVDU) may not be surgical candidates (Chirouze 2015). Additionally, any indwelling
devices or hardware should be removed, if possible.
DIAGNOSIS AND ROLE OF EMPIRIC

THERAPY
The diagnosis of IE requires integration of clinical, laboratory,
and echocardiographic findings, typically through use of the
Modified Duke Criteria (Li 2000). If major IE diagnostic criteria

with the following:
Basic knowledge of infective endocarditis, including risk factors, etiology, pathophysiology, clinical
presentation, diagnosis and prognosis
Pharmacology of common antimicrobials used for
the treatment of infective endocarditis, including
mechanisms of action, pharmacokinetic profile,
adverse effects, and drug interactions
ADDITIONAL READINGS
Baddour LM, Wilson WR, Bayer AS, et al. Infective
endocarditis in adults: diagnosis, antimicrobial
therapy, and management of complications. A
scientific statement for healthcare professionals
from the American Heart Association. Infective
endocarditis in adults: diagnosis, antimicrobial
therapy, and management of complications. A
scientific statement for healthcare professionals
from the American Heart Association. Circulation
2015;132:1-52.
PHARMACOLOGIC MANAGEMENT OF
CAUSATIVE ORGANISMS
Wilson W, Taubert KA, Gewitz M, et al. Prevention

of infective endocarditis: guidelines from the
American Heart Association: a guideline from the
American Heart Association Rheumatic Fever,
Endocarditis, and Kawasaki Disease Committee,
Council on Cardiovascular Disease in the Young,
and the Councils on Clinical Cardiology, Stroke, and
Cardiovascular Surgery and Anesthesia, and the
Quality of Care and Outcomes Research
Interdisciplinary Working Group. Circulation
2007;116:1736-54.
Viridans Group Streptococci
The incidence of IE caused by VGS has declined over the past

few decades, potentially as a result of improved oral hygiene
and prevention of dental disease (Baddour 2015; Slipczuk
2013; Wilson 2007). The term viridans group streptococci
refers to a large number of different species (e.g., S. mutans,
S. oralis, S. sanguinis) that are often found in the human mouth
and gingiva and that are common causes of community-acquired IE involving native valves (NVE), particularly in patients
112
without IVDU. Streptococcus gallolyticus (formerly S. bovis) is
Aminoglycoside dosing in IE is typically used for gram-positive synergy with cell wall-active agents. Accordingly, the
dosing is generally lower than that required for gram-negative
infections. For the treatment of IE, aminoglycosides are typically dosed three times daily rather than once daily. However,
in the treatment of streptococcal IE with MICs of 0.5 g/dL
or less, it has been demonstrated that a single daily dose (3
mg/kg) is as effective as divided doses. For strains of VGS
with MICs greater than 0.5 g/dL, the dosing recommendation continues to be 1 mg/kg intravenously three times daily;
this recommendation is based on the lack of data supporting
once-daily dosing (Baddour 2015).
not a VGS but is included in this group because it requires

the same treatment approach. Infective endocarditis caused
by S. gallolyticus is often associated with GI pathology, especially colon carcinoma. As such, patients with S. gallolyticus
bacteremia or IE should undergo a diagnostic colonoscopy
(Baddour 2015).
Antimicrobial regimens for IE caused by VGS have been
well studied and, in uncomplicated cases, produce response
rates up to 98% (Figure 2-1). These organisms remain penicillin susceptible, although the degree of susceptibility can
vary. As a result, the penicillin MIC for all VGS should be
determined in order to guide both the dose and the duration
Enterococcus spp.
of therapy. A variety of treatment regimens may be consid-
Enterococcal IE is becoming increasingly prevalent among

the elderly and in patients with comorbidities, and is more
commonly acquired in the health care setting. The growing
prevalence is likely caused by an increase in the number of
urogenital and abdominal procedures and in the number of
enterococcal catheter-related bacteremias. Mortality rates of
enterococcal IE are reported to be as high as 20% (FernandezGuerrero 2007). The two most common species implicated
are Enterococcus faecalis and Enterococcus faecium; of the
ered for susceptible VGS, and the decision regarding the most
optimal treatment regimen should be based on the perceived
risk versus benefit for the patient. For patients with PVE or
other prosthetic material and infection caused by VGS or S.
gallolyticus, choices of treatment are similar to those without
prosthetic material; however, treatment durations should be
extended to 6 weeks to ensure eradication of the infecting
organism (Table 2-1).
Viridans group streptococci and S. gallolyticus infective endocarditisa
Penicillin MIC < 0.12 mcg/mL
Penicillin MIC > 0.120.5 mcg/mL
Native valve
Penicillin or ceftriaxone
+/- gentamicinb,d
Vancomycinc
Prosthetic valve
Penicillin or ceftriaxone
Vancomycinc
Native valve
High-dose penicillin plus
gentamicind
Ceftriaxonee
Vancomycinc
Prosthetic valve
High-dose penicillin or ceftriaxone
plus gentamicind
Vancomycinc
Figure 2-1. Treatment of infective endocarditis caused by penicillin-susceptible viridans group streptococci and
Streptococcus gallolyticus.
a
Penicillin MIC > 0.5 mcg/mL should be treated as enterococcal IE (see Figure 2-2).
Addition of gentamicin is optional if patient qualifies for 2-week duration; otherwise, duration of treatment is 4 weeks (see Table 2-1).
For penicillin allergy, desensitization is suggested. If unable to desensitize, then vancomycin should be considered.
Gentamicin may be administered as a once-daily dose for strains highly and relatively susceptible to penicillin (MIC 0.5 g/dL). For
higher penicillin MICs, the same total daily dose should be administered in three divided doses.
Ceftriaxone alone may be considered a reasonable alternative if the isolate is susceptible
113
Table 2-1. Optimal Treatment Duration for Common Causative Pathogens

Organism
Valve Status
Duration (weeks)b
Native
MIC < 0.12
MIC > 0.120.5
MIC > 0.5
24c
4 (2 weeks gentamicin)
46
Prosthetic
MIC < 0.12
MIC > 0.12
6
6
Native
46d
Prosthetic
Vancomycin-resistant enterococci
Native or prosthetic
>6
MSSA
Native
Prosthetic
> 6 (2 weeks gentamicin)
Native
Prosthetic
> 6 (2 weeks gentamicin)
Viridans group streptococci
Ampicillin-susceptible enterococci
MRSA
MIC is for penicillin G in mcg/mL.
Suggested treatment duration is specific for all antibiotics indicated, except where otherwise noted in parentheses.
Two-week regimen indicated only for uncomplicated cases in which patients are also at low risk for aminoglycoside adverse events.
Four-week regimen indicated only if symptoms present for < 3 months and when utilizing ampicillin plus gentamicin combination.
Six-week therapy recommended for symptoms > 3 months and when utilizing dual -lactam therapy or vancomycin-containing
regimen
MSSA = methicillin-susceptible Staphylococcus aureus; MRSA = methicillin-resistant Staphylococcus aureus.
two, E. faecalis continues to be the more common isolate

(Baddour 2015).
The treatment approach for IE caused by enterococci
does not vary with the patients valve status or presence of
indwelling hardware. However, treatment duration may vary.
For example, patients with enterococcal NVE experiencing
symptoms for less than 3 months may only require 4 weeks
of treatment instead of 6 weeks (see Table 2-1). Whereas most
strains of E. faecalis continue to remain ampicillin-susceptible, many strains of E. faecium have not. Therefore, initial
empiric treatment should target ampicillin-resistant enterococcus, and definitive therapy should be determined once
susceptibilities are finalized (Figure 2-2).
In cases of ampicillin-susceptible enterococcal IE, preferred therapy is generally either ampicillin or penicillin G in
combination with gentamicin (or streptomycin). Ampicillin
may be preferred over penicillin based on in vitro data suggesting improved efficacy, likely as a result of lower MICs to
ampicillin (Murray 2000). However, no clinical outcomes data
verify such differences in efficacy.
Bactericidal activity of ampicillin against enterococci is
dependent on synergistic activity with aminoglycosides,
including gentamicin or streptomycin. All strains of E. faecium
and many strains of E. faecalis are intrinsically resistant to

other aminoglycosides (e.g., tobramycin, amikacin). These
agents are not used in clinical practice for treatment of enterococcal IE. Gentamicin is considered the aminoglycoside of
choice; this is because streptomycin plasma concentrations
are less readily measured, higher risk of ototoxicity, and the
drug may be difficult to obtain. Although some data support once-daily dosing for synergy in streptococcal IE, this
approach has not been sufficiently evaluated for patients with
enterococcal IE. Therefore, the gentamicin dosing recommendation for treatment of enterococcal IE continues to be 1 mg/
kg IV three times daily (Baddour 2015).
The frequency of E. faecalis isolates with high-level aminoglycoside resistance (HLAR) for both gentamicin and streptomycin
have increased (Baddour 2015). This is an issue for management because HLAR renders the -lactam/aminoglycoside
combination no longer bactericidal. Per the AHA/IDSA 2015
guideline recommendations, when the organism demonstrates
HLAR to gentamicin, susceptibilities for streptomycin should
be obtained since some strains may be susceptible to streptomycin. If the organism does not also demonstrate HLAR to
streptomycin, it may be used as an alternative to gentamicin
at a dose of 15 mg/kg intravenous daily in two divided doses.
114
E. faecalis IE
-Lactam susceptible?
Yes
No
Gentamicin susceptible?
Yes
Noe
Yes
Noe
AMP-SUL + GENTa
AMP + CTXb
AMP + GENT
Streptomycin
VANC + GENTc
Vancomycin
susceptible?
DAP + AMP or CEFf,g
susceptible?
VANC + GENTc
LINf,g
Yes
AMP + CTXb
AMP + STREP
VANC + STREPc
Yes
Noe
AMP + CTX
AMP-SUL + STREPa
AMP-SULa,d
VANC + STREP
VANC d
b,f
VANC c,f
Noe
DAP + AMP or CEFf,g
DAP + AMP or CEFf,g
LINf,g
LINf,g
Figure 2-2. Treatment of IE caused by Enterococcus faecalis in native and prosthetic valves.
Rare cases of beta lactamase-producing strains.
a
b
c
d
e
f
May be considered first-line, especially in patients at high risk of renal toxicity.
For penicillin allergy, desensitization to AMP is suggested. If unable to desensitize, VANC (if susceptible) plus an aminoglycoside (if
susceptible) should be considered.
Treatment durations > 6 weeks may be required (see Table 2-1).
High-level aminoglycoside resistance.
Treatment durations > 8 weeks may be required (see Table 2-1).
Considered salvage for treatment of ampicillin and vancomycin resistant strains.
AMP = ampicillin; AMP-SUL = ampicillin-sulbactam; CEF = ceftaroline; CTX = ceftriaxone; DAP = daptomycin; GENT = gentamicin; IE
= infective endocarditis; LIN = linezolid; VANC = vancomycin; STREP = streptomycin.
Information from: Munita MM, Cesar AA, Murray BE. Enterococcal endocarditis: can we win the war? Curr Infect Dis Rep
2012;14:339-49.
be used. -lactamaseproducing strains are often resistant

to aminoglycosides, in which case treatment with ampicillin/
sulbactam as monotherapy should be at least 6 weeks in duration (see Table 2-1) (Baddour 2015). In the even less common
setting of IE caused by ampicillin- and vancomycin-resistant strains of E. faecalis, data supporting effective treatment
strategies are scarce. Treatment of these multidrug-resistant
strains typically includes combination therapy and should be
considered salvage. Agents commonly used in these scenarios include linezolid as monotherapy or daptomycin with or
without a -lactam (Baddour 2015; Lauridsen 2012; SierraHoffman 2012; Sakoulas 2011; Crank 2010; Wareham 2006).
However, because of the previously described limitations with

the use of streptomycin, and nephrotoxicity concerns with the
use of aminoglycosides, clinicians have more recently sought
alternative means to treat enterococcal IE.
E. faecalis
Most E. faecalis isolates remain susceptible to ampicillin. As

such, the combination of ampicillin plus gentamicin remains
the treatment of choice for IE caused by ampicillin-susceptible E. faecalis. In the rare setting of -lactamaseproducing E.
faecalis IE, -lactamase inhibitor combinations such as ampicillin/sulbactam in combination with an aminoglycoside can
115
daily as recommended for treatment of enterococcal IE, and

gentamicin trough concentrations were not reported (Munita
2013). In recent years, more clinicians have adopted this dual
-lactam treatment strategy for the treatment of enterococcal
IE caused by strains demonstrating either HLAR or non-HLAR
based on its similar efficacy and favorable safety profile over
aminoglycoside-containing regimens.
For patients with severe -lactam allergies, it is strongly
recommended to desensitize when treating -lactam-susceptible enterococcal IE. Vancomycin plus gentamicin may
be considered an alternative treatment strategy only when
desensitization is not possible because of this combination
being less efficacious, more likely to cause nephrotoxicity,
and requiring a longer duration of therapy (see Table 2-1)
(Baddour 2015). For cases that mandate use of vancomycin/gentamicin, renal function should be closely monitored
because of the significantly increased risk of nephrotoxicity.
Although, in the setting of severe penicillin allergy, consideration has been made for the use of alternative treatment
strategies (i.e., linezolid alone, daptomycin alone, or daptomycin in combination with gentamicin), no strong clinical data
support these regimens.
Further discussion of IE caused by vancomycin-resistant

enterococcus follows in the section on E. faecium.
Concerns about the rising rates of HLAR and aminoglycoside-induced nephrotoxicity have led clinicians to seek
alternative treatment strategies. One such strategy has targeted a shortened duration of aminoglycoside therapy for IE
caused by enterococcal strains. Two retrospective studies
in non-HLAR E. faecalis IE examining 2 versus 46 weeks of
aminoglycosides in combination with 46 weeks of a -lactam have shown similar outcomes. Longer treatment with an
aminoglycoside was associated with a higher incidence of
nephrotoxicity (Dahl 2013; Olaison 2002). In combination with
a -lactam, shorter durations (2 weeks) of -lactam/aminoglycoside therapy, followed by -lactam monotherapy, may
be considered for patients with less severe cases presenting with shorter symptom durations (i.e., less than 3 months)
(Baddour 2015).
A second strategy to combat the issues associated with
increased incidence of HLAR or the concerns of nephrotoxicity with prolonged aminoglycoside therapy is dual -lactam
therapy. In the last 10 years, literature has been published
supporting the use of ceftriaxone plus ampicillin for the treatment of E. faecalis IE. This combination may be preferred in
some cases based on experimental and clinical studies that
show comparable efficacy and reduced nephrotoxicity compared with the standard therapy of ampicillin plus gentamicin
(Pericas 2014; Fernandez-Hidalgo 2013, Gavalda 2007). In
fact, the AHA/IDSA 2015 guidelines endorse this new regimen as a reasonable treatment option, specifically for
ampicillin-susceptible E. faecalis IE, regardless of gentamicin
susceptibility (Baddour 2015).
A large prospective, observational, multicenter cohort
study compared the outcomes of ampicillin 2 g intravenously
every 4 hours plus ceftriaxone 2 g intravenously every 12
hours versus standard therapy (ampicillin 2 g intravenously
every 4 hours plus gentamicin 3 mg/kg/day) in adult patients
with E. faecalis IE. A total of 159 patients received ampicillin/
ceftriaxone and 87 patients received ampicillin/gentamicin.
Demographic and clinical features (i.e., presence of prosthetic valve) between the two groups were similar except for
a higher incidence in chronic renal failure, neoplastic disease,
and transplantation in the dual -lactam group. No differences
in mortality between groups were evident during therapy or at
3-month follow up. In a subgroup of patients with E. faecalis IE
caused by non-HLAR strains (101 patients treated with ampicillin/ceftriaxone and 87 treated with ampicillin/gentamicin),
similar mortality results were observed. Overall, the study
patients who received gentamicin had much higher rates of
drug discontinuation as a result of adverse events, mainly
related to renal failure (23% vs. 0%, p<0.001) (FernandezHidalgo 2013). Notable criticisms of this study are that it was
nonrandomized, the definition of renal failure could have overestimated the rates of kidney injury, less than one-half of the
subjects in the gentamicin group received the drug three times
E. faecium
The incidence of nosocomial-acquired enterococcal IE caused

by multidrug-resistant E. faecium has steadily increased. A
high proportion of E. faecium isolates in the United States are
reported as ampicillin-resistant, and many exhibit high-level
resistance (MICs greater than 64 mg/L) (Baddour 2015). For
many years, vancomycin has been considered the alternative
drug of choice when dealing with ampicillin-resistant E. faecium infections; however, modern isolates are increasingly
resistant to vancomycin (Hidron 2008).
Because IE secondary to vancomycin-resistant enterococci (VRE) is still considered to be rare, there are few data on
effective therapy (Hidron 2008). Infective endocarditis caused
by VRE is therefore generally difficult to manage because of
the limited number of available active agents and supporting
evidence. In general, combination therapy is warranted and
treatment is considered salvage. Drugs with FDA-approved
labeling for treatment of VRE include quinupristin/dalfopristin (approved in 1999) and linezolid (approved in 2000). Drugs
that may be used for IE caused by VRE but which do not have
FDA-approved labeling include tigecycline and daptomycin.
Reports of clinical success with quinupristin/dalfopristin,
particularly in combination with high-dose ampicillin, permit
its use as a viable option for treatment of multidrug-resistant E. faecium IE (Perez 2006; Baddour 2015; Bethea 2004;
Thompson 2003). However, the use of quinupristin/dalfopristin in clinical practice has fallen out of favor because
of its adverse effect profile, metabolic interactions through
inhibition of CYP 3A4, and the need for a central line placement for administration.
116
Staphylococcus spp.
Linezolid is an oxazolidinone antibiotic that exhibits

bacteriostatic activity against enterococci. Although one
observational study demonstrated successful clinical outcomes with the use of linezolid as rescue treatment for
left-sided IE, all enterococcal blood isolates were E. faecalis
(Lauridsen 2012). However, because linezolid has demonstrated in vitro activity against E. faecium, it may also be
considered an alternative option for treatment of vancomycin-resistant E. faecium IE (Baddour 2015). In a case report
of vancomycin-resistant E. faecium bacteremia, a combination of linezolid and gentamicin resulted in a cure; however, a
time-kill curve did not demonstrate in vitro synergy (Noskin
1999). Similarly, the addition of gentamicin or vancomycin
to linezolid when used for treatment of PVE caused by vancomycin-resistant E. faecalis did not result in synergy or
antagonism (Wareham 2006). Compared with daptomycin
for VRE bacteremia, treatment with linezolid resulted in similar rates of mortality (46.3% vs. 29.4%; p=NS) (Crank 2010).
Linezolid-induced myelosuppression has been well documented, particularly when the agent has been used for longer
than 2 weeks. This effect of myelosuppression may limit its
utility in treating IE in patients who are thrombocytopenic at
baseline or who develop this toxicity with prolonged treatment. Caution should also be exercised in patients receiving
concomitant serotonergic agents because of the risk of serotonin syndrome secondary to linezolids ability to weakly
inhibit monoamine oxidase (Lawrence 2006).
Tigecycline is a glycylcycline antibiotic that displays bacteriostatic activity against Enterococcus spp. Based on
concerns about its large volume of distribution (causing
high tissue concentrations and low serum concentrations),
bacteriostatic activity, low cure rates, and increased mortality compared with other antibiotics, the off-label use of
tigecycline as monotherapy for enterococcal IE is discouraged (Prasad 2012; Anthony 2008). There have, however,
been reports of clinical success with tigecycline when used
in combination with high-dose daptomycin ( 8 mg/kg/day)
for the treatment of IE caused by vancomycin-resistant E.
faecium. Thus, the combination of tigecycline/high-dose daptomycin may be a viable salvage treatment option (Polidori
2011; Schutt 2009; Jenkins 2007).
Daptomycin monotherapy for the treatment of vancomycin-resistant enterococcal IE has been studied with variable
clinical success and should be considered with caution
due to concerns for emergence of daptomycin-resistance
during treatment (Baddour 2015; Kullar 2013; 2011; Mohr
2009 CORE; Moise 2009). As such, daptomycin in combination with another agent is preferred over monotherapy.
Ampicillin and ceftaroline have demonstrated the strongest
synergistic in vitro activity and clinical efficacy when used in
combination with daptomycin; less active (in vitro) combination options include daptomycin plus gentamicin, rifampin or
tigecycline (Baddour 2015; Sierra-Hoffman 2012; Sakoulas
2011; Sakoulas 2013) (Figure 2-3).
In the United States, the percentage of IE caused by S.

aureus has been growing, likely attributed to a rise in IVDU,
the aging population, and an increased number of patients
undergoing placement of intracardiac devices. Depending
on the region and patient setting, methicillin-resistance rates
are about 40%60% of all S. aureus isolates (Bamberger
2007). Implications of higher incidences of IE caused by S.
aureus versus other bacteria include a higher mortality rate,
increased length of stay and hospitalizations, and higher cost
(Chirouze 2015; Boucher 2008). Cure rates for staphylococcal IE are highly dependent on the presence of a prosthetic
valve, right versus left-sided valvular involvement, whether it
is coagulase-negative staphylococcus or positive (S. aureus),
elevated MICs of the organism, and whether it is methicillin
sensitive or resistant.
Coagulase-Negative Staphylococcus
Although coagulase-negative staphylococcus is generally

considered less virulent than S. aureus, it is a well-documented
pathogen in both NVE and PVE. There are many species of
coagulase-negative staphylococcus and they vary in degree
of virulence and susceptibility patterns; however, many laboratories do not speciate them and the different strains will
not be discussed here. Most strains, particularly those causing PVE, are methicillin resistant and should be treated as
such until susceptibilities are finalized. Vancomycin remains
the treatment of choice in combination with adjunctive therapy (e.g., rifampin, gentamicin) in the presence of prosthetic
valves (Baddour 2015).
S. aureus
Right-sided IE caused by S. aureus is associated with higher

cure rates, and treatment duration is generally shorter than
left-sided IE. S. aureus is further subdivided by whether it is
methicillin susceptible (MSSA) or resistant (MRSA). Initial
treatment should empirically target MRSA, and definitive
therapy should be determined once susceptibilities are finalized. Infective endocarditis caused by MSSA, in absence of
a -lactam allergy, should be treated with a -lactam with or
without other agents depending on valve status.
Methicillin-Susceptible S. aureus
The management of IE caused by MSSA has not changed significantly over the past several years. Recommendations are
still consistent with nafcillin or oxacillin as first-line therapy
and the addition of rifampin and gentamicin in the presence of
a prosthetic valve (Figure 2-4). Cefazolin is listed in the guidelines as an acceptable alternative for patients with a penicillin
allergy (e.g., rash) that would otherwise preclude the use of
nafcillin or oxacillin.
Despite these guideline recommendations, many clinicians have adopted the use of cefazolin as their -lactam
of choice in the setting of IE caused by MSSA, regardless of
117
E. faecium IE
Ampicillin susceptible?
Yes
No
Yes
Vancomycin susceptible?
Nob
Yes
Noc
AMP + DAP
AMP + GENT
Streptomycin
VANC + GENT
VANC + GENT
susceptible?
CEF + DAP
TIG + DAP
Linezolid
Yes
AMP + STREP
VANC + STREPa
No
VANCa
Figure 2-3. Treatment of infective endocarditis caused by Enterococcus faecium in native and prosthetic valves.
a
For penicillin allergy, desensitization to AMP is suggested. If unable to desensitize, VANC (if susceptible) plus an aminoglycoside (if
susceptible) should be considered
High-level aminoglycoside resistance
Vancomycin-resistant enterococcus whereby treatment options are considered salvage.
AMP=ampicillin; CEF = ceftaroline; DAP = daptomycin; GENT = gentamicin; STREP = streptomycin; TIG = tigecycline; VANC =
vancomycin.
Information from: Munita MM, Cesar AA, Murray BE. Enterococcal endocarditis: can we win the war? Curr Infect Dis Rep
2012;14:339-49.
the 2-g, 2-g, 3-g (between the 72-hour sessions) dosing regimen (Stryjewski 2007). It is also important to note however,
that cefazolin has poor central nervous system penetration.
Therefore, in cases of IE complicated by septic emboli in the
brain or brain abscesses, nafcillin or oxacillin are preferred. If
an allergy exists, vancomycin is preferred in these cases over
cefazolin (Baddour 2015).
Based on the documented inferiority over first-generation cephalosporins and anti- staphylococcal penicillins,
vancomycin should be reserved for patients with severe IgEmediated penicillin allergies (McConeghy 2013; Schweizer
2011; Kim 2008). Because of the inferiority of vancomycin in
MSSA, some literature supports empirically treating patients
with suspected IE caused by S. aureus with vancomycin plus
a -lactam (i.e., cefazolin or nafcillin) until susceptibilities are
finalized (McConeghy 2013; Van Hal 2012; Stryjewski 2007).
For many years, the role of gentamicin in the treatment of
MSSA IE has been controversial. Based on in vitro and rabbit
models from the 1970s, the guidelines state that addition of
gentamicin is optional in NVE caused by MSSA. Based on the
allergy status. Newer data suggest that cefazolin not only

has similar efficacy to nafcillin for MSSA bacteremia but
also is better tolerated, leading to less interrupted therapy
and drug-related discontinuation rates (Li 2014; Youngster
2014; Lee 2011). These studies identified significantly higher
rates of nafcillin/oxacillin discontinuation; most commonly
caused by rash, renal impairment, and elevated transaminases. The designated alternative status of cefazolin is partly
based on two cases of relapse and/or failure from an older
case series (Bryant 1977). Evidence also correlates a high
inoculum effect with cefazolin treatment failure. More recent
clinical trials have not demonstrated higher rates of treatment failure with cefazolin compared with nafcillin or oxacillin
(Nannini 2013, 2009; Rincon 2013). Therefore, it is difficult to
know whether the treatment failures observed in these case
series were attributed to other factors such as source control,
including device removal. If cefazolin is chosen, a dose of 2 g
intravenously every 8 should be used for patients with normal
renal function. Cefazolin may also be preferred in intermittent
hemodialysis patients because of ease of administration using
118

reveals gram-positive cocci in chains. Empiric vanco-
B.R. is a 69-year-old man (height 71 in, weight 64 kg)

with a history of severe mitral regurgitation after a bioprosthetic mitral valve replacement 6 months ago. He
is admitted to the hospital with complaints of progressive fatigue over the past month as well as fevers, chills,
and night sweats for 1 week. He has no known drug allergies. On admission, his temperature is 38C, WBC is 20.2
10 3 cells/mm3, and Scr is 2.3 mg/dL (baseline 1.6 mg/
dL). Two sets of blood cultures are drawn, and Gram stain
mycin therapy is initiated. On day 3 of admission, blood

cultures revealed E. faecalis growing in all four bottles.
Transthoracic echocardiography (TTE) is performed and
reveals a moderately sized (3 x 6 mm) mobile vegetation
on the mitral valve. The physician asks for your assistance
in selecting antibiotics for this patient, based on the below
susceptibility report for the organism:
Antibiotic
MIC
Susceptibility
Ampicillin
2 mg/dL
Gentamicin synergy screen
N/A
Vancomycin
1 mg/dL
Daptomycin
0.5 mg/dL
Linezolid
2 mg/dL
ANSWER
shown to be as efficacious as ampicillin plus gentamicin,

and, in the absence of antibiotic allergies, dual -lactam
combination may be a better option. It should be noted
that ampicillin plus gentamicin is not incorrect from an
efficacy standpoint. A 4-week treatment duration is likely
to be sufficient because the patient was symptomatic for
less than 3 months. This approach is presuming bacterial
eradication and clinical improvement.
This patient has enterococcal IE as evidenced by positive blood cultures and vegetation found on TTE. Although
the guideline-recommended treatment strategy includes
ampicillin plus gentamicin in this susceptible organism,
in this case of renal insufficiency, gentamicin is less preferred because of additive nephrotoxicity. Ceftriaxone 2 g
intravenous every 12 hours plus ampicillin 2 g intravenous
every 4 hours (adjusted for renal insufficiency) has been
Fernandez-Hidalgo N, Almirante B, Gavalda J, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating
Enterococcus faecalis infective endocarditis. Clin Infect Dis 2013;56:1261-8.
Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association: endorsed by the Infectious Diseases
Society of America. Circulation 2015;132:1-52.
(Kullar 2014). Based on many reports of therapeutic failures
higher rates of observed nephrotoxicity and no known mortality benefit, its usage has fallen out of favor. In a prospective
cohort study that evaluated the safety of low-dose gentamicin
in 236 patients with S. aureus bacteremia and NVE, patients
who received gentamicin had higher rates of nephrotoxicity. The study authors recommend against its routine use
because of the lack of proven clinical benefit and the higher
rates of nephrotoxicity (Cosgrove 2009). In MSSA PVE, however, gentamicin is still recommended during the first 2 weeks
of therapy (Baddour 2015).
with vancomycin, alternative regimens have been studied. In

addition, vancomycin MICs greater than 1 have been associated with therapeutic failure, and alternative agents should
generally be chosen in these cases (Lodise 2008).
Daptomycin has FDA-approved labeling for S. aureus bacteremia and right-sided IE at doses of 6 mg/kg/day. However,
because of a killing profile that is concentration dependent,
daptomycin doses of 812 mg/kg/day have been studied and
are recommended in certain situations, particularly when vancomycin MIC values are above 1 mg/L, in critically ill patients,
Methicillin-Resistant S. aureus
in those who have been failed by vancomycin therapy, or if
Although vancomycin remains the mainstay of therapy for

IE caused by MRSA regardless of valve status (Figure 2-5),
newer data suggest earlier modification of therapy for persistent MRSA bacteremia and IE. In fact, some experts have
proposed changing the definition of persistent bacteremia/
therapeutic failure for MRSA from 7 or more days to 3 or 4
days; this would require an earlier modification in therapy
emerging resistance is a concern (Smith 2014; Carugati 2013).

Except for the potential for mild to moderate elevations in creatine phosphokinase (CPK), these higher doses have been
shown to be safe and well tolerated (Casapao 2013; Kullar
2011). Published data on the use of daptomycin in left-sided
IE and in IE involving implantable cardiac devices are limited,
119
although some studies have shown promising success rates
2014, 2013). High-dose ceftaroline (600 mg intravenous every
(Durante-Mangoni 2012; Liu 2011).
8 hours) was shown to be successful without relapse after
Ceftaroline does not have FDA-approved labeling for MRSA
standard therapy had failed in a patient with PVE caused by
bacteremia or endocarditis; however, it has been evaluated in
MRSA (Pagani 2014). Ceftaroline has lung penetration similar
case studies and case series with promising results. Rapid
to other -lactams; therefore, patients with endocarditis and
MRSA blood clearance with initiation of ceftaroline has been
concomitant pulmonary disease such as pneumonia or septic
shown despite persistently positive cultures while on daptomy-
pulmonary emboli may also benefit from ceftaroline because
cin or vancomycin (Casapao 2014; Lin 2013; Polenakovik 2013;
daptomycin is inactivated by lung surfactant.
Ho 2012). This clearance is likely caused by ceftarolines ability
Ceftaroline is considered safe and well tolerated with
to retain activity, at least in vitro, to vancomycin and daptomy-
adverse effects similar to other -lactams (e.g., diarrhea, rash,
cin nonsusceptible or intermediate strains of S. aureus (Werth
myelosuppression). A few case reports have documented
Methicillin-susceptible staphylococcal IE
Native valve
Prosthetic valve
Nafcillin
Oxacillin
Cefazolina
Vancomycinb
Nafcillin or oxacillin or
cefazolina or vancomycinb
plus gentamicin plus rifampin
Figure 2-4. Treatment of IE caused by methicillin-susceptible Staphylococcus aureus.

a
For penicillin allergy (nonanaphylactoid type), cefazolin can be used safely instead of nafcillin or oxacillin.
For true penicillin allergy (anaphylactoid type), desensitization is suggested. If unable to desensitize, vancomycin should be
considered. For duration of treatment, see Table 2-1.
IE = infective endocarditis.
Methicillin-resistant staphylococcal IE
Native valve
Prosthetic valve
Vancomycin
Daptomycin
Salvage therapya
Vancomycin plus gentamicin

plus rifampin
Salvage therapya
Figure 2-5. Treatment of IE caused by methicillin-resistant Staphylococcus aureus.

a
Salvage therapy is typically indicated when vancomycin MIC greater than 1 mg/dL or after therapeutic failures (see text).
IE = infective endocarditis; MIC = minimum inhibitory concentration.
120
eosinophilic pneumonia secondary to ceftaroline therapy

(Desai 2013; Griffiths 2014). Because of relatively limited data
supporting its use as monotherapy as well as its higher cost
compared to vancomycin, it would be prudent to reserve its
use for salvage therapy. Patients with MRSA strains that are
vancomycin or daptomycin intermediate or nonsusceptible
may benefit from ceftaroline.
The use of ceftaroline in combination with daptomycin has
also shown clinical and microbiologic success, and although
the combination is very costly (about $1000/day), it is likely
to be an effective option. Despite its clinical success in case
series, large clinical trials evaluating ceftaroline use in MRSA
bacteremia and/or endocarditis are lacking. A multicenter
study in MRSA bacteremia has been completed, although
results are not available at this time.
Other antibiotics (e.g., telavancin) may have a role in IE
caused by S. aureus, although established clinical data are
lacking. Some data exist for telavancin usage in salvage therapy for vancomycin-intermediate S. aureus (VISA) (Marcos
2010). Tedizolid is a gram-positive, bacteriostatic agent
that received FDA-approved labeling in June 2014 for acute
skin and skin-structure infections. Because of the lack of
sufficient efficacy or dosing data, tedizolid should not be considered an alternative for IE caused by S. aureus. Agents with
bacteriostatic activity, such as linezolid and tedizolid, are less
preferred (ORiordan 2014).
Although the more recently FDA-approved MRSA active
antibiotics (e.g., oritavancin, dalbavancin) demonstrate potent
in vitro activity against MRSA, data evaluating their use in
bloodstream infections and IE are limited. Dalbavancin was
compared with vancomycin in a small study of 75 patients
with gram-positive bloodstream infections. Although dalbavancin had greater overall clinical success, there were few
MRSA isolates (5 in the dalbavancin group, 9 in the vancomycin group), and complicated bacteremias including IE were
excluded (Raad 2005). Both oritavancin and dalbavancin have
extremely long half-lives (245 and 346 hours, respectively);
this is a consideration if adverse effects or allergies are of
concern. Although these agents may be promising because of
their potency, bactericidal action, and ease of administration
(one or two injections), data relating to their efficacy, safety,
and dosing for infections requiring longer durations of therapy such as in IE are not available (Tice 2012).
suboptimal doses, or inadequate source control. Improvement

in the clinical signs and symptoms of infection is typically
observed within the first week of effective treatment. Patients
should experience resolution of fever, chills, malaise, fatigue,
and appetite suppression within this period. It is important to
note that day 1 of therapy duration should be considered the
first day of negative blood cultures, rather than the first day of
antimicrobial therapy.
Safety
More detailed information regarding adverse effects of specific antimicrobials is available in Table 2-2 and in the specific
package inserts. This discussion focuses only on major
adverse effects that may be prevented by laboratory monitoring and therefore would benefit from a pharmacists input.
Nephrotoxicity secondary to vancomycin and aminoglycosides is well documented in the literature. Over the past decade
or so, vancomycin dosing has become more aggressive with
higher goal troughs (1520 mcg/mL) for many indications,
including IE caused by gram-positive bacteria (Lodise 2008;
Hidayat 2006). Because aminoglycosides are used for synergy in gram-positive IE (i.e., streptococci and enterococci),
doses are much lower than when used for gram-negative
infections (Baddour 2015). With aminoglycoside synergy dosing in IE, the goal peaks and troughs are lower than those used
to treat gram-negative infections. Three-times-daily gentamicin and streptomycin dosing should be adjusted to achieve
1-hour peak concentrations of 3 to 4 mcg/mL and 20 to 35
mcg/mL, and trough concentrations of less than 1 mcg/mL
and less than 10 mcg/mL, respectively (Baddour 2015). When
using once-daily dosing of gentamicin, trough concentrations should be monitored with a goal of less than 1 mcg/mL.
Peak concentrations for once-daily dosing are not routinely
obtained in clinical practice.
Although the lower dosing strategy may reduce the risk of
nephrotoxicity, the risk certainly remains, particularly in older
patients receiving therapy for an extended duration. Despite this
risk, aminoglycosides continue to be recommended in select
bacterial causes of IE based on improved outcomes (Buchholtz
2009). To minimize the risk of nephrotoxicity caused by vancomycin or aminoglycosides, it is crucial to avoid concomitant
nephrotoxins, frequently assess renal function, measure urine
output in hemodynamically unstable patients, and monitor
levels (Elyasi 2012). Dosage adjustments based on levels is
mandatory, particularly when aminoglycosides are used for an
extended period, such as in IE.
Despite the established toxicity of myopathy and possible rhabdomyolysis associated with daptomycin, especially
at high doses, the actual incidence is debatable. Elevations
in CPK are observed in about 3% to 9% of patients, although
this finding does not necessarily correlate with associated
myopathy, which is much less common (Berg 2014). Dosedependence was thought to be a factor; however, one study
EVALUATION OF THERAPEUTIC
OUTCOMES
Efficacy
At least 2 sets of blood cultures should be repeated at least

every 24 to 48 hours until negative after treatment initiation.
Thereafter, repeat blood cultures are not necessary unless the
patients clinical status worsens (Baddour 2015). Persistently
positive blood cultures may be indicative of ineffective antimicrobial(s), subtherapeutic concentrations because of
121
did not show significant correlation between daptomycin dose
note, renal function should periodically be assessed for most
(including 8 mg/kg/day or more) and elevation in CPK (Kullar
-lactams because renally adjusting these agents is import-
2011). In this context, patients on concurrent statin therapy
ant for dose-related toxicities, such as potential lowering of
should be monitored closely. For these reasons, weekly CPK
seizure threshold and myelosuppression. Drug fever is also a
is recommended regardless.
concern for this antibiotic class and usually manifests within 7
-Lactams commonly used for IE (i.e., ampicillin, ceftriax-
to 10 days of therapy. Also, antibiotic-associated diarrhea can
one, nafcillin, oxacillin, cefazolin) are generally well tolerated
occur (more so with -lactams than other agents used for IE);
with little laboratory monitoring required. Delayed hypersensi-
therefore, ruling out C. difficile-associated diarrhea would be
tivity reactions, including fever and rash, have been reported
prudent in certain cases. Nafcillin and oxacillin are also uncom-
in up to one-third of patients receiving -lactam therapy. Of
mon causes of acute interstitial nephritis, and identifying the
Table 2-2. Common Antimicrobials Used in the Treatment of Gram-positive IE

Agent
Aqueous crystalline
penicillin G sodium
Usual Dosing Regimen
1230 MIU per day IV,

divided every 4 hours
Renal
Adjustment
Selected
Laboratory
Parametersa
Yes
Additional Information
For streptococcal IEb, 1218 MIU

per day when penicillin MIC <
0.12; 24 MIU per day when 0.12
0.5; 30 MIU per day when > 0.5 or
when treating enterococcal IE
Ampicillin
2 g IV every 4 hours
Yes
Cefazolin
Yes
Nafcillin or oxacillin
No
Ceftriaxone sodium
2 g IV or IM every 24 hours
2 g IV or IM every 12
hours (enterococcal IE)
No
Vancomycin
15 mg/kg IV every
812 hours
Yes
Trough at steady
state; then weekly
Goal trough:
1520 mg/dL
Loading dose of 2530 mg/kg may

be administered; doses should
be calculated using actual body
weight; dosing interval should be
determined based on renal function
Daptomycin
812 mg/kg IV
every 24 hours
Yes
CPK at baseline,
then weekly
Doses should be calculated

using actual body weight
10-12 mg/kg/dose recommended
when used as monotherapy
Concern for AIN, elevated

transaminases
Ceftaroline
600 IV q8h
Yes
Linezolid
600 mg IV or PO
every 12 hours
No
Gentamicin sulfate
3 mg/kg/day IV, divided

every 8 or 24 hours
Yes
For q8h doses:

Peak: 34 mcg/mL
Trough: < 1 mcg/mL
For q24h doses:
Trough: <1 mcg/mL
Dose should be calculated using

ideal body weight or adjusted body
weight if > 120% of ideal body weight
Rifampin
300 mg IV or PO
every 8 hours
No
LFTs at baseline,
then weekly
Strong CYP inducer; exercise caution

with concomitant CYP substrates
In addition to CBC and basic metabolic panel.
MIC is for penicillin G in mcg/mL.
Caution use with concomitant

serotonergic agents
AIN = acute interstitial nephritis; CPK = creatine phosphokinase; CYP = cytochrome P450; IE = infective endocarditis; IV =
intravenous; LFT = liver function test; MIU = million international units; PO = oral; q8h = every 8 hours; q24h = every 24 hours.
122
presence of urine eosinophils should be a consideration as part

of the work-up for this toxicity. Hematologic toxicities can occur
with many antimicrobial classes including -lactams, vancomycin, and linezolid. Linezolid, in particular, can cause severe
thrombocytopenia, often seen after 2 weeks of therapy.
considered candidates for OPAT. Consideration of antibiotic

compatibility, stability at room temperature, number of doses
per day, and access to ancillary equipment should be made
when selecting the optimal antibiotic for outpatient infusion.
Drugs with limited stability (e.g., penicillin, ampicillin) are not
ideal; therefore, substitution with a more stable therapeutic
option may be needed to allow optimal outpatient therapy. A
common example of this is the substitution of once-daily ceftriaxone for penicillin G in the treatment of IE caused by VGS.
Guidelines for the use of OPAT are available online; an update
is anticipated in 2016.
MANAGEMENT OF ANTIBIOTIC
ALLERGIES
In patients with immediate-type I hypersensitivity reactions
to penicillin, use of a standardized desensitization protocol should be considered for IE caused by VGS, MSSA, or
ampicillin-susceptible enterococci (Baddour 2015). If desensitization is not an option, then vancomycin may be chosen as
second-line therapy; however, this approach to therapy is an
inferior option. Test doses may be an option in patients without a history of anaphylaxis if they can be closely monitored.
In patients with a history of rash to penicillins, a cephalosporin can be safely chosen as an alternative for treatment
of -lactamsusceptible streptococcal and staphylococcal
IE. In the setting of enterococcal IE, vancomycin is a suitable alternative agent. Selection of the optimal therapy must
always be guided by susceptibilities.
Outpatient Oral Antibiotic Therapy
The role of oral antibiotics in the treatment of IE is controversial because of the risk of death with suboptimal therapy.
However, oral agents may have to be used in certain patient
populations, such as in those with multiple antibiotic allergies,
active IVDU, or inability to obtain intravenous access. The
only regimen that has been supported (in a small clinical trial)
is oral ciprofloxacin plus rifampin for native valve, right-sided
IE caused by S. aureus in patients with IVDU (Heldman 1996).
A lack of robust clinical data in support of oral antibiotic therapy limits its use routinely; however, oral ciprofloxacin plus
rifampin for native valve, right-sided IE caused by S. aureus
may be considered when intravenous therapy is not an option.
ROLE OF OUTPATIENT ANTIBIOTIC

THERAPY
For patients who qualify, the use of outpatient antibiotic therapy (OAT) can significantly increase quality of life, allowing
most normal daily activities while treatment is ongoing. Patient
education and support are imperative for home infusion therapy. Because extended treatment duration is common, patients
should understand the importance of adhering to the treatment
and monitoring plan, as well as reporting any associated toxicities that may occur to the health care team (Tice 2004).
ANTIMICROBIAL PROPHYLAXIS
The most recent revision of the AHA Guidelines for IE prophylaxis was published in 2007 and clarified several point from
the 1997 version, including the following: (1) IE is more likely
to occur with everyday activities such as teeth brushing and
chewing food than with a single medical or dental procedure;
(2) the benefit of very few cases of IE prevented with antibiotic
prophylaxis before dental procedures does not outweigh the
risk of adverse effects and cost associated with such prophylaxis; and (3) consistently good oral hygiene and dental care
is more beneficial in preventing IE than a single dose of antibiotics (Wilson 2007).
Since the publication of these more restrictive antimicrobial prophylaxis guidelines in 2007, there has been a
significant rise in the incidence of and hospitalization secondary to streptococcal IE in the United States. However,
the rates of valve replacement for IE before and after the
new guideline have not changed (Pant 2015). According to
the new guideline, it may be considered reasonable to provide prophylaxis for only four patient groups at highest risk
of adverse outcomes if they were to develop IE: (1) patients
with prosthetic valve(s); (2) patients with previous IE; (3)
patients with congenital heart disease (CHD), classified as
either unrepaired cyanotic CHD (including shunts and conduits), completely repaired CHD with prosthetic material
(only for the first 6 months), or repaired CHD with residual
defects near the site of prosthetic material; and (4) patients
Outpatient Parenteral Antibiotic Therapy
The use of outpatient parenteral antimicrobial therapy (OPAT) can

significantly reduce hospital length of stay and associated cost
(Tice 2004). Moreover, costs associated with monitoring may be
reduced secondary to less frequent laboratory testing. Although
objective quality-of-life data are limited, surveys in patients receiving OPAT suggest positive results (Chapman 2012).
Because long-term intravenous antibiotic therapy is necessary to treat IE, OPAT is a reasonable treatment option for
select patients. Patient-specific considerations include his/
her ability to either travel to an outpatient infusion center or
receive antimicrobial therapy at home (by self- or caregiver
administration); cognitive and physical ability to self-administer the medication; whether the patient has a home where
treatment can be received; insurance coverage; and whether
the patient has a history of IVDU. Patients with recent histories of IVDU or with serious complications (e.g., poorly
controlled heart failure, valve ring abscesses, persistent
fever, persistently positive blood cultures) are generally not
123
with cardiac transplantation with development of cardiac

valvulopathy (Wilson 2007). Patients with mitral valve prolapse with or without mitral regurgitation and patients with
bicuspid aortic valves no longer require prophylaxis under
the revised guideline.
The number of dental procedures that require prophylaxis
has also been reduced. Antibiotic prophylaxis is given a weak
recommendation for dental procedures involving manipulation or perforation of oral mucosa. Procedures excluded from
prophylaxis include routine anesthetic injections through
noninfected tissue, dental radiographs, placement or adjustment of orthodontic devices, and trauma to the lips or teeth.
For respiratory tract procedures, antibiotic prophylaxis is also
given a weak recommendation for any invasive procedure that
involves incision or biopsy of the respiratory mucosa (e.g.,
tonsillectomy). An exception is bronchoscopy, which requires
no prophylaxis.
Administration of prophylactic antibiotics solely to prevent
IE is no longer recommended for patients undergoing invasive
GI or genitourinary (GU) tract procedures because of a lack of
published data linking these procedures to IE (Wilson 2007;
Strom 1998). If a patient has an established GI or GU tract infection and is undergoing an elective GI or GU tract manipulation,
then the infection should be eradicated before the procedure.
Selection of a prophylactic antibiotic should be guided
by the patients ability to tolerate oral medication, medication allergies, and the most likely pathogen. For dental and
respiratory tract procedures, the most likely pathogens are

VGS. Therefore, oral amoxicillin or intravenous/intramuscular
ampicillin, cefazolin, or ceftriaxone are considered first-line
choices. The prophylactic dose should be administered 60
minutes before the procedure for oral regimens or 30 minutes
before the procedure for parenteral regimens.
There is currently no indication for dental, GI or GU procedural prophylaxis for patients with implantable cardiovascular
devices. However, prophylaxis with an anti-staphylococcal
antibiotic is strongly recommended at the time of device
implantation and for any subsequent manipulation of the
device pocket (Baddour 2010).
CONCLUSION
Infective endocarditis is a very complicated infectious disease
often requiring surgery and high-dose, intravenous, and prolonged antimicrobial therapy. Rising antimicrobial resistance
has posed challenges in its management, and limited therapeutic options with robust clinical evidence exist. In general,
therapy will be guided by susceptibility patterns of the causative organism as well as patient considerations, including
the aging populations and their associated comorbidities. The
pharmacist plays an integral role in assisting in the selection
and dosing of optimal antimicrobials, in careful monitoring for
prevention of adverse events, and in ensuring that therapeutic
outcomes are achieved.
Practice Points
When evaluating a patient for suspected or confirmed IE,
For IE caused by MSSA, nafcillin or cefazolin are similar in
determine valve status and underlying comorbidities of the
efficacy; however, cefazolin may be better tolerated.
patient, including renal function.
Vancomycin continues to be recommended as a first-line
In most cases, vancomycin serves as the empiric treatment
choice for treatment of IE caused by MRSA; however, other an-
of choice for gram-positive IE because it provides broad
timicrobials may be preferred in certain case scenarios such
coverage against most strains of MRSA, ampicillin-resistant
as when the vancomycin MICs are >1 mcg/mL.
enterococcus, and streptococcus.
With appropriate source control and antimicrobial selection,
Susceptibility results are imperative for definitive therapy in
blood cultures should clear within 48 hours and improve-
order to achieve optimal outcomes.
ment in the clinical signs and symptoms of infection can be
Low-dose gentamicin is often used for synergy in gram-posi-
observed within the first week of treatment; day 1 of therapy is
tive IE; once-daily dosing is supported by clinical data only in
defined as the first day of negative blood cultures.
the setting of streptococcal IE.
Because of prolonged treatment courses, careful monitoring
For streptococcal IE, penicillin or ceftriaxone are the -lactams
and dosage adjustment for organ dysfunction should be em-
of choice and their usage is dependent on the penicillin MIC.
ployed to avoid drug-related toxicities.
For enterococcal IE, ampicillin remains the drug of choice for
Candidates for OPAT must be carefully chosen based on
susceptible strains. For patients qualifying for aminoglyco-
concerns regarding adherence, monitoring and follow-up
side synergy treatment and increased risk of or baseline renal
requirements, and cost.
impairment, dual -lactam therapy may be considered an
Recent guidelines for prophylaxis of IE have provided re-
alternative treatment strategy.

Treatment of IE caused by VRE is complicated and considered
stricted indications, which have since resulted in increased
salvage therapy based on a lack of strong clinical data sup-
incidence of streptococcal IE without evidence of negative
porting newer antimicrobials active against this organism.
clinical outcomes.
124
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128
erythema around the port. She is ill-appearing and looking

worse according to the nurse. After TTE identifies mobile
vegetations on the mitral valve, a diagnosis of infective endocarditis (IE) is made. Blood cultures are sent from L.T.s port
as well as from a peripheral venous site and broad-spectrum
empiric antibiotics are started. Pertinent findings are: WBC 16
103 cells/mm3, SCr 0.8 mg/dL, BUN 18 mg/dL, Temperature
102.3F, heart rate 85 beats/minute, and blood pressure 90/50
mm Hg. L.T. has no known drug allergies.
T.M. is a 58-year-old man (weight 75 kg, height: 510) who

presents to his local hospital with complaints of fatigue, persistent low-grade fevers, night sweats, weakness, and a 15-lb
weight loss over the last month. He reports having had an invasive dental procedure 1 month ago and believes the onset of
his problems started shortly thereafter. He has very poor dentition and has no prosthetic material or foreign devices. T.M.
has a penicillin allergy and reports the reaction to be a rash.
Two sets of blood cultures are drawn in the ED with a Gram
stain showing gram-positive cocci in pairs and chains. Two
days later, blood cultures reveal VGS growing in all four bottles
(MIC 0.3 mcg/mL). Because of persistently positive blood cultures, a trans-esophageal echocardiogram (TEE) is completed
which shows a large vegetation on the aortic valve. Pertinent
laboratory results include WBC 19 103 cells/mm3 (88% polymorphonuclear leukocytes), SCr 0.9 mg/dL, and BUN 21 mg/dL.
24. A Gram stain of L.T.s blood culture reveals gram-positive

cocci in clusters. Which one of the following drugs is best
to recommend for empiric gram-positive coverage for
L.T.?
A.
B.
C.
D.
21. Which one of the following regimens is best to recommend for T.M.?
25. Two days later, identification and susceptibilities of L.T.s

blood cultures are finalized; Staphylococcus aureus is
found to be growing from her port and in peripheral sets
of blood cultures. The port is subsequently removed for
source control. The susceptibility panel is as follows:
A. Penicillin G 2 million units intravenous every 4 hours

plus gentamicin 3 mg/kg every 24 hours
B. Ceftriaxone 2 g intravenous every 12 hours plus
gentamicin 3 mg/kg every 24 hours
C. Ceftriaxone 2 g intravenous every 24 hours plus
D. Vancomycin 15 mg/kg every 12 hours plus
Antibiotic
22. Which one of the following treatment durations is best to

recommend for T.M.?
A.
B.
C.
D.
2 weeks for all agents

4 weeks (2 weeks gentamicin)
4 weeks for all agents
6 weeks (2 weeks gentamicin)
Gentamicin duration would be longer

Gentamicin dose would be higher
Rifampin would need to be added
Vancomycin would replace the -lactam
Susceptibility
Ciprofloxacin
0.5
Cefazolin
0.5
Daptomycin
0.5
Linezolid
Nafcillin
0.5
Vancomycin
Which one of the following is best to recommend for L.T.?
26. Which one of the following treatment durations is best to

recommend for L.T.?
L.T. is a 70-year-old woman (height 5 4, weight 65 kg) who

is brought to the ED complaining of fever, chills, fatigue, and
night sweats for the previous week. She is undergoing chemotherapy and has a chemotherapy port where she is administers
her weekly injections. She has no prosthetic valves and her
oncology team is willing to remove the port if necessary. Her
oncologist comes to evaluate L.T. in the ED and he notices
MIC (mg/dL)
A. Vancomycin 1000 mg intravenous every 12 hours

B. Cefazolin 2 g intravenous every 8 hours plus
gentamicin 65 mg intravenous every 8 hours plus
rifampin 300 mg oral every 8 hours
C. Vancomycin 1000 mg intravenous every 12 hours
plus gentamicin 65 mg intravenous every 8 hours
plus rifampin 300 mg oral every 8 hours
D. Cefazolin 2 g intravenous every 8 hours
23. Which one of the following statements best describes

how treatment would differ if T.M. had a prosthetic valve?
A.
B.
C.
D.
Nafcillin 2 g intravenous every 4 hours

Cefazolin 2 g intravenous every 8 hours
Vancomycin 1000 mg every 12 hours
Daptomycin 500 mg intravenous every 24 hours
A.
B.
C.
D.
2 weeks
4 weeks
6 weeks
8 weeks
27. A patient with native valve endocarditis (NVE) caused

by methicillin-resistant Staphylococcus aureus (MRSA) is
129
the patient was awake and alert, but febrile (102.5F). His
cardiac examination was remarkable for a new murmur
suggestive of IE. He has no known drug allergies. Four sets
of blood cultures were drawn and he was started on empiric
vancomycin. Results of culture and susceptibility results
show 4 of 4 sets positive for S. aureus:
undergoing treatment with daptomycin 8 mg/kg intravenous daily. The patient also has a history of myocardial
infarction status-post 3-vessel coronary artery bypass,
hypertension, and type 2 diabetes. Renal function is
normal. His home drugs include aspirin 81 mg daily,
carvedilol 12.5 mg twice daily, lisinopril 20 mg daily, atorvastatin 80 mg daily, and metformin 1000 mg twice daily.
Which one of the following is most important to monitor in
this patient?
A.
B.
C.
D.
Antibiotic
Creatine phosphokinase
Liver function test
Serum lactate
Erythrocyte sedimentation rate
Vancomycin
Daptomycin
0.5
Which of the following is best to recommend for this

patient?
Stop vancomycin and start linezolid
Stop vancomycin and start daptomycin
Stop vancomycin and start nafcillin
Continue vancomycin
32. A 78-year-old man with enterococcal IE requires treatment

with intravenous antibiotics. The infectious diseases team
would like to use gentamicin for gram-positive synergy
and is seeking your assistance in antimicrobial selection.
Assuming the organism is susceptible, which one of the following antimicrobials is best to recommend in combination
with gentamicin for gram-positive synergy in this patient?
29. A 60-year-old woman with a medical history of diabetes (uncontrolled), hypertension, and end-stage-renal
disease on hemodialysis (M,W,F) is being treated in the
hospital for infective endocarditis. Assuming the infecting pathogen is susceptible, which one of the following
would be the best dosage for dialysis as an outpatient?
A. Linezolid
B. Ceftriaxone
C. Ampicillin
D. Vancomycin
Nafcillin 2g intravenous every 4 hours

Ceftriaxone 1 g intravenous every 12 hours
Daptomycin 10 mg/kg every 24 hours
Cefazolin 2 g every 8 hours
S.R. is a 50-year-old man (height 69 in, weight 118 kg) with a

history of hypertension and type 2 diabetes. He is admitted for
management of IE caused by E. faecalis (ampicillin-sensitive).
S.R. has an allergy to penicillin (rash). His most recent laboratory results include WBC 18.3 103 cells/mm3 and SCr 0.6
mg/dL.

for outpatient parenteral antimicrobial therapy (OPAT)?
A. An 85-year-old man with poorly controlled heart
failure currently receiving inpatient therapy for
enterococcal prosthetic valve endocarditis.
B. A 28-year-old woman with persistently positive blood
cultures currently receiving inpatient therapy for
MRSA NVE
C. A 55-year-old man with VGS NVE who is pending
discharge but clinically stable and has already
completed 2 weeks of therapy
D. A 42-year-old with MSSA NVE who is clinically stable
and has already completed 6 weeks of therapy.
33. S.R.s medical team would like a recommendation on

gentamicin dosing. Which one of the following dosing regimens is best to recommend for S.R.?
A.
B.
C.
D.
90 mg intravenous every 8 hours

34. Which one of the following best describes S.R.s candidacy for antibiotic prophylaxis before future invasive
dental procedures?
A. He is not a candidate for antibiotic prophylaxis
because he does not have a prosthetic valve
31. A 24-year-old man with a history of intravenous drug abuse,

alcohol abuse, and prior IE caused by MRSA treated with
vancomycin is admitted to the hospital after being found
down in a park by paramedics. Upon arrival to the ED,
Nafcillin
A.
B.
C.
D.
A. Vancomycin 15 mg/kg every 12 hours

B. Cefazolin 2 g intravenous every 8 hours plus
C. Nafcillin 2 g intravenous every 4 hours
D. Cefazolin 2 g intravenous every 8 hours
A.
B.
C.
D.
Susceptibility
Linezolid
28. A 40-year-old man is found to have native valve endocarditis secondary to methicillin susceptible Staphylococcus
aureus. He has an allergy to amoxicillin (rash). He has
normal renal function and no underlying comorbid conditions. Which one of the following is best to recommend
for this patient?
MIC (mg/dL)
130
B. He is not a candidate for antibiotic prophylaxis

because he does not have a history of infective
endocarditis
C. He is a candidate for antibiotic prophylaxis and
should receive cephalexin
D. He is a candidate for antibiotic prophylaxis and
should receive amoxicillin
Antibiotic
Susceptibility
Gentamicin synergy
screen
N/A
Streptomycin synergy
screen
N/A
0.5 mg/dL
Vancomycin
35. A 51-year old man is expected to complete the remainder of a 4-week course of outpatient ceftriaxone therapy
for the treatment of viridans group streptococcal IE. He
has a history of myocardial infarction, for which he is taking aspirin 81 mg/day, metoprolol 25 mg twice daily, and
simvastatin 20 mg/day bedtime for 5 years with no complaints. His SCr is 0.8 mg/dL. Which one of the following
monitoring parameters would best ensure the safety of
this patients antibiotic regimen?
Which of the following is the best therapy for this patient?

A.
B.
C.
D.
Ampicillin plus gentamicin

Ampicillin plus ceftriaxone
Vancomycin plus gentamicin
Vancomycin plus ceftriaxone
38. A 63-year-old patient with a history of diabetes mellitus,

renal insufficiency, and peripheral vascular disease presents with NVE caused by E. faecium. The patient is started
on empiric treatment with vancomycin. The laboratory
calls to report that the pathogen is resistant to vancomycin, ampicillin, and linezolid; is sensitive to daptomycin
and tigecycline; and exhibits high-level aminoglycoside
resistance to both gentamicin and streptomycin. Which
of the following is best to recommend initiating for this
patient?
A. Creatine kinase
B. Liver function tests
C. CBC
D. SCr
36. A patient with a history of aortic insufficiency, mitral
regurgitation (bioprosthetic valve replacement 3 years
ago), and benign prostatic hyperplasia develops IE evidenced by complaints of generalized fatigue, fevers, and
chills for the past 1 month. Blood cultures persistently
produce Streptococcus mutans (penicillin MIC 0.12 mg/
dL), and there is evidence of vegetations on TTE. Which
one of the following is best to recommend for this patient?
A. Tigecycline
B. Daptomycin
C. Ampicillin plus ceftriaxone
D. Ampicillin plus gentamicin
39. A 60-year-old man with persistent MRSA bacteremia (day
5 of positive blood cultures) is found to have endocarditis after a TEE reveals a large vegetation on the tricuspid
valve. He was started on vancomycin on day 1 with therapeutic troughs throughout. Vancomycin MIC is 1 mcg/
mL. Which one of the following is best to recommend for
this patient?
A. Ceftriaxone 2 g intravenous every 12 hours for 6

weeks
B. Ceftriaxone 2 g intravenous every 12 hours for 6
weeks plus gentamicin 1 mg/kg intravenous every 8
hours for 2 weeks
C. Ceftriaxone 2 g intravenous every 24 hours for 6
weeks
D. Ceftriaxone 2 g intravenous every 24 hours for 6
weeks plus gentamicin 1 mg/kg intravenous every 8
hours for 6 weeks
A. Continue vancomycin as long as the MIC does not

increase to greater than 1 mcg/mL
B. Because persistent MRSA bacteremia is now defined
as 7 days versus 3 days, therapy modification is not
necessary
C. As long as there is adequate source control,
vancomycin can be continued regardless of how long
the patient has been bacteremic
D. Because it has been more than 34 days of
persistent bacteremia, therapy modification should
be considered regardless of source control
37. A 73-year-old woman (height 63 in, weight 70 kg) with a

history of gout and osteoarthritis is admitted to the hospital with symptoms concerning for NVE. She has no known
drug allergies. Upon admission, her temperature is 38.5
C, WBC count is 17.6 103 cells/mm3, and SCr is 0.8 mg/
dL. Two sets of blood cultures are drawn and Gram stain
reveals gram-positive cocci in chains. Empiric vancomycin therapy is initiated. On day three of admission, blood
cultures revealed E. faecalis growing in all four bottles. A
TTE is performed and reveals a mobile vegetation on the
mitral valve. The physician asks for your assistance in
selecting antibiotics for the patient.
MIC
2 mg/dL
Ampicillin
40. A 37-year-old woman is admitted to a local hospital with

severe sepsis and respiratory distress. Two days later she
is found to have high-grade MRSA bacteremia. After 3
days of persistently positive cultures, she is transferred
to a larger hospital for escalation of care. She had been
started on intravenous vancomycin at the outside hospital (troughs were therapeutic), and this was continued
131
after transfer. Upon arrival, blood cultures are obtained

and TTE as well as chest CT are performed. She is found
to have numerous pulmonary emboli, a small vegetation
on her tricuspid valve, and bilateral lower lobe pulmonary
infiltrates. New blood cultures are positive again (day 5 of
persistent bacteremia). Susceptibility profile of the MRSA
is as follows:
Antibiotic
MIC (mg/dL)
Susceptibility
Ceftaroline
0.5
Daptomycin
Linezolid
Vancomycin
Based on these findings, which one of the following is

A.
B.
C.
D.
Change therapy to vancomycin plus rifampin

Change therapy to daptomycin
Change therapy to ceftaroline
Change therapy to linezolid
132
Learner Chapter Evaluation: Infective Endocarditis.


30. Design an empiric treatment regimen for the patient with
suspected infective endocarditis using patient-specific
factors and the most likely bacteria.
Strongly agree
Agree
Neutral
Disagree
Strongly disagree

31.
Apply pharmacokinetic and pharmacodynamic principles to develop a definitive antimicrobial regimen for the
treatment of infective endocarditis according to patientand pathogen-specific factors.
32. Justify the role of alternative antimicrobials in the management of infective endocarditis based on recently
published evidence.

33. Design strategies for preventing and managing adverse

drug reactions for antimicrobials commonly used for the
treatment of infective endocarditis.

3 4. Analyze the role of different antimicrobials in the management of infective endocarditis in patients transitioning
care to the outpatient setting.

35. Determine which high-risk patient populations warrant

antibiotic prophylaxis for endocarditis during certain
medical procedures.

were effective.


effective.
were effective.

133
Oral Anticoagulants for VTE and

Stroke Prevention in Atrial Fibrillation
By Nancy L. Shapiro, Pharm.D., FCCP, BCPS; and Shubha Bhat, Pharm.D., BCACP
Reviewed by Thaddaus Hellwig, Pharm.D., BCPS; and Allison M. Mann, Pharm.D., BCPS
LEARNING OBJECTIVES
1.
Design an evidence-based therapeutic plan for the treatment of venous thromboembolism.
2. Devise an evidence-based treatment strategy for stroke prevention in atrial fibrillation.

3.
Distinguish the potential risks and benefits of the new oral anticoagulants compared with the vitamin K antagonist,
warfarin.
4.
Formulate an appropriate anticoagulation plan with monitoring parameters in special patient populations.
ACCP
AF
DOAC
DVT
ESC
LMWH
PE
TTR
VKA
VTE
UFH

Physicians
Atrial fibrillation
Direct oral anticoagulant
Deep vein thrombosis
European Society of Cardiology
Low-molecular-weight heparin
Pulmonary embolism
Time in therapeutic range
Vitamin K antagonist
Venous thromboembolism
Unfractionated heparin
INTRODUCTION
For many years, vitamin K antagonists (VKA), mainly warfarin, were
the only long-term option for the management of venous thromboembolism (VTE) and atrial fibrillation (AF). Now, with the availability of
direct oral anticoagulants (DOAC), there are several pharmacologic
options to choose from. This range of options makes pharmacists
more valuable because decisions about which agent to use, appropriate dosage regimens, how and when to monitor, and reversal options
must be considered.
Venous thromboembolism encompasses pulmonary embolism
(PE) and deep venous thrombosis (DVT). The objectives of anticoagulation in VTE treatment are to prevent thrombus extension, avert
recurrence of VTE, and minimize the risk of long-term complications,
such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension.
The most common arrhythmia, AF, is associated with significantly
increased risk of arterial thromboembolism and ischemic stroke
caused by embolization of thrombi within the left atrium of the heart.
In patients with valvular AF (with hemodynamically significant mitral
stenosis or a mechanical prosthetic valve in place), the risk of thrombogenicity is further increased. The objective of anticoagulation in AF
is to prevent thromboembolic complications in addition to providing
proper rate and rhythm control.
ANTICOAGULANT PHARMACOLOGY
Mechanism of Action, Pharmacokinetics, Dosage
Forms, and Administration
A major difference between warfarin and DOACs is warfarins complex mechanism of action. Warfarin inhibits the activation of vitamin
K-dependent clotting factors II, VII, IX, and X, and anticoagulants
135
Anticoagulants in VTE and AF
protein C and protein S, whereas DOACs target only one clotting factor. The nomenclature of these newer anticoagulants
has been extensively discussed since their approval, but the
Scientific and Standardization Committee (SSC) for Control of
Anticoagulation of the International Society for Thrombosis
and Haemostasis (ISTH) recently recommended DOAC as
the acronym for non-vitamin K oral anticoagulants, including direct factor Xa inhibitors and direct factor IIa (thrombin)
inhibitors. Rivaroxaban, apixaban, and edoxaban are the oral
direct factor Xa inhibitors approved by the FDA, whereas dabigatran is the only oral direct thrombin inhibitor currently
approved. The pharmacokinetics, dosage forms, storage, and
administration for oral anticoagulants used for VTE and AF
treatment are shown in Table 3-1.
Drug Interactions
Dosing
TREATMENT OF VTE
Warfarin is known for its drug and herbal interactions caused

by the CYP enzyme system, primarily CYP2C9, and interactions with foods containing a high content of vitamin K, which
can cause fluctuating INRs if the diet is not consistent (Table
3-3). Most of the drug and herbal interactions that alter warfarin concentrations can be managed by adjusting the warfarin
dose. The DOACs offer advantages over warfarin with far
fewer interactions to consider, although effective management of interactions may be difficult as laboratory monitoring
of DOAC concentrations is not readily available at most institutions. Both warfarin and the DOACs can increase the risk for
bleeding when patients are taking concomitant antiplatelet
drugs; thus clinicians should use these agents with caution.
The dosing recommendations for each DOAC vary with indication, renal function, and existing drug interactions (Table 3-2).
It is important for clinicians to ensure the appropriate dose is
being used to enhance the safety profile of these medications.
Acute Management
Rapid therapeutic anticoagulation is necessary in patients

with acute VTE to prevent thrombus extension, cardiovascular and hemodynamic collapse, and mortality. Acute-phase
treatment consists of parenteral anticoagulation (intravenous
unfractionated heparin [UFH], subcutaneous UFH, low-molecular-weight heparin [LMWH], or fondaparinux) for the first
510 days, which should overlap VKA therapy until INR is
23. Alternatively, parenteral anticoagulation can be followed
by dabigatran or edoxaban, whereas rivaroxaban or apixaban
may be started without initial parenteral therapy.
Recently, the DOACs have been evaluated for both initial
and long-term management of VTE, with dabigatran, rivaroxaban, apixaban, and edoxaban receiving FDA label approval
for the initial management of VTE. All DOACs were compared
with LMWH/VKA and found to be noninferior for the primary
end point of rate of recurrent VTE.
In the EINSTEIN-PE clinical trial, rivaroxaban had similar rates of clinically relevant non-major (CRNM) bleeding,
51% reduction in major bleeding, and greater patient satisfaction with less need for efficacy monitoring (Bller 2012;
Prins 2013). In the AMPLIFY trial, apixaban was associated
with a significant reduction in both major bleeding and major
plus CRNM bleeding (Agnelli 2013). A pooled analysis of the
RE-COVER I and RE-COVER II trials using dabigatran 150 mg
twice daily after standard parenteral therapy for a mean of
10 days showed similar rates of major bleeding (Schulman
2014). In the Hokusai-VTE trial, edoxaban was compared with
warfarin after patients received parenteral therapy for a minimum of 5 days (Bller 2013). In contrast to the other trials,
the primary outcome of recurrent VTE or VTE-related death
was measured 12 months after initiation of treatment, regardless of the time on treatment. There was no difference in the
rate of major bleeding; however, there was a significantly
lower incidence of first major bleeding or CRNM bleeding in
the edoxaban arm. Additional details for the DOAC studies are
in Table 3-4.

with the following:
General knowledge of the clotting cascade
Pathophysiology of atrial fibrillation (AF) and
venous thromboembolism (VTE)
Pharmacology and dosing considerations of
vitamin K antagonists and unfractionated heparin/
low-molecular-weight heparin used for AF/VTE
treatment
Table of common laboratory reference values.
ADDITIONAL READINGS
Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice
Guidelines. Chest 2012;141(2_suppl).
2014 AHA/ACC/HRS guidelines for the management of patients with atrial fibrillation: a report of
the American College of Cardiology/American
Heart Association Task Force on Practice
Guidelines and the Heart Rhythm Society . J Am
CDC. Deep Vein Thrombosis (Blood Clots) [homepage on the Internet].
136
Table 3-1. Pharmacokinetics, Dosage Forms, Administration, and Storage of Oral Anticoagulants
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Tmax (hours)
1.253
24
34
12
T (hours)
40
1217;
Up to 27 in severe
renal impairment
59;
1113 in elderly
patients
12
1014
Metabolism
CYP2C9 primary,
(CYP3A4, 1A2, 2C19
minor pathways)
Conjugation (no CYP

involvement)
Oxidation (via CYP3A4

and CYP2J2) and
hydrolysis
Oxidation (via
CYP3A4) and
conjugation
Minimal by
oxidation,
conjugation and
hydrolysis
Elimination
Renal, primarily as
metabolites
Renal (80% unchanged Renal (36% unchanged Renal (27%

drug)
drug)
unchanged drug)
Renal (35%
unchanged drug)
1, 2, 2.5, 3, 4, 5, 6,
7.5, 10
75, 150
15, 30, 60
Capsule
Pharmacokinetics
Dosage Forms, Administration, Storage

Strengths (mg)
10, 15, 20
2.5, 5
Dosage Form
Tablet
Tablet
Tablet
Tablet
Splitting,
Crushing, or
Chewing
May split tablet in half No; will increase

May crush tablet
exposure to
and mix with water
medication
or applesauce
immediately before
use
May crush tablet

and mix with water
or applesauce
immediately before
use
Do not administer via
feeding tubes placed
distal to the stomach
due to decreased
absorption
May be crushed
and suspended
in 60 mL D5W
and immediately
delivered through
nasogastric tube
No
recommendations
provided
Dietary Concerns
With or without food

Maintain consistent
vitamin K intake
Acute alcohol
ingestion can
increase INR
With or without food
Doses > 10 mg need

to be taken with
evening meal (no
specific minimum kcal
provided)
With or without food With or without food
Storage
Considerations
None
Capsules must be
None
stored in original
bottle or blister pack
to protect against
moisture. Bottle must
be discarded 4 months
after being opened
None
None
T = half-life
Information from: Hull RD, Gersh MH. The current landscape of treatment options for venous thromboembolism: a focus on novel
oral anticoagulants. Curr Med Res Opin 2015;31:197-210; and package inserts.
of recurrent VTE, and rivaroxaban and apixaban demonstrated

a lower risk of major bleeding. Selected VTE anticoagulation treatment recommendations from clinical guidelines by
American College of Cardiology (ACCP) and European Society
of Cardiology (ESC) are listed in Table 3-5.
A meta-analysis found no statistically significant differences for efficacy or safety outcomes associated with most
DOAC treatment strategies used to treat acute VTE compared
with LMWH/VKA combination (Castellucci 2014). However,
the UFH/VKA combination was associated with a higher rate
137
Chronic Management
warfarin 10 mg daily for the first 2 days, followed by dosing based

on INR measurements, rather than starting with an estimated
maintenance dose (Grade 2C) (Holbrook 2012). There has also
been interest in the value of warfarin pharmacogenomics to
guide appropriate dosing strategies. The CYP2C9 and vitamin K
epoxide reductase complex 1 (VKORC1) genotypes may affect
warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be
predictive of stable warfarin dose (Johnson 2015). However, two
recent randomized clinical trials evaluating genotype-guided
warfarin dosing produced mixed results, questioning the utility of this approach (Kimmel 2013; Pirmohamed 2013). Based
on current data that fail to show a benefit, ACCP recommends
against the routine use of pharmacogenetic testing for guiding
doses of VKA (Grade 1B). Until recently, the standard of care
for patients treated with warfarin included INR testing every
4 weeks. However based on the results of three randomized
controlled trials showing no difference in rates of bleeding,
thromboembolism, or INR control, ACCP suggests that it is
appropriate to postpone the testing duration to 12 weeks for
Choice of Therapy
Recommendations for anticoagulation agent selection in

the chronic phase of VTE treatment (out to 3 months) are
summarized in Table 3-5. The ESC recommends rivaroxaban or apixaban as suitable alternatives to a parenteral
anticoagulant with VKA, and dabigatran or edoxaban as alternatives to VKA after acute-phase parenteral anticoagulation
(Konstantinides 2014). In patients with VTE who are treated
with VKA for chronic treatment, ACCP recommends a therapeutic INR range of 2.03.0 (target 2.5) over a lower range
(INR <2) or higher range (INR 3.0-5.0) for all treatment durations (Grade 1B) (Kearon 2012). This recommendation is per
the ELATE trial, which showed that lower-intensity anticoagulation (INR 1.51.9) was less effective at preventing recurrent
VTE than standard anticoagulation and did not lower the risk
of bleeding (Kearon 2003).
For patients sufficiently healthy to be treated as outpatients,
ACCP suggests initiating VKA therapy with a loading dose of
Table 3-2. Approved Dosing of Warfarin and DOACs for AF and VTEa
Drug
Atrial Fibrillationb
VTE Treatment
Warfarin
Individualize dosing to goal INR 23
Individualize dosing to goal INR 23
Dabigatran
CrCl >30 mL/min: 150 mg BID

CrCl 15-30 mL/min: 75 mg BID
CrCl <15 mL/minute or on dialysis: Dosing
recommendation cannot be provided
CrCl >30 mL/minute: LMWH or UFH x 5-10 days,

then dabigatran 150 mg BID
CrCl 30 mL/minute or on dialysis: Dosing
recommendation cannot be provided
Extended treatment to prevent VTE recurrence with
CrCl >30 mL/min: 150 mg BID
Rivaroxaban
CrCl >50 mL/min: 20 mg daily

CrCl 15-50 mL/min: 15 mg daily
CrCl <15 mL/min: Avoid
15 mg BID x 21 days, then 20 mg daily for CrCl 30

mL/min
CrCl <30 mL/min: Avoid
Extended treatment to prevent VTE recurrence: 20
mg daily
Apixaban
Most patients: 5 mg BID

If with two or more factors: SCr 1.5 mg/dL or age 80
years or weight 60 kg: 2.5 mg BID
10 mg BID x 7 days, then 5 mg BID

No dose adjustment recommended for renal
function
Extended treatment to prevent VTE recurrence: 2.5
mg BID
Edoxaban
CrCl > 95 mL/min: Do not use

CrCl 5195 mL/min: 60 mg daily
CrCl <15 mL/min: use is not recommended
CrCl >50 mL/min: LMWH or UFH x 510 days, then

edoxaban 60 mg daily
CrCl <15 mL/min: use is not recommended
Patients 60 kg: 30 mg daily
Dosing recommendations to accommodate certain drug interactions are provided in Table 3-3.
DOACs are indicated only for non-valvular atrial fibrillation.
BID = twice daily; LMWH = low-molecular-weight heparin; UH = unfractionated heparin; VTE = venous thromboembolism.
Information from package inserts.
138
patients who have maintained consistently stable INRs for at

least 6 months (Grade 2B) (Holbrook 2012). In clinical practice,
these data and the change in recommendation provide an extra
level of flexibility for clinicians when determining how often to
repeat INR monitoring in well-controlled patients.
monitoring includes the recommended safeguards (i.e., discussion with their anticoagulation provider).
Studies show that individuals performing self-testing almost
weekly have better time in therapeutic range (TTR) than patients
undergoing in-clinic testing every 4 weeks using high-quality
anticoagulation management (defined as designated, trained
staff responsible for patients visits and follow-up; using a
standard, local procedure at each study site for anticoagulation management) (Matchar 2010). A substudy of this trial also
showed that individuals receiving chronic anticoagulation who
perform self-testing more often (i.e., weekly or twice weekly) had
a modestly higher TTR than with monthly testing (Matchar 2014).
Although the costs of the self-testing meter and supplies are
often covered by the patients insurance, the poor reimbursement provided to clinic personnel who are making the dose
adjustment recommendations often limits provider willingness
to offer this service. If this method of reimbursement is not a
concern, then patient self-testing can be a way to empower
patients to take control of their warfarin management and
reduce the burden of frequent outpatient visits.
Patient Self-Testing of Warfarin
Traditional provider-based INR monitoring presents barriers

to quality warfarin management that include keeping appointments and visits to a laboratory for INR testing. Pending
insurance approval, patients may have access to an INR
meter while on warfarin. These meters allow for self-testing of INRs, with results discussed with a provider, as well
as self-management, in which patients trained in self-testing
and well-educated about warfarin and its risks are allowed to
adjust their warfarin doses without provider input. It is ACCPs
suggestion that self-management may be used for patients
treated with VKAs who are motivated and demonstrate competency in self-management strategies and equipment
use (Grade 2B). However, for all other patients, suggested
Table 3-3. Drug Interactions with Warfarin and the DOACs
Drug
Recommendation
Warfarin
For patients taking CYP2C9, CYP3A4, CYP1A2 inhibitors and inducers: consider avoiding concomitant use or
adjusting warfarin dose with close INR monitoring
For initiation or changes with medications that have high protein binding: consider increased INR monitoring
Dabigatran
p-GP inhibitors:
AF
CrCl 3050 mL/minute: decrease dose to 75 mg BID with ketoconazole or dronedarone
CrCl < 30 mL/minute: avoid concomitant use

VTE
CrCl <50 mL/min: avoid concomitant use

p-GP inducers (e.g., rifampin): avoid concomitant use
Rivaroxaban
Dual p-GP inhibitors and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, indinavir,
conivaptan):
avoid concomitant use
Dual p-GP inducers and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. Johns wort):
Apixaban
Dual p-GP inhibitors and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir,
clarithromycin): for patients receiving doses of 5 or 10 mg BID, reduce dose by 50%; in patients taking 2.5
mg BID, avoid co-administration
Dual p-GP inducers and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. Johns wort):
Edoxaban
p-GP inhibitors (e.g., verapamil, quinidine, or short term-concomitant administration of azithromycin, clarithromycin,
erythromycin, oral itraconazole, or oral ketoconazole):
AF: no dose reduction is recommended
VTE: reduce dose to 30 mg daily
p-GP inducers: avoid concomitant use with rifampin
AF = atrial fibrillation; BID = twice daily; DOAC = direct oral anticoagulant; VTE = venous thromboembolism
Information from package inserts.
139
Table 3-4. Phase 3 Trials of DOACs vs. Standard of Care for Acute VTE Treatment
Trial
RECOVER
1 and 2
pooled analysis
(n=5107)
EINSTEIN
pooled analysis
(n=8282)
AMPLIFY
(n=5395)
HOKUSAI-VTE
(n=8240)
DOAC
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Dosing
Parenteral
anticoagulation 5 days,
then 150 mg PO BID
15 mg PO BID x 21 days,
then 20 mg PO daily
10 mg PO BID x 7 days,
then 5 mg PO BID
Parenteral anticoagulation
5 days, then 60 mg PO
daily
Comparator
Parenteral anticoagulation (UFH, LMWH, or fondaparinux) bridge to VKA
Duration of therapy
(months)
Recurrent VTE
Major bleeding, %
ICH, n
GI, n
3, 6, or 12
3, 6, or 12
2.4% Dabigatran vs. 2.2% 2.1% Rivaroxaban vs. 2.3%

VKA
VKA
2.3% Apixaban vs. 2.7%

VKA
3.2% Edoxaban vs. 3.5%

VKA
1.4% Dabigatran vs.2%

VKA
ICH: n=2 Dabigatran vs.
5 VKA
GI: n=48 Dabigatran vs.
33 VKA
0.6% Apixaban vs. 1.8%

VKAa
ICH: n=3 Apixaban vs.
6 VKA
GI: n=7 Apixaban vs. 18
VKA
1.4% Edoxaban vs. 1.6% VKA

ICH: n=6 Edoxaban vs. 18
VKA
GI: n=1 Edoxaban vs. 2 VKA
(only fatal events reported
1.0% Rivaroxaban vs. 1.7%

VKAa
ICH: n=5 Rivaroxaban vs. 13
VKA
GI: n=1 Rivaroxaban vs. 3 VKA
(only fatal events reported)
Statistically significant reduction with DOAC.
Italics = actual number of cases of ICH and GI bleeding reported.

BID = twice daily; DOAC = direct oral anticoagulant; ICH = intracranial hemorrhage; LMWH = low-molecular-weight heparin; PO = by
mouth; UH = unfractionated heparin; VKA = vitamin K antagonist; VTE = venous thromboembolism
Information from: Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or
warfarin and pooled analysis. Circulation 2014;129:764-72; Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus
standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE
randomized studies. Thromb J 2013;11:21; Agnelli G, Bller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous
thromboembolism. N Engl J Med 2013;369:799-808; Bller HR, Dcousus H, Grosso MA, et al. Edoxaban versus warfarin for the
treatment of symptomatic venous thromboembolism. N Engl J Med 2013;9:1406-15.
Duration of Therapy
Provoked VTE
The many known risk factors for the development of VTE have
been well described. The strongest predictor of recurrent VTE is
a history of VTE. When evaluating a patients risk factors for VTE,
it is important to consider whether the VTE was provoked as a
result of a temporary or reversible risk factor (surgery, trauma,
immobilization, pregnancy, and drugs, including estrogens
and certain chemotherapies such as lenalidomide within the 3
months before diagnosis) or unprovoked, with no identified risk
factors present. The presence of continuing risk factors may be
used in deciding the length of anticoagulation therapy.
The VKAs are highly effective at reducing the rate of recurrent events while patients are on treatment, but that benefit
subsides after treatment is discontinued (Douketis 2007). The
10-year risk for recurrent VTE is 30%, and the risk of recurrence is highest in the first 2 weeks of therapy (Heit 2012).
Both ACCP and ESC Guidelines for PE endorse a minimum of
3 months of anticoagulation for the treatment of VTE (Kearon
2012; Konstantinides 2014). Table 3-6 compares the recommendations for duration of therapy between these two groups.
Both the ACCP and ESC have endorsed 3 months of anticoagulation therapy for VTE provoked by known causes. If patients
have poor quality of anticoagulation control with a low TTR, it
is reasonable to extend the interval until 3 continuous months
of quality anticoagulation has been obtained. Although many
clinicians still use 6 months as the intended length of treatment, neither the ACCP nor the ESC recommend this duration.
Many patients inquire about whether imaging is necessary to
see if their clot is gone; however, there are no formal recommendations for or against this testing, and this use of imaging
remains an area of controversy.
Unprovoked VTE
For unprovoked proximal DVT and PE, the minimal duration

of treatment recommended is 3 months, after which time
the patients individual risk of recurrence, bleeding risk, and
willingness to take long-term anticoagulation must be considered. In contrast, because of the lower risk of embolization
with unprovoked distal DVT, current ACCP recommendations
140
Table 3-5. Selected VTE Anticoagulation Treatment Recommendations
Initial VTE
treatment
American College of Chest Physicians (ACCP) 2012
European Society of Cardiology (ESC)

2014
LMWH, fondaparinux, IV UFH, or SC UFH, over no initial treatment

(Grade 1B)
Start VKA on first treatment day (Grade 1B)
Overlap treatment with parenteral anticoagulation and VKA for at
least 5 days and until INR 2 at least 24 hours (Grade 1B)
If INR >3.0 prematurely, it is acceptable to stop parenteral
anticoagulation before 5 days of treatment
High-risk PE (with shock or hypotension):

IV UFH without delay (Grade 1C)
Intermediate-or low risk (PE without
shock or hypotension): parenteral
anticoagulation without delay while
diagnostic workup in progress (Grade
1C)
Anticoagulation LMWH (Grade 2C) or fondaparinux (Grade 2B) over IV UFH

selection
LMWH (Grade 2B) or fondaparinux (Grade 2C) over SC UFH
If concern about the adequacy of SC absorption, or fibrinolytics
being considered or planned: Initial treatment with IV UFH
preferred over the use of SC therapies
VTE in the absence of cancer: VKA therapy over LMWH for longterm therapy (Grade 2C)
VTE in the absence of cancer, not treated with VKA: LMWH over
dabigatran or rivaroxaban for long-term therapy (Grade 2C)
Most patients (without shock or

hypotension): LMWH or fondaparinux
(Grade 1A), with VKA treatment to goal
INR 2-3 (Grade 1B)
Alternative to parenteral/VKA:
Rivaroxaban or apixaban (Grade 1B)
Alternatives to VKA after acute-phase
parenteral anticoagulation: Dabigatran
or edoxaban (Grade 1B)
IV = intravenous; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; SC = subcutaneous; UFH = unfractionated heparin; VKA = vitamin K antagonist.
Information from: Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute
pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European Society of
Cardiology (ESC) endorsed by the European Respiratory Society (ERS). Eur Heart J 2014;35:3033-69; and Kearon C, Akl EA,
Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American
College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e419S-94S.
are 3 months of anticoagulation versus a longer treatment
VKA, provided the patient does not have severe renal impairment (Class IIa Level B) (Konstantinides 2014).
For patients thought to be unsuited for warfarin therapy or
who refuse long-term anticoagulation, aspirin 100 mg daily
reduces the rate of VTE recurrence compared with placebo
without increasing the risk for major bleeding (Beccatini
2012). The treatment effect of aspirin (about 40% reduction
in events) is much less than that achieved with warfarin, dabigatran, rivaroxaban, or apixaban (more than 80%) (see Table
3-7). There is no mention by ACCP of the use of aspirin for
the extended treatment of VTE; however, ESC does state that
aspirin is a reasonable option only in patients who would otherwise not be receiving oral anticoagulants (Class IIa Level B)
(Konstantinides 2014).
duration (Kearon 2012).

Options for Extended Treatment of VTE
Until recently, warfarin has been the mainstay of extended

therapy (beyond the first 3 months) for patients at high risk
of VTE recurrence. With the approval of DOACs, other options
now exist. Rivaroxaban, dabigatran, and apixaban have FDA
label approval for the extended treatment of VTE, whereas
edoxaban has not yet been studied for this indication. Results
of the major trials for extended therapy are shown in Table 3-7.
For rivaroxaban and dabigatran, the full treatment dose is
continued when the extended treatment phase begins; in contrast, a reduced dose of 2.5 mg twice daily was approved for
apixaban. The DOACs have been associated with low rates of
STROKE PREVENTION IN ATRIAL

FIBRILLATION
VTE recurrence and low rates of major bleeding, comparable with warfarin. Currently, ACCP recommends that patients
receiving extended therapy be treated with the same antico-
Risk Stratification
agulant that was used in the first 3 months (Grade 2C) (Kearon
Atrial fibrillation is a major risk factor for ischemic stroke, which

often results in severe disability and high mortality. Without anticoagulation, the average risk of stroke is 5% per year; however,
2012), whereas the more recent ESC guidelines recommend

rivaroxaban, dabigatran, or apixaban as an alternative to a
141
Table 3-6. Recommended Duration of Secondary Prevention of VTE

Length of
Therapy
Indication
ACCP (2012)
ESC (2014)
3 Months
Provoked proximal DVT or PE
1B
IB
Provoked isolated distal DVT
2C
First unprovoked proximal DVT or PE with high

bleeding risk
1B
Second unprovoked VTE, high bleeding risk
2B
At Least 3 Months First unprovoked isolated DVT or PE
1B
IA
1B
IC
2B (low bleeding risk)

2B (moderate bleeding risk)
IIaB
Second unprovoked VTE with low or moderate

bleeding risk
1B (low bleeding risk)

2B (moderate bleeding risk)
IB
DVT of leg or PE with active cancer
1B (low-moderate bleeding risk)

2B (high bleeding risk)
IIaC
Evaluate for risk-benefit of extended therapy at 3

months
Extended Therapy First unprovoked proximal DVT or PE, low or
moderate bleeding risk
ACCP = American College of Chest Physicians; DVT = deep vein thrombosis; ESC = European Society of Cardiology; PE = pulmonary
embolism VTE = venous thromboembolism.
Information from: Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute
pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European Society of
Cardiology (ESC) endorsed by the European Respiratory Society (ERS). Eur Heart J 2014; 35:3033-69; Kearon C, Akl EA, Comerota
AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-94S.
the decision to initiate and continue anticoagulation depends
these tools may be used to assist in deciding whether a patient
on the individual patients thromboembolism and bleeding risk.
with non-valvular AF warrants anticoagulation therapy, they
Multiple risk stratification tools are available to assist with iden-
should not replace clinical judgment. Other factors to consider
tifying a patients stroke and bleeding risk.
in determining whether initiation of anticoagulation therapy
The validated CHADS2 and CHA2DS2VASc are simple tools to
is appropriate include the pharmacokinetic profiles, patient
identify stroke risk in patients with non-valvular AF. Traditionally,
co-morbidities, socioeconomic factors, and patient preferences.
CHADS2 was the scoring tool preferred by clinicians. The
CHA2DS2VASc (Table 3-8) was then used in the setting of a cal-
Choice of Therapy
factors and further stratify stroke risk. However, the CHADS2
tion therapy may be warranted if the benefit of preventing a
culated CHADS2 score of 0 or 1, to account for additional risk
Depending on a patients CHA 2DS 2VASc score, anticoagula-
tool has limitations: it underestimates stroke risk in patients who
thromboembolic event outweighs the risk of major bleeding
have experienced a prior stroke and leaves clinicians questioning
(Table 3-10).
Until recently, warfarin was the only effective treat-
the lack of treatment in patients with CHADS2 score of 0 because
these patients have a 2% annual stroke risk. To overcome these
ment option for stroke prevention; it is associated with 64%
weaknesses, the 2014 American Heart Association/American
risk reduction in stroke and systemic embolism, and 25%
College of Cardiology/Heart Rhythm Society guideline recom-
reduction in mortality. The emergence of the DOACs signifi-
mend stratifying AF patients using CHA2DS2VASc.
cantly expands the options for anticoagulation. All currently
a patients bleeding risk (Table 3-9). Unfortunately, none of these
warfarin for stroke prevention in AF (Table 3-11).
approved DOACs have been compared with adjusted-dose
Multiple scoring systems have been developed to determine
have been associated with high predicative accuracy, and thus
Overall, the DOACs have been shown to be as effective
are not recommended for routine use in practice. Although
as warfarin for stroke prevention in patients with AF and are
142
Table 3-7. Phase III Trials with Warfarin, DOACs, and Aspirin for Extended VTE
Trial
Treatment Groups
(Treatment Duration)
Recurrent VTE
(%)
Risk Reduction
for Recurrent
VTE (%)
Major Bleed
(%)
Major Bleed +
CRNM
(%)
PREVENT
(n=508)
Warfarin INR 1.52.0 vs.

placebo
(4.3 years)
Active treatment 2.6c

Comparator 7.2c
64

Comparator 0.9c
Active treatment NR
Comparator NR
ELATE
(n=738)
Warfarin INR 2-3 vs.

warfarin INR 1.51.9
(2.4 years)

Comparator 1.9c
64

Comparator 1.1c
Active treatment NR
Comparator NR
RE-SONATEa
(n = 1343)
Dabigatran 150 mg BID

vs. placebo
(6 months)
Active treatment 0.4

Comparator 5.6
92

Comparator 0

Comparator 1.8
RE-MEDYa
(n=2856)
Dabigatran 150 mg BID

vs. VKA INR 23
(036 months)

Comparator 1.3
Risk difference
0.38 vs. VKA

Comparator 1.8
Active treatment 5.6d

Comparator 10.2
EINSTEIN-EXTb Rivaroxaban 20 mg daily

(n=1196)
vs. placebo
(6 or 12 months)

Comparator 7.1
82

Comparator 0
Active treatment 6
Comparator 1.2
AMPLIFY-EXTb Apixaban 5 mg BID or

(n=2486)
2.5 mg BID vs. placebo
(1 year)
Active treatment:
5 mg: 1.7
2.5 mg: 1.7
Comparator 8.8
5 mg: 80
2.5 mg: 81
Active treatment:
5 mg: 0.1
2.5 mg: 0.2
Comparator 0.5
Active treatment:
5 mg: 3.2
2.5 mg: 4.3
Comparator 2.3
WARFASA
(n=402)
Aspirin 100 mg daily vs.

placebo
(24 months)
Active treatment 6.6c,e 40

Comparator 11.2c

Comparator 2
Active treatment 1c
Comparator 1c
ASPIRE
(n=822)
Aspirin 100 mg daily vs.

placebo
(4 years; actual 27
months)

Comparator 6.5c
26

Comparator 1.4

Comparator 0.6c
Patients had completed 3 months of anticoagulant treatment before study entry.
Patients had completed 6 to 12 months of anticoagulant treatment before study entry.

Incidence per patient-year.
d
HR 0.54 (0.410.71) p<0.001.
e
HR 0.58; 95% CI, 0.36 to 0.93; p = 0.02.
BID = twice daily; CRNM = clinically relevant non-major bleeding; ICH = intracranial hemorrhage; NR = not reported.
Information from: Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of
recurrent venous thromboembolism. N Engl J Med 2003;348:1425-34; Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of lowintensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous
thromboembolism. N Engl J Med 2003;349:631-9; Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or
placebo in venous thromboembolism. N Engl J Med 2013;368:709-18; Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban
for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510; Agnelli G, Bller HR, Cohen A, et al. Apixaban for
extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708; Becattini C, Agnelli G, Schenone A, et al. Aspirin
for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366:1959-67; Brighton TA, Eikelboom JW, Mann K, et
al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012;367:1979-87.
b
c
associated with less intracranial hemorrhage and reduced
ARISTOTLE, ENGAGE AF-TIMI 48), and bioprosthetic valves
all-cause mortality. However, the DOACs, except apixaban,
(RE-LY, ROCKET-AF, ARISTOTLE). One study (RE-ALIGN)
are associated with a 25% increase in risk of GI bleeding
actually found an increased risk of stroke and bleeding in
(Ruff 2014). Additionally, patient populations excluded from
patients with mechanical heart valve treated with dabiga-
the clinical trials include those with CrCl <30 mL/minute
tran compared with warfarin (Eikelboom 2013). Additionally,
(RE-LY, ROCKET-AF, ENGAGE AF-TIMI), CrCl <25 mL/minute
a subanalysis of ENGAGE AF-TIMI 48 found a higher rate of
(ARISTOTLE), mechanical heart valves (RE-LY, ROCKET-AF,
ischemic stroke in patients treated with edoxaban 60 mg daily
143
shown in several meta-analyses to identify patients at higher

risk of developing recurrent VTE (Bruinstroop 2009; Douketis
2010; Marcucci 2013; Verhovsek 2008), independent of the timing of D-dimer testing, patient age, and the assay cut point used
(Douketis 2010). A low D-dimer value in this setting may identify
patients at low risk of recurrence who can discontinue warfarin, whereas a positive D-dimer test may identify patients with
a persistent prothrombotic tendency. However, one consideration to note is that D-dimer is an acute-phase reactant that is
nonspecific and may be elevated by other conditions.
compared with warfarin in patients with CrCl >95 mL/min, a

finding that led to a boxed warning and absolute contraindication for patients with that renal function.
TREATMENT CONTROVERSIES
Utility of D-dimer Testing
D-dimer testing performed several weeks after 3-6 months of

warfarin therapy has been completed is a strategy identified to
predict the likelihood of recurrent VTE and the need for continuing anticoagulation. A positive D-dimer (typically >0.5 mg/dL)
at the time of warfarin discontinuation or shortly thereafter was
Management of Residual Vein Thrombosis
Residual vein thrombosis (RVT), also called chronic thrombus,

indicates a prothrombotic state and may guide the determination of optimal anticoagulation duration. Persistence of RVT
on duplex ultrasonography after an episode of proximal DVT
was identified as an independent risk factor for recurrent VTE
and confirmed in two separate meta-analyses (Donadini 2014;
Tan 2011). Residual thrombosis predicts recurrent ipsilateral
DVT, as well as contralateral DVT and even PE that is not associated with DVT. Whether algorithms that use the presence
of RVT together with other strong clinical baseline and postevent factors help predict the risk of recurrent VTE is an area
of research that still needs to be explored. Until then, it may be
reasonable to use duplex ultrasonography in the evaluation of
whether anticoagulation should be discontinued.

A 36-year-old woman with a medical history of PE
(unprovoked) and acid reflux on pantoprazole 40 mg
daily completed 3 months of warfarin therapy with therapeutic INRs. A repeat CT scan showed resolution of
thrombus. However, within 14 days of discontinuing warfarin, the patient experiences new onset of shortness of
breath and chest pain. She denies any risk factors such
as immobility, trauma, or long travel. She reports her
father died from a stroke. In the ED, she is found to have
a new PE. Her current INR is 0.9 and the rest of her laboratory values are within normal limits. The patient does
not want to take warfarin but is amendable to trying a
DOAC that is dosed once daily. What is the best anticoagulation plan and duration of therapy for this patient?
Table 3-8. CHA 2DS 2VASc Definition and Stroke Risk
ANSWER
Based on the patients preference for a therapy dosed

once daily, she could be started on LMWH for 510 days
and then transitioned to edoxaban 60 mg daily. If she
is unwilling or unable to perform LMWH injections, an
appropriate alternative is rivaroxaban 15 mg twice daily
for 21 days; then transition to 20 mg daily if she agrees
to take rivaroxaban twice daily for the 21-day period.
Both apixaban and dabigatran need to be dosed twice
daily and are therefore not preferred by the patient.
Since the patient did well on warfarin and had stable
INRs, this is also a reasonable option, depending on her
rationale for not wanting to start it again. Considering
the patient had one unprovoked event before and now
has a second event of unidentified etiology, it would be
reasonable to consider lifelong anticoagulation therapy
in this patient.
Points
C: Congestive Heart Failure
H: Hypertension
A: Age 75 years
D: Diabetes
S: Previous stroke/transient ischemic 2

attack/systemic embolus
V: Vascular disease (prior myocardial 1
infarction, angina, coronary artery
bypass grafting, aortic plaque)
1. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of
Chest Physicians evidence-based clinical practice guidelines.
Chest 2012;141:e419S-94S.
2. Bller HR, Dcousus H, Grosso MA, et al. Edoxaban versus
warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;9:1406-15.
A: Age 6574 years
Sc: Sex category (female)
Total Points = Stroke Rate (%/year)
0 (0); 1 (1.3); 2
(2.2); 3 (3.2); 4
(4); 5 (6.7); 6 (9.8);
7 (9.6); 8 (6.7); 9
(15.2)
Information from: January CT, Wann LS, Alpert JS, et al. 2014
AHA/ACC/HRS guidelines for the management of patients
with atrial fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on
Practice Guidelines and the Heart Rhythm Society. J Am
3. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban

versus standard therapy for the treatment of symptomatic
venous thromboembolism: a pooled analysis of the EINSTEINDVT and PE randomized studies. Thromb J 2013;11:21.
CHA2DS2VASc
144
Clinical Prediction Models
Currently, the Men Continue and HERDOO2 model is being
The identification of patients at low risk of recurrence who are

suitable candidates for anticoagulation discontinuation has
been an area of ongoing research. Two clinical prediction mod-
validated in a prospective, multi-national cohort study (Rodger
els, DASH and Vienna, have proved useful for evaluating the
risk of VTE recurrence in patients with unprovoked VTE (Table
3-12). Both models must be performed 1 month after antico-
need for a repeat visit and avoiding the risk of exposing patients
agulation discontinuation, which limits their practicality.
els, are needed before clinicians use them routinely in practice.
2014). Unlike the Vienna and DASH models, this model is applied
while patients are on anticoagulation, thereby eliminating the
to time off anticoagulation. Results of this prospective trial, as
well as other studies using the DASH and Vienna prediction mod-
Table 3-9. Tools to Identify Risk of Major Bleed

Tool
Criteria
Point
Total Points
(Bleeding Rate [%/year])
HAS-BLED
Hypertension (uncontrolled, systolic BP >160 mm Hg)
Abnormal liver or renal function (cirrhosis, bilirubin >2x

normal, AST/ALT >3x normal; SCr >2.6 mg/dL, dialysis,
transplant)
1 (each)
Stroke history
Bleed history (or anemia)
Labile INR (<60% of time therapeutic)
Elderly (age > 65 years)
0 (1.13)
1 (1.02)
2 (1.88)
3 (3.74)
4 (8.7)
5 (7.4)
68 (insufficient data
because of study sample
size but considered high
risk of bleeding)
Drugs (anti-platelet agent/NSAID use or alcohol use of >8

drinks/week)
1 (each)
Anemia
Severe renal disease (GFR <30mL/minute or

dialysis-dependent)
ATRIA
HEMORR 2HAGES
Age >75 years
Any prior hemorrhage diagnosis (e.g., GI bleed, intracranial

hemorrhage)
Hypertension history
Hepatic or renal disease
Ethanol (alcohol) abuse
Malignancy
Older (age >75 years)
Reduced platelet count or function (aspirin use,

thrombocytopenia or blood dyscrasia)
Rebleeding risk
Hypertension (uncontrolled)
Anemia
Genetic factors (CYP2C9 polymorphisms)
Excessive fall risk
Stroke
03 (0.76)
4 (2.6)
510 (5.76)
01 (2.5)
2 (5.3)
3 (8.4)
4 (10.4)
5 (12.3)
Information from: Pisters R, Lane D, Nieuwlatt R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding
in patients with atrial fibrillation. The Euro Heart Survey. Chest 2010;138:1093-1100; Fang M, Go A, Chang Y, et al. A new risk scheme
to predict warfarin-associated hemorrhage: the ATRIA (anticoagulation and risk factors in atrial fibrillation) study. J Am Coll Cardiol
2011;58:395-401; Gage B, Yan Y, Milligan P, et al. Clinical classification schemes for predicting hemorrhage: results from the National
Registry of Atrial Fibrillation (NRAF). Am Heart J 2006;151:713-9.
145
Monitoring Considerations
Table 3-10. Recommended Antithrombotic Therapy
Monitoring of anticoagulation for warfarin is well established:
According to CHA 2DS 2VASc Scorea
INRs serve as a way to determine safety, efficacy, and adherence; anticoagulation clinics serve as a way to increase TTR
Score
Recommended Therapy
No antithrombotic therapy
No antithrombotic therapy OR treatment with oral

anticoagulant or aspirin may be considered (IIB,
level C)
Warfarin (INR 23) (I, level A), dabigatran (I, level

B), rivaroxaban (I, level B), or apixaban (I, level B)
and reduce anticoagulation-related complications. In contrast,

the DOACs do not require routine monitoring of efficacy, and
laboratory testing to determine treatment adherence is not readily available in most institutions. Patient adherence with DOACs
in observational studies has been poorer than that observed
in clinical trials. It is important to note that suboptimal adherence to dabigatran has been associated with an increased risk
of stroke and death. Because DOACs do not need dose titra-
At time of guideline publication, edoxaban was not yet

approved by the FDA
tion or drug concentration or clinical effect monitoring, it is not

known whether patients would benefit from a monitoring infra-
Information from: January CT, Wann LS, Alpert JS, et al.

2014 AHA/ACC/HRS guidelines for the management of
patients with atrial fibrillation: a report of the American
College of Cardiology/American Heart Association Task
Force on Practice Guidelines and the Heart Rhythm
Society. J Am Coll Cardiol 2014;64:e1-76.
structure similar to what is in place for warfarin.

A study involving retrospective quantitative and cross-sectional qualitative data at Veterans Health Administration sites
found variation in patient adherence to dabigatran, defined by
proportion of days covered (ratio of days supplied by prescription to follow-up duration) of 80% or more (Shore 2015). The
Table 3-11. Comparison of DOACs vs. Adjusted-Dose Warfarin for Stroke Prevention in Atrial Fibrillation
Outcome
RE-LY
(dabigatran)
ROCKET-AF
(rivaroxaban)
ARISTOTLE
(apixaban)
Dose
150 mg BIDa
20 mg/day OR 15 mg/
day if CrCl 3049 mL/
min
5 mg BID OR 2.5 mg
BID if 2 of following:
age 80 years, SCr
1.5 mg/dL, body
weight 60 kg
60 mg/day OR 30 mg/
day; dose was halved
if CrCl 3050 mL/
min, weight 60 kg, or
concomitant use of
verapamil or quinidine
Mean CHADS 2 score
2.1
3.5
2.1
2.8
TTR of warfarin (%)
64
55
62.2
68.4
Stroke or systemic
embolism
0.66 (0.530.82)
0.88 (0.751.03)
0.79 (0.660.95)
0.79 (0.630.99)
H: 0.26 (0.140.49)
H: 0.59 (0.370.93)
H: 0.51 (0.350.75)
H: 0.54 (0.380.77)
I: 0.76 (0.60.98)
I: 0.94 (0.751.17)
I: 0.92 (0.741.13)
I: 1 (0.831.19)
0.93 (0.811.07)
1.04 (0.91.2)
0.69 (0.60.8)
0.8 (0.710.91)
ICH: 0.4 (0.270.6)
ICH: 0.67 (0.470.93)
ICH: 0.42 (0.30.58)
ICH: 0.47 (0.340.63)
GI: 1.5 (1.191.89)
GI: 3.15 (No CI

reported)
GI: 0.89 (0.71.15)
GI: 1.23 (1.021.5)
Death from vascular

causes
0.85 (0.720.99)
0.89 (0.731.1)
0.89 (0.761.04)
0.86 (0.770.97)
Death from any cause
0.88 (0.771)
0.85 (0.71.02)
0.89 (0.80.998)
0.92 (0.831.01)
Major bleeding
ENGAGE AF-TIMI 48
(edoxaban)
Dabigatran 110 mg BID was also studied and found to have reduction in stroke or systemic embolism, but higher rates of GI bleed when
compared with warfarin; thus it is currently not an FDA approved dose.
BID = twice daily; H = hemorrhagic stroke; I = ischemic stroke; ICH = intracranial hemorrhage.
Information from: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J
Med 2009;361:1139-51; Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J
Med 2011;354:883-91; Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N
Engl J Med 2011;365:981-92; Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N
Engl J Med 2013;369:2093-104.
146
authors also found variation in anticoagulation management

strategies used, with some sites using pharmacists and others deferring management solely to clinicians. Appropriate
patient selection (RR 1.14; 95% CI, 1.051.25) and provision
of pharmacist-led monitoring (RR 1.25; 95% CI, 1.111.41)
were associated with better patient adherence. Additionally,
adherence was improved by longer duration of monitoring
and provision of more intensive care to nonadherent patients
in collaboration with the clinician. These findings suggest
that such site-level practices provide modifiable targets to
improve patient adherence to dabigatran versus patient characteristics that often cannot be modified.
Patients on a DOAC should have their renal function and
CBC checked at baseline. Table 3-13 provides general recommendations for minimum intervals thereafter. A follow-up
phone call to patients after treatment initiation may help confirm that they have received the DOAC without insurance
barriers and transitioned to it appropriately while discontinuing previous anticoagulation therapy, if applicable.
Additionally, clinical improvement (in setting of VTE) and
adverse effects should be assessed. Patients at higher risk
(e.g., those with lower health literacy and multiple medical
problems) may benefit from face-to-face clinical visits if this
information cannot be obtained by other reliable methods.

Centralized anticoagulation services are expanding beyond
traditional monitoring to include patients on DOACs by prospectively following them to ensure optimal therapeutic outcomes.
In some cases it may be necessary to test for the presence of
DOAC (e.g., a patient with acute stroke or major bleeding warranting urgent surgery). Current tests used include thrombin
time and activated partial thromboplastin time (aPTT) for dabigatran, and prothrombin time or an anti-factor Xa calibrated for
the factor Xa inhibitors (Cuker 2015, 2014). No strong recommendations about the best tests to detect drug presence can be
made presently, because many of the tests are not readily available or sufficiently reliable to exclude drug presence.
Anticoagulant Reversal
Clinical scenarios remain in which the availability of an antidote to DOACs is desired. Few antidotes have been developed
and are briefly discussed in the following.
Idarucizumab (Praxbind) was recently granted accelerated
approval by the FDA for patients on dabigatran warranting anticoagulation reversal for emergent procedure or life-threating and
uncontrolled bleeding. This agent is a humanized monoclonal antibody fragment with >350-fold preferential binding to dabigatran
Table 3-12. Clinical Prediction Models for VTE Recurrence

Tool
Criteria
Point
Total Points
(VTE Recurrence Rate
[%/year])
DASH
Abnormal D-dimer after stopping anticoagulation (>500 ng/mL)
+2
Age <50 years
+1
Male Sex
+1
1 (3.1)
2 (6.4)
3 (12.3)
Vienna
Men Continue
and HERDOO2
VTE not associated with Hormonal therapy in women
-2
Patients sex
Male
60
Location of initial VTE

Proximal DVT
70
Pulmonary Embolism
90
D-dimer levels in individual patients

Continuous
0100
Postthrombotic signs (Hyperpigmentation, Edema, or Redness in

either leg)
D-dimer 250 mg/l (during anticoagulation)
Obesity (BMI > 30 kg/m2)
Older age (>65 years)
Low risk (rate of

recurrence of 4.4%)
when points according
to nomogram are 180
Men (always long-term

anticoagulation)
Women (long-term
anticoagulation if score
2)
Information from: Tosetto A, Iorio A, Marcucci M, et al. Predicting disease recurrence in patients with previous unprovoked venous
thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012;366:1019-25; Eichinger S, Heinze G, Jandeck LM, et
al. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction
model. Circulation 2010;121:1630-6; Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low
risk for recurrence who can discontinue anticoagulant therapy. CMAG 2008;179:417-26.
147
Table 3-13. Recommended Safety Monitoring for DOACs

Monitoring Parameter
Frequency
Renal Function
CrCl >60 mL/minute
Annually
CrCl 3060 mL/minute,

age >75 years, or
presence of drug interactions
Every 6 months
CrCl 1530 mL/minute or fluctuating CrCl
Every 3 months
Most patients
Annually
Patients with low baseline hemoglobin/hematocrit,

presence of drug interactions, or age >75 years
Every 6 months or more often if clinically indicated
CBC
Information from: Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association practical guide on the use of new
oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-51.
compared to thrombin. Once idarucizumab is bounded to dab-
Special Populations
igatrans active site, dabigatran binding to thrombin is inhibited
Malignancy
without triggering thrombin-induced coagulation. Interim results
Venous thromboembolism is a leading cause of mortality in

patients with malignancy. Several organizations have published guidelines that recommend monotherapy with LMWH
for VTE treatment in patients with active cancer based on its
superiority over VKAs in this population (Kearon 2012; Lyman
2015; NCCN 2014). Extended anticoagulant therapy is suggested as long as the patient has active cancer, but individual
patient bleeding risk, patient preferences, tolerability, and
drug costs should also be considered.
A meta-analysis of randomized controlled trials for dabigatran, rivaroxaban, apixaban, and edoxaban for VTE treatment,
which included more than 1000 patients with cancer, found no
difference in the safety or effectiveness of DOACs compared
with conventional VKA treatment (Vedovati 2015). The results
of an ongoing phase III trial comparing 6 months of rivaroxaban versus dalteparin in patients with active cancer and
symptomatic VTE will help determine in which cases DOACs
are appropriate alternatives to LMWH for cancer-associated
VTE. For now, in patients who cannot tolerate, afford, or feasibly use LMWH long term, treatment with a DOAC, having a
fixed-dose regimen and need for minimal laboratory monitoring, is an attractive option versus a VKA. However, there are
factors to consider, such as potential drug interactions with
concomitant chemotherapy, antimicrobials, and anti-emetics,
because no tests are readily available to measure the extent of
these interactions on DOAC drug concentrations.
The occurrence of AF in conjunction with cancer is common.
The question of appropriate anticoagulation in this scenario
arises because of potential increased bleeding risk in patients
with certain cancers, as well as the potential for drug and dietary
interactions with chemotherapy and supportive medications.
Although the CHADS2 score was predictive of thromboembolism
from RE-VERSE AD, a phase III study that enrolled 90 patients

on dabigatran with uncontrolled or life-threatening bleeding or
requiring emergency procedures, demonstrate reversal of anticoagulant effect with idarucizumab (Pollack 2015).
Andexanet alfa is a recombinant modified human factor Xa decoy protein that binds to and sequesters with high
specificity direct and indirect factor Xa inhibitors (apixaban,
edoxaban, rivaroxaban, LMWH, fondaparinux). Once bound,
factor Xa inhibitors are unable to target factor Xa, allowing for
restoration of factor Xa activity. Two studies, ANNEXA-R and
ANNEXA-A, have evaluated the efficacy and safety of andexanet alfa and the primary end point of reversed anticoagulant
effect per anti-Xa levels have been met. Results from these
phase III studies have been published in the ANNEXA study
(Siegal 2015). A phase IV study (ANNEXA-4) is ongoing in
patients receiving rivaroxaban, apixaban, edoxaban, or enoxaparin who present with an acute major bleed. Data from this
study along with the phase III studies will be submitted to the
FDA for approval of andexanet alfa, which is currently designated as breakthrough therapy.
Ciraparantag (formerly known as aripazine and PER977),
is a water-soluble synthetic molecule designed to bind to
LMWH and UFH; it has been shown to bind in a similar way to
fondaparinux, direct thrombin inhibitors, and direct factor Xa
inhibitors, inhibiting their anticoagulant effect in animal studies. Ciraparantag does not bind coagulation factors and has
not been shown to have its own anticoagulant or procoagulant effect. A phase I trial recently completed showed reversal
of anticoagulant effect after a single dose of edoxaban, and
phase III trials are planned for 2016 (Ansell 2014).
148
risk in patients with baseline AF in a large cohort of 24,125

patients with newly diagnosed cancer, it did not predict thromboembolic events in those with new-onset AF (i.e., AF occurring
after cancer diagnosis). Currently, there are no formal recommendations regarding anticoagulation in patients with cancer
and AF. However, an algorithm has been proposed suggesting
no anticoagulation in patients with high bleeding risk features,
optional anticoagulation for patients with CHA2DS2VASc score
of 0 or HAS-BLED score of 3 or greater, and anticoagulation for
CHA2DS2VASc score of 1 or greater and HAS-BLED of less than 3
(Farmakis 2014). Ultimately, the decision to initiate anticoagulation in patients with cancer must be individualized.
and reduction in the risk of recurrent VTE, no apixaban dose

reduction was made for renal function; thus the dosing recommendations approved by the FDA for these indications do not
include a renal dose reduction. For patients on hemodialysis,
apixaban may be dosed at 5 mg twice daily or 2.5 mg twice daily
if age 80 years or older or with body weight of 60 kg or less.
However, patients on hemodialysis were not included in clinical
trials for apixaban, and the approved dosing recommendation
is currently based on pharmacokinetic and pharmacodynamic
data (anti-factor Xa activity) performed on 8 patients with endstage renal disease on hemodialysis. Until further clinical data
are available, caution is warranted if apixaban is used in patients
with end-stage renal disease. Renal function should be considered when making decisions about the use and dose of DOACs.
Obesity
Pharmacokinetic studies of the DOACs indicate that obesity

has no meaningful effect on drug exposure compared with
non-obese patients. In clinical trials of direct factor Xa inhibitors for VTE treatment, 15%19% of patients enrolled (more
than 1000) had a body weight of 100 kg or greater (Agnelli
2013; Bauersachs 2010; Bller 2013, 2012). No trends have
been identified thus far that suggest changes in clinical outcomes at these weights. Data are limited on the use of DOACs
in patients with extremes in body weight (i.e., >150 kg or
<50 kg), and the choice of agent for chronic management in
patients with morbid obesity should be individualized.
Pharmacoeconomic Considerations
Thromboembolism is associated with significant cost burden;

by 2050, U.S. stroke expenditures are estimated to be $2.2 trillion, and venous thromboembolic events are expected to cost
$69 billion. Although anticoagulation is indicated to prevent
complications, the cost of the selected therapy and its associated outcomes should be considered. For example, to ensure
minimal bleeding and thrombotic events, warfarin requires
monitoring and dose adjustments to maintain optimal TTR.
Depending on the monitoring model used (e.g., primary care
management, anticoagulation clinics, home INR self-monitoring), the cost of warfarin management ranges from $396 to
$860 per year (Lafata 2000). Conversely, one touted benefit of
DOACs is the eliminated need for efficacy monitoring. However,
the cost of these newer agents is higher than warfarin, and
many insurance companies restrict coverage of DOACs, often
approving their use only in the setting of warfarin failure.
In determining the medical cost differences of DOAC versus warfarin in AF and VTE, one study performed univariate
and multivariate sensitivity analyses using clinical end points
from phase III studies and incremental annual costs (defined
as U.S. health payers cost of clinical event). Findings yielded
medical-cost differences in patients treated with dabigatran
($3.7 million), rivaroxaban ($4.2 million), apixaban ($11.5
million), and edoxaban ($6.6 million) (Amin 2015). However,
another study found that warfarin therapy is more cost effective when TTR is 70% or greater (Janzic 2015).
As more DOACs become available, the market price may
decrease because of drug competition. However, warfarin will
remain an affordable option in patients who have stable INRs
and 46 weeks of follow-up testing. The overall clinical picture of
efficacy and safety outcomes associated with certain anticoagulation therapies should be taken into consideration (Table 3-14).
Renal Dysfunction
For mild renal impairment (CrCl 5079 mL/minute), rivaroxaban, apixaban, and dabigatran were shown in a meta-analysis
to be associated with lower rates of major or CRNM bleeding
and stroke or systemic embolism compared with conventional
agents (warfarin and LMWH). In moderate renal impairment
(CrCl 3049 mL/minute), the DOACs had a lower rate of
stroke or systemic embolism and comparable rates of bleeding (Sardar 2014). Rivaroxaban significantly reduced the risk
of major bleeding compared with LMWH/VKA in a subgroup
analysis in patients with VTE and moderate renal impairment (Prins 2013). Clinical data are scant on the safety of the
DOACs in severe renal impairment because this factor was an
exclusion criterion in the major clinical trials with these drugs.
For the pharmacokinetics and approved dosing of the
DOACs, see Table 3-1 and Table 3-2. In clinical trials involving DOACs for AF, patients with certain renal function cutoffs
were excluded; however, there are certain FDA-approved dosing recommendations for these agents. Although dabigatran
was contraindicated in patients with CrCl less than 30 mL/
minute in the clinical trials, a reduced dosage of 75 mg twice
daily was approved by FDA based on pharmacokinetic models. For rivaroxaban, clinical trial data included patients with
CrCl less than 30 mL/minute; however, use in patients with
even lower CrCl (< 15 mL/minute) is contraindicated.
For apixaban, patients with a CrCl less than 25 mL/minute were excluded from the clinical trials, and a reduced dose
is recommended. However, in clinical trials for VTE treatment
CONCLUSION
New options for anticoagulation therapy exist for VTE and
AF treatment. Thus, clinicians who are well trained in anticoagulation management are more valuable because decisions
149
Table 3-14. Summary of Clinical Considerations in Selecting DOAC or Warfarin
Characteristic
Preferred DOAC
Rationale for preferred DOAC
Rationale for warfarin
Increased risk of GI
bleeding (GIB)a
Apixaban
Dabigatran, rivaroxaban, and edoxaban were

associated with increased risk of GIB vs. warfarin
Dabigatran was associated with GI adverse effects
(e.g., dyspepsia and gastritis) and more treatment
discontinuations especially during the beginning of
treatment
Warfarin has a reversal agent

and INR can be monitored
Increased risk of
bleeding
Apixaban, edoxaban,
dabigatran
Clinical reductions in MB found with apixaban and

edoxaban vs. warfarin
Dabigatran was associated with increased risk of
ECH vs. warfarin
Dabigatran had trend of more MB vs. warfarin in
patients 75 years
Dabigatran has a reversal agent
Rivaroxaban had trend of increased risk of clinically
relevant bleeding vs. warfarin in patients >75 years
Apixaban was associated with less MB in all patients,
including the subgroup of patients 75 years
Edoxaban had no difference in the rate of MB;
however, a significantly lower incidence of first MB or
CRNM bleeding occurred with edoxaban
Warfarin has a reversal agent

and INR can be monitored
Renal impairment
Apixaban
Apixaban has least dependency on renal elimination

INR can be monitored with
of all the DOACs
warfarin
While apixaban is not contraindicated in hemodialysis
patients, only pharmacokinetic data is available and
caution is advised
Dietary concerns
Dabigatran, apixaban,
edoxaban
Must take rivaroxaban doses >10 mg with meal for

adequate absorption
Other DOACs can be taken without regard to food
Warfarin requires consistency

with vitamin K intake
Adherence issues
Rivaroxaban, edoxaban
Once-daily dosing with rivaroxaban and edoxaban

Dabigatran and apixaban are both dosed twice daily
Adherence to warfarin can be

measured with INR testing but
requires adherence with INR
follow-up
Drug interactions
Edoxaban, dabigatran
Apixaban and rivaroxaban are substrates of both

CYP3A4 and P-glycoprotein; inhibitors of CYP3A4
and P-glycoprotein increase exposure to DOACs
and increase the risk of bleeding; inducers decrease
exposure to a DOAC and increase the risk of
thromboembolism
Dabigatran and edoxaban are not metabolized
through the CYP450 pathway
Most PK drug interactions

with warfarin can be managed
through INR monitoring
Pregnancy
Data not available; not

Use all DOACs with caution in pregnancy, if at all;
recommended
pregnant patients were excluded from clinical trials
LMWHs are the
preferred anticoagulants
in pregnant patients
Warfarin is teratogenic
and should be reserved for
pregnant patients with high-risk
mechanical heart valves, if at all
Examples of patients at increased risk of GIB include patients with anemia, prior history of GI bleeding, advanced age, renal impairment, hypertension, prior history of stroke.
ECH = extracranial hemorrhage; LMWH = low-molecular-weight heparin; MB = major bleed; PK = pharmacokinetic.
150
about which agent to use, appropriate dosage regimens, how

and when to monitor, and reversal must be considered. In
selecting anticoagulation, clinicians need to evaluate clinical
factors such as indication, drug interactions, renal dysfunction,
extremes of body weight, presence of cancer, and individual
bleeding risk. It is also important to consider possible barriers to each treatment option, including high copays, obstacles
for monitoring, and difficulties in maintaining consistent diet.
It is critical to monitor the safety and efficacy of all DOACs.
Recommendations should be re-evaluated by all clinicians
involved in the care of the patient as new information that could
affect efficacy and safety comes to light.
Practice Points
Pharmacists face challenges in their efforts to optimize
pharmacotherapy for patients considering the increased
variety of therapeutic options. Four DOACs are approved
for VTE and AF treatment and can serve as alternatives
to warfarin. As a result, guidelines/recommendations,
new indications for existing medications, new therapeutic entities, and safety issues continue to evolve:
DOACs are non-inferior to warfarin for VTE treatment and
rivaroxaban and apixaban have shown a significant reduction in major bleeding
Dabigatran and apixaban are superior to warfarin for stroke
prevention in AF and have a lower risk for major bleeding
LMWH remains the preferred choice for treatment of VTE
in patients with cancer; however, current data suggest the
DOACs may be a viable alternative to warfarin. Ongoing
studies are comparing DOACs to enoxaparin in this population
Decisions on length of treatment for unprovoked VTE
should include the patients risk for bleeding and VTE
recurrence, as well as patient preferences. Clinical markers
such as D-dimer and residual vein thrombosis may help
determine VTE recurrence
CHA2DS2VASc is the preferred screening tool to assess
stroke risk
Idarucizumab has been approved for dabigatran reversal. The other DOACs do not yet have a reversal agent
approved; however, several potential antidotes are nearing
approval
Clinical pharmacists should be aware of the differences
among the DOACs so they can make informed decisions
regarding the most appropriate anticoagulation therapy
New agents in the treatment of VTE and AF continue to
evolve
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152
the hospital. Which one of the following is best to recommend for this patient?
P.Q., a 42-year-old man who was injured in a motor vehicle crash, develops osteomyelitis and is started on a 6-week
course of intravenous antibiotics and rifampin. Three days
later, P.Q. develops a new popliteal deep vein thrombosis (DVT)
and is started on enoxaparin (CrCl 72 mL/minute). The patient
endorses difficulty keeping clinic appointments because of
limited mobility and transportation issues.
A. Dabigatran
B. Edoxaban
C. Rivaroxaban
D. Warfarin
41. Which one of the following is best to recommend for P.Q.

upon hospital discharge?
E.P. is a 58-year-old man (height 72 inches, weight 68 kg) who

presents to the ED with a new femoral DVT. He denies recent surgery, immobility, prior venous thromboembolism (VTE), smoking,
obesity, and other known VTE risk factors. E.P. has hypertension
and osteoarthritis and is taking lisinopril 10 mg daily and acetaminophen 1000 mg twice daily. His SCr is 0.9 mg/dL. The team
decides to initiate dabigatran 150 mg twice daily.
A. Dabigatran 150 mg twice daily

B. Warfarin dosed to INR 23, to be monitored through
INR home testing
C. Rivaroxaban 15 mg twice daily for 21 days followed
by 20 mg daily
D. Apixaban 10 mg twice daily for 7 days followed by 5
mg twice daily
45. Which one of the following, after 3 months of anticoagulation therapy, is best to recommend regarding treatment of
E.P.s VTE?
42. During discharge counseling, P.Q. asks about the differences between direct oral anticoagulants (DOACs) and
warfarin. Which of the following is the best counseling
point to provide to P.Q.?
A.
B.
C.
D.
A. DOACs have less renal elimination compared with

warfarin.
B. DOACs do not require safety monitoring compared
with warfarin.
C. DOACs have fast onset and offset compared with
warfarin.
D. DOACs must be taken twice a day compared with
warfarin.
46. If extended therapy is considered for E.P., which one of the

following would have the lowest risk of VTE recurrence?
A.
B.
C.
D.

for dabigatran 150 mg twice daily?
Aspirin 100 mg daily

Warfarin, target INR 1.51.9
Rivaroxaban 20 mg daily
Dabigatran 75 mg daily
N.C. is a 48-year-old woman status-post right total knee arthroplasty. On post-procedure day 3, she complains of severe pain,
warmth, and redness in right lower extremity. A duplex is positive for DVT. Laboratory results are notable for CrCl of 28 mL/
minute. N.C.s medical history includes hyperlipidemia, hypertension, and diabetes; she denies VTE-related risk factors. Her
home drugs include rosuvastatin 10 mg daily, metoprolol XL
150 mg daily, and insulin.
A. A 35-year-old with athletes foot, on ketoconazole,

and CrCL of 45 mL/minute taking enoxaparin for 1
week for a new VTE
B. A 47-year-old with well-controlled seizures,
on carbamazepine, taking treatment doses of
enoxaparin for 1 week for a new VTE
C. A 50-year-old with atrial fibrillation, mechanical heart
valve, and diabetes currently taking metformin and
metoprolol
D. A 58-year-old with atrial fibrillation and latent
tuberculosis currently being treated with rifampin
47. If she receives rapid therapeutic anticoagulation, which

one of the following is N.C. most likely to experience?
A.
B.
C.
D.
44. A 47-year-old woman presents to the ED with lower extremity pain, swelling, and redness; she receives a diagnosis
of DVT. The patient is amendable to starting anticoagulation but has severe vision impairment and would prefer to
avoid use of low molecular weight heparin (LMWH) injections. Additionally, she is opposed to being admitted to
Discontinue anticoagulation.
Evaluate risk-benefit of therapy.
Decrease dabigatran to 75 mg daily.
Continue with another anticoagulant.
Increased risk of bleeding

Increased risk of mortality
Reduced thrombus extension
Reduced treatment of 1 month
48. N.C. is successfully treated with anticoagulation. Two

years later, she develops a left lower extremity DVT 2
days after undergoing left total knee arthroplasty. Per
153
B. A 45-year-old with a medical history of alcohol abuse

and cirrhosis on spironolactone, thiamine, folic acid,
furosemide, and nadolol
C. A 67-year-old with a medical history of anemia and
stroke currently only on aspirin
D. A 73-year-old with a medical history of anemia
currently taking ferrous sulfate
American College of Chest Physicians (ACCP) guidelines,

which one of the following durations of anticoagulation
therapy is best to recommend for N.C.?
A. 3 months, then discontinue anticoagulation
B. At least 3 months, then evaluate risk-benefit of
therapy
C. 6 months, then perform repeat duplex for
determination
D. 12 months, then switch to aspirin for extended
therapy
J.M., a 40-year-old man on indefinite anticoagulation for AF,

presents for anticoagulation follow-up appointment on May 6,
2015 with INR of 2.7. He denies drug/diet changes and missed
doses. His CrCl is 55 mL/minute and hemoglobin is 14g/dL.
The table below presents J.M.s recent INR monitoring results
while taking warfarin 4 mg daily.
T.V., 75-year-old man (height 65 inches, weight 60 kg), presents to the ED with severe palpitations, diaphoresis, and
general malaise. He is diagnosed with persistent non-valvular atrial fibrillation (AF). Physical examination demonstrates
blood pressure of 136/70 mm Hg and irregular pulse of 124
beats/minute at rest. His laboratory values are notable for K
4.8 mEq/L and SCr 1.3 mg/dL (currently at baseline). T.V.s
medical history is significant for hypertension, congestive
heart failure, type 2 diabetes mellitus, and gout. His home
drugs include metoprolol XL 25 mg daily, lisinopril 20 mg daily,
furosemide 20 mg daily, and allopurinol 100 mg/day.
49. Which one of the following best represents T.V.s calculated CHA 2DS 2-VASc score?
November 5, 2014
2.5
December 3, 2014
2.2
January 2, 2015
2.1
February 4, 2015
2.7
March 4, 2015
2.4
April 1, 2015
2.5
A.
B.
C.
D.
50. T.V. is amendable to starting a DOAC. Which one of the following is best to recommend for T.V.?
2 weeks
4 weeks
8 weeks
12 weeks
54. J.M. asks you for information about DOACs, which he has
seen advertised. Which one of the following education
points is best to give J.M.?
Apixaban 5 mg twice daily

Edoxaban 60 mg daily
A. All of the DOACs are free of dietary limitations.

B. There are no significant drug interactions with the
DOACs.
C. DOACs require kidney function monitoring to ensure
appropriate dosing.
D. All DOACs have been shown to have superior
outcomes compared with warfarin.
51. A patient with AF (CHA 2DS 2-VASc = 3) is advised to start

anticoagulation. However, she is worried about bleeding risk because her mother was admitted to the ICU for
management of GI bleed. The patient is not amendable to
frequent monitoring. Which one of the following is best to
recommend for this patient?
55. J.M. is considering switching to a DOAC but would like to

know how often his therapy would need to be monitored.
Which one of the following describes the best monitoring
plan for J.M.?
A. Apixaban
B. Dabigatran
C. Rivaroxaban
D. Warfarin
A. Once a year for renal function and CBC

B. Once a year for renal function and every 6 months for
CBC
C. Every 6 months for renal function and CBC
D. Every 6 months for renal function and once a year for
CBC
52. Which one of the following patients is at greatest risk of

experiencing a major bleed per HAS-BLED?
A. A 35-year-old with a medical history of atrial
fibrillation and controlled hypertension on warfarin
with therapeutic INRs
INR
53. You instruct J.M. to continue warfarin 4 mg daily. Which

one of the following is the longest interval to recommend
before J.M. has his INR checked again?
A. 3
B. 4
C. 5
D. 6
A.
B.
C.
D.
Date
154
60. A 50-year-old woman (height 60 inches, weight 50 kg)

presents to the ED with shortness of breath and palpitations and receives a diagnosis of AF (CHA 2DS 2-VASc of
5). Her medical history is also significant for CKD Stage
4, not on dialysis (SCr 2 mg/dL, CrCl 26 mL/minute).
The inpatient team would like to initiate anticoagulation.
Which one of the following is best to recommend for this
patient?
56. A 65-year-old woman presents to the ED with acute

GI bleeding and loss of consciousness. Her daughter
reports that the patient recently switched to a new blood
thinner pill but she doesnt know which one and no longer takes warfarin. The patient requires emergent care
and the team would like to reverse the effect of the new
blood thinner pill immediately. Assuming all agents are
approved and available to you, which one of the following
is best to recommend for this patient?
A.
B.
C.
D.
A. Andexanet alfa
B. Ciraparantag
C. Idarucizumab
D. Phytonadione
Apixaban 5 mg daily
Edoxaban 30 mg daily
57. A 57-year-old woman (weight 148 kg, height 75 inches,

CrCl 62 mL/min) has a history of unprovoked DVT and
pulmonary embolism (PE) (3 years ago). She has now
experienced a new DVT caused by subtherapeutic INRs
while on warfarin and presents for her first anticoagulation management visit. She states she is adherent to
warfarin therapy, but she is unable to come to appointments regularly because of limited mobility caused by
arthritis. You are asked for a recommendation regarding
discontinuing this patients warfarin in favor of a DOAC.
Which one of the following is best to recommend for this
patient?
A. A DOAC is not recommended because of her obesity.
B. Apixaban 10 mg twice daily for 7 days, then 5 mg
twice daily.
C. Edoxaban 30 mg daily; no LMWH is required.
D. Rivaroxaban is contraindicated because of her renal
function.
58. A 70-year-old man with CHA 2DS 2VASc score of 4 and end
stage renal disease on hemodialysis is to be initiated on
anticoagulation for AF. The patient refuses to take warfarin because of dietary restrictions, but he is amendable
to taking a DOAC. Which one of the following would best
avoid accumulation in this patient?
A. Apixaban
B. Dabigatran
C. Edoxaban
D. Rivaroxaban
59. A 52-year-old man with prostate cancer presents with
shortness of breath, cough, and chest pain to his oncology appointment. Chest CT determines the presence of
PE. His laboratory results are within normal limits. Which
one of the following is best to recommend for this patient?
A. Edoxaban
B. Dalteparin
C. Rivaroxaban
D. Warfarin
155
Learner Chapter Evaluation: Oral Anticoagulants in VTE and AF.


Strongly agree

Agree

Neutral

Disagree

Strongly disagree
49. Design an evidence-based therapeutic plan for the treatment of venous thromboembolism.
50. Devise an evidence-based treatment strategy for stroke
prevention in atrial fibrillation.
51. Distinguish the potential risks and benefits of the new
oral anticoagulants compared with the vitamin K antagonist, warfarin.
52. Formulate an appropriate anticoagulation plan with monitoring parameters in special patient populations.




Questions 5557 apply to the entire Cardiology II learning

module.

were effective.
effective.
55. How long did it take you to read the instructional materials in this module?

were effective.
56. How long did it take you to read and answer the assessment questions in this module?
57. Please provide any additional comments you may have

regarding this module:
156
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Pulmonary and
Emergency Medicine
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May 15, 2018
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IMPORTANT INFORMATION ON THE RELEASE OF

BOOK FORMATS AND CONTENT

Director of Professional Development: Nancy M. Perrin, M.A., CAE

Blood Pressure Management

Valvular Heart Disease

By Karen J. McConnell, Pharm.D., FCCP, BCPS-AQ Cardiology;

By Douglas L. Jennings, Pharm.D., FCCP, FAHA, AACC, BCPS,

Mitral Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

HTN with Concomitant Disease States . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ambulatory and Home Blood Pressure Monitoring . . . . . . . . . . . . .

Hypertensive Urgency and Emergency . . . . . . . . . . . . . . . . . . . . . . . . . . .

HTN and Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Evaluation of Therapeutic Outcomes

New Dyslipidemia Management Guidelines . . . . . . . . . . . . . . . . . . . . .

Cardiovascular Risk Assessment

Application of Recommendations to Patient Care

Oral Anticoagulants for VTE and

Traditional and Nontraditional Risk Factors

By Nancy L. Shapiro, Pharm.D., FCCP, BCPS;

New Evidence for Use of Nonstatin Agents

Stroke Prevention in Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . .

Emerging Therapies for Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Role of Outpatient Antibiotic Therapy

Historical Approach to Dyslipidemia Treatment

Pharmacologic Management of Causative Organisms

By Laura H. Waite, Pharm.D., BCPS, CLS, BC-ADM;

Diagnosis and Role of Empiric Therapy

Pulmonary Arterial Hypertension

By Kristen T. Pogue, Pharm.D., BCPS, AQ-Cardiology;

PSAP 2016 Book 1 Cardiology

A Message from the Editors

Every new edition of the Pharmacotherapy Self-Assessment

It is our hope that these efforts will build on and further

John E. Murphy and Mary W. Lee, series editors

PSAP 2016 Book 1 Cardiology

John E. Murphy, Pharm.D., FCCP, FASHP

Tyan F. Thomas, Pharm.D., BCPS

Mary Wun-Len Lee, Pharm.D., FCCP, BCPS

Stacy L. Elder, Pharm.D., BCPS

Cassandra D. Benge, Pharm.D., BCPS, AQ-Cardiology, AACC

Pulmonary Arterial Hypertension

The American College of Clinical Pharmacy and the authors

Disclosure of Potential Conflicts of Interest

Continuing Pharmacy Education and

Blood Pressure Management

ABBREVIATIONS IN THIS CHAPTER

Ambulatory blood pressure

PSAP 2016 Book 1 Cardiology

Blood Pressure Management

A thorough knowledge of contemporary HTN management

Since the inception of the Joint National Committee guidelines

patient care, given the increased rates of atherosclerotic and

BASELINE KNOWLEDGE STATEMENTS

Readers of this chapter are presumed to be familiar

HTN Guideline Controversy

Although the various HTN guidelines differ, one controversial

American Diabetes Association (ADA). Standards

PSAP 2016 Book 1 Cardiology

Blood Pressure Management

Table 1-1. Comparison of International Guidelines on HTN Goals (mm Hg)

< 150/90, age 60 yr

< 150/90, age 80 yr

< 150/90, age 80 yr