Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials

Jo E. Rodgers, Pharm.D., BCPS One of Four Continuing Education Programs in the Series, Acute Decompensated Heart Failure: Integrating Consensus Guidelines and Individual Patient Characteristics into Optimal Treatment Regimens

Recorded August 1, 2006 Chicago, Illinois

Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
Target Audience
This continuing education program is beneficial for pharmacists and pharmacy managers in all practice settings who are involved in improving care for patients with ADHF.

Program Description
Acute decompensated heart failure (ADHF) accounts for almost one million hospitalizations per year, and rehospitalization within six months is as high as 50%. The annual mortality rate in patients frequently hospitalized with ADHFthose with New York Heart Association class III or IV symptomsapproaches 50%. While ADHF was traditionally viewed as a disorder associated with sodium and water retention and left-ventricular dysfunction, it is now understood to be associated with neurohormonal activation. This program will provide an overview of the pathophysiology of ADHF, including risk stratification criteria based on observational data of patients hospitalized with ADHF. The primary focus, however, will be on key clinical trials that guide treatment selection for patients with ADHF. Understanding the design and limitations of these studies is essential to offering optimal care to the ADHF population. This program is the recommended starting point in the series for pharmacists who do not have a strong background in cardiology.

Learning Outcomes
After listening to this program, the participant should be able to: Identify the role of neurohormonal activation in ADHF. Describe in-hospital mortality risk based on risk stratification data for ADHF. Identify key factors in applying the results of clinical trials to various subpopulations of patients with ADHF.

Continuing Education Accreditation

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This continuing education program provides 1.0 hours (0.1 CEUs) of continuing education credit (program number 204-000-06-424-H01). This program is provided free of charge. After participating in the program, pharmacists may complete the CE test online at the ASHP Advantage CE Testing Center (www.ashp.org/advantage/ce). A passing grade of 70% is required to receive continuing education credit for this program, and pharmacists can print their CE statement immediately. Continuing education credit for this program is available from September 15, 2006, through September 14, 2007.

Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
Program Faculty
Jo E. Rodgers, Pharm.D., BCPS
Clinical Assistant Professor University of North Carolina at Chapel Hill School of Pharmacy Chapel Hill, North Carolina Jo E. Rodgers, Pharm.D., is Clinical Assistant Professor at the University of North Carolina (UNC) at Chapel Hill School of Pharmacy. She maintains an active clinical practice with the UNC Cardiomyopathy and Cardiac Transplantation Service at UNC Hospitals. She serves as co-coordinator of the cardiology specialty residency, coordinator of the cardiology therapeutics module and the acute care and critical care electives, and advisor to both the UNC Clinical Scholars Program and Kappa Epsilon. Dr. Rodgers research interests focus on the care of heart failure and cardiac transplant patients. After obtaining both her Bachelor of Science in Pharmacy and Doctor of Pharmacy degrees at the University of North Carolina (UNC) at Chapel Hill, Dr. Rodgers completed a pharmacy practice and critical care specialty residency at the Medical College of Virginia. She then returned to UNC for a fellowship in cardiovascular pharmacotherapy. Dr. Rodgers is a reviewer for Pharmacotherapy and Annals of Pharmacotherapy, and her research has recently been published in Critical Care Medicine and Journal of Thrombosis and Thrombolysis. She is an active member of the American College of Clinical Pharmacy, and she currently serves as chair-elect of the Cardiology PRN and secretary-elect of the Triangle College of Clinical Pharmacy. Dr. Rodgers received the 2004-05 national Outstanding Advisor Award from Kappa Epsilon Fraternity.

Faculty Disclosure Statement

In accordance with the Accreditation Council for Continuing Medical Educations Standards for Commercial Support, ASHP Advantage requires that all faculty members involved in the development of program content to disclose their relevant financial relationships. A faculty member has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the CME activity content over which the faculty member has control. The existence of these relationships is provided for the information of attendees and should not be assumed to have an adverse impact on faculty presentations. The faculty reports the following relationships: Dr. Rodgers declares that she has served as a consultant for Abbott Laboratories and Scios Inc. and has been on the speakers bureau for Scios Inc.

Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
ASHP Advantage Instructions for Receiving Your CE Credit and Statements Online for Podcast Activities
The online ASHP Advantage CE Testing Center allows participants to obtain their CE statements conveniently and immediately using any computer with an Internet connection.* To take the CE test and obtain your CE statement for this ASHP Advantage Podcast activity, please follow these steps: 1. Type www.ashp.org/advantage/ce/ in your internet browser. 2. If you have previously logged in to the ASHP Advantage site, then you need only enter your e-mail address and password. If you have not logged in to the ASHP Advantage site before, click on Create Account and follow the brief instructions to set up a user account and password. You will only need to create your account once to have access to register, take CE tests, and process CE online from ASHP Advantage in the future. 3. After logging in, you will see the list of activities for which CE is available. To process CE for one of the activities in the list, click on the Start button next to the name of the activity. This activity is listed under ADHF Series. 4. Click on the radio button next to the correct answer for each question. Once you are satisfied with your selections, click Finish CE to process your test and complete the remaining steps to print your CE statement. 5. Repeat the above steps for each Podcast activity in which you participate. If you have any problems processing your CE, contact ASHP Advantage at support@ashpadvantage.com. *Except that this site does not support the AOL Web browser.

Learning Objectives
Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
Jo E. Rodgers, Pharm.D., Pharm.D., BCPS
Clinical Assistant Professor
Division of Pharmacotherapy, School of Pharmacy University of North Carolina at Chapel Hill

Describe the epidemiology of acute decompensated heart failure (ADHF). Identify the role of neurohormonal activation in ADHF. Describe in-hospital mortality based on risk stratification for ADHF. Identify key factors in applying the results of clinical trials to various subpopulations of patients with ADHF.

Scope of the Problem

Incidence: 550,000 new cases/yr Prevalence: 5 million
(continues to increase)

Epidemiology

Morbidity: 1 million hospitalizations/yr Mortality: 50% at 5 years Economic costs: $29.6 billion (direct and indirect)

American Heart Association. Heart disease and stroke statistics2006 update; 2006.

Economic Impact
60.6% Hospitalization $23.1 billion 38.6% Outpatient care $14.7 billion

Hospitalization
Initial episode 21%

Total = $38.1 billion (5.4% of total health care costs)

0.7% Transplants $270 million

Repeat visit 79%

Rates of readmission 2% within 2 days 20% within 1 month 50% within 6 months

OConnell JB et al. J Heart Lung Transplant. 1994; 13:S107-S12.

Neurohormonal Hypothesis
LV function

Pathophysiology and Etiology

Impedance

Cardiac output

Abnormal reflexes
RAAS, SNS AVP, BNP, ET-1 TNF-, IL-6

Salt and water retention

Neurohormone activation

Progressive heart failure (HF)

RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system; AVP = arginine vasopressin; BNP = B-type natriuretic peptide; ET-1 = endothelin-1; TNF- = tissue necrotizing factor ; IL-6 = interleukin-6; LV = left ventricular

Neurohormonal Imbalance
Norepinephrine Angiotensin-II Aldosterone Endothelin Vasopressin ANP BNP Nitric oxide Bradykinin Prostacyclin

Common Causes of ADHF

Dietary noncompliance 24% Medication noncompliance 24%

Vasoconstriction Tachycardia Fluid retention

Vasodilation Suppress SNS/RAAS Natriuresis and diuresis

16% Inappropriate prescribing

19% Failure to seek care

17% Other

Shah M et al. Rev Cardiovasc Med. 2001; 2(Suppl 2):S2-S6.

Adapted from Vinson JM et al. J Am Geriatr Soc. 1990; 38:1290-5.

ADHF: Signs and Symptoms

Fluid Overload Low Cardiac Output
Fatigue Nausea and vomiting Early satiety Weight loss Increased serum creatinine Weight gain Dyspnea on exertion Paroxysmal nocturnal dyspnea (PND) Orthopnea Rales Peripheral edema Jugular venous distension Ascites Hepato-/splenomegaly

Diagnosis and Prognosis

B-type Natriuretic Peptide: Usefulness in ADHF Diagnosis

Correlation with BNP level ADHF diagnosis, disease severity, mortality Breathing Not Properly study (n=1,586) Patients presenting with dyspnea BNP assay

In-Hospital Mortality: Risk Stratification

BUN
< 43
2.7%

> 43
9% < 115 5.5% > 115 6.4% < 115 15.3%

SBP

> 115 2.1%

BNP > 100 pg/mL - 83% accuracy for diagnosis

Evaluate BNP in context of clinical picture

SCr

Lowest Risk

< 2.75 12.4%

> 2.75 22%

BNP < 100 pg/mL BNP 100 500 pg/mL BNP > 500 pg/mL

HF highly unlikely Consider HF history and other potential causes HF highly likely
BUN = blood urea nitrogen SBP = systolic blood pressure SCr = serum creatinine

Highest Risk
Fonarow GC et al. JAMA. 2005; 293:572-80.

Maisel AS et al. N Engl J Med. 2002; 347:161-7; Adams KF et al. J Card Fail. 2006; 12:10-38.

Patient Selection and Treatment

Pulmonary Capillary Wedge Pressure (mmHg) 15-18 mmHg 5 Cardiac Index (L/min/m2) 4 3 2.2 L/min/m2 2 1 Subset I (Normal) Warm and dry Subset II (Congestion) Warm and wet

ADHF: Therapeutic Options

Diuretics Inotropes Vasodilators and Natriuretic Peptide
Preload and afterload

Subset IV Subset III (Hypoperfusion) (Congestion and hypoperfusion) Cold and dry Cold and wet 10 20
Low SVR

Fluid volume (preload)

Contractility

30
High SVR

PCWP = pulmonary capillary wedge pressure CI = cardiac index Adapted from Nohria A et al. JAMA. 2002; 287:628-40. SVR = systemic vascular resistance

Furosemide Bumetanide Torsemide

Dobutamine Milrinone

Nitroglycerin Nitroprusside Nesiritide

ADHF: Goals of Therapy

Improve signs and symptoms of congestion or hypoperfusion or both Identify etiology and precipitating factors Minimize adverse effects Optimize chronic oral drug therapy

Diuretic Therapy in Fluid Overload

ADHF: Signs and Symptoms

Fluid Overload
Weight gain Dyspnea on exertion PND Orthopnea Rales Peripheral edema Jugular venous distension Ascites Hepato-/splenomegaly

Patient Selection and Treatment

Cardiac Index (L/min/m2) 5 4 3 2.2 L/min/m2 2 1 Pulmonary Capillary Wedge Pressure (mmHg) 15-18 mmHg Subset I (Normal) Warm and dry Subset II (Congestion) Warm and wet

Low Cardiac Output

Fatigue Nausea and vomiting Early satiety Weight loss Increased serum creatinine

Diuretics

Subset IV Subset III (Hypoperfusion) (Congestion and hypoperfusion) Cold and dry Cold and wet 10 20
Low SVR

30
High SVR

Adapted from Nohria A et al. JAMA. 2002; 287:628-40.

Diuretics
Primarily used to reduce congestion Limited literature supporting impact on outcomes Diuretic resistance frequently limits efficacy Association with increased mortality

Chronic Diuretic Therapy: Mortality

No Diuretic Diuretic

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.8 5.5 2.7 3.3

ADHERE Registry > 46,000 hospitalizations
(Both p < 0.0001)

% Mortality

SCr < 2 mg/dL

SCr > 2 mg/dL

Odds ratio (OR) 1.3 (1.2-1.5) 2.4 (2.1-2.6) p value <0.001 <0.001

Mortality Risk risk Chronic diuretics SCr > 2 mg/dL

Costanzo MR et al. American College of Cardiology (ACC) scientific sessions. 2004 March.

Acute Diuretic Therapy: Mortality, LOS, and ICU LOS

Outcome Mortality I.V. Diuretics (n=50,882) 2.3% No I.V. Diuretics (n=5,602) 2.0% Adjusted OR (95% CI) 1.29 (1.04-1.59) 1.49 (1.40-1.58) 1.59 (1.26-2.0) p value 0.02

Ultrafiltration (UF)
Principles and benefits
Provides an additional modality for fluid removal Rapidly removes salt and water (up to 500 mL/hr) Allows for a predictable amount of fluid to be removed Safer than diuretics because removal of sodium and water is isotonic Patients with diuretic resistance Patients with renal impairment

LOS > 4 day

52.1%

40.8%

<0.001

ICU LOS > 3 day

30%

19.7%

<0.001

Potential indications

CI = confidence interval, LOS = length of stay, ICU = intensive care unit Emerman C et al. J Card Fail. 2004; 10(Suppl 4):S116-7.

UNLOAD Trial
Ultrafiltration versus I.V. Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure
Design: Population: Prospective, randomized trial in patients with ADHF due to volume overload n=200, 2 signs of volume overload, randomized within 24 hours of admission, hemodynamically stable, and no prior i.v. vasoactive drugs Ultrafiltration vs. aggressive i.v. diuretic therapy Weight loss and dyspnea score at 48 hours
Costanzo MR et al. ACC scientific sessions. 2006 March 14.

UNLOAD Trial: Ultrafiltration vs. Diuresis

End points 48 hours Weight loss (kg) Dyspnea score (mean) Net fluid loss (L) Potassium < 3.5 mEq/L (%) Need for vasoactive therapy (%) UF 5.0 6.4 4.6 1 3 Diuresis 3.1 6.1 3.3 12 13 p value 0.001 0.35 0.001 0.018 0.015

Treatment: Endpoints:

Costanzo MR et al. ACC scientific sessions. 2006 March 14.

UNLOAD Trial: Ultrafiltration vs. Diuresis (cont)

End points 90 days Rehospitalization (%) Rehospitalization days (mean) Unscheduled office or emergency department (%) UF 18 1.4 Diuresis p value 32 3.8 0.022 0.022

Inotropic Therapy in Low Cardiac Output

21

44

0.009

Costanzo MR et al. ACC scientific sessions. 2006 March 14.

ADHF: Signs and Symptoms

Fluid Overload
Weight gain Dyspnea on exertion PND Orthopnea Rales Peripheral edema Jugular venous distension Ascites Hepato-/splenomegaly

Patient Selection and Treatment

Pulmonary Capillary Wedge Pressure (mmHg) 15-18 mmHg 5 Cardiac Index (L/min/m2) 4 Subset I (Normal) Warm and dry Subset II (Congestion) Warm and wet

Low Cardiac Output

Fatigue Nausea and vomiting Early satiety Weight loss Increased serum creatinine

3 2.2 L/min/m2 2 1

Subset IV Subset III (Hypoperfusion) (Congestion and hypoperfusion) Cold and dry Cold and wet 10 20
Low SVR

30
High SVR

Inotropes
Dobutamine Milrinone

Adapted from Nohria A et al. JAMA. 2002; 287:628-40.

Limitations of Positive Inotropes

Increased mortality Milrinone1 Enoximone2 Imazodan3 Vesnarinone4 Dobutamine5,6 Xamoterol7 Ibopamine8
1Packer

OPTIME-CHF Trial
Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure Design: Double-blind, placebo-controlled trial

Arrhythmias Neurohormonal activation Tachyphylaxis Physiologic effects antagonized by -blockade

Population: n=951 patients with ADHF Treatment: Endpoint: Intravenous milrinone vs. placebo for 48 hrs Rehospitalization for cardiovascular events at 60 days
Cuffe MS et al. JAMA. 2002; 287:15417.

M et al. N Engl J Med. 1991; 325:1468-75. 2Uretsky BF et al. Circulation. 1990; 82:774-80. 3Yusuf SF. Circulation. 1990; 82:III-673. 4Cohn JN et al. N Engl J Med. 1998; 339:1810-6. 5Dies F et al. Circulation. 1986; 74:II-38. 6OConnor CM et al. Am Heart J. 1999; 138(1 Pt 1):78-86. 7Xamoterol in Severe Heart Failure Study Group. Lancet. 1990; 336:1-6. 8Hampton JR et al. Lancet. 1997; 349:971-7.

OPTIME-CHF Trial: Study Results

There was no significant difference in hospitalization for cardiovascular events within 60 days. Milrinone (n = 477)
Number of patients Median hospital stay (days) Mean hospital stay (days) Days until discharge 477 6 12.3 14 5.7 13

OPTIME-CHF Trial: Adverse Events

Milrinone Control (n = 477) (n = 472) Adverse event Sustained hypotension Acute myocardial infarction Atrial fibrillation (new-onset)
* p = 0.004 **p < 0.001

Control (n = 472)
472 7 12.5 14 5.9 13

12.6% ** 10.7% ** 1.5% 4.6% *

2.1% 3.2% 0.4% 1.5%

Total mortality rates (in hospital and at 60 days) were not significantly different between the two treatment groups.
Cuffe MS et al. JAMA. 2002; 287:15417. Cuffe MS et al. JAMA. 2002; 287:15417.

ADHERE Registry: Mortality Comparing Vasodilators vs. Inotropes

Odds Ratio* NTG vs. MIL NTG vs. DOB NES vs. MIL NES vs. DOB NES vs. NTG DOB vs. MIL 0.69 0.46 0.59 0.47 0.94 1.24 Confidence Interval 0.53-0.89 0.37-0.57 0.48-0.73 0.39-0.56 0.77-1.16 1.03-1.55 p Value <0.005 <0.005 <0.005 <0.005 0.58 0.027

Vasodilator Therapy in Fluid Overload and Low Output

NTG = nitroglycerin, NES = nesiritide, MIL = milrinone, DOB = dobutamine *Adjusted for covariates and propensity score Abraham WT et al. J Am Coll Cardiol. 2005; 46:57-64.

Patient Selection and Treatment

Pulmonary Capillary Wedge Pressure (mmHg) 15-18 mmHg Cardiac 5 Index 4 (L/min/m2) 3 2.2 L/min/m2 2 1 Subset I (Normal) Warm and Dry Subset II (Congestion) Warm and Wet

Natriuretic Peptides: Physiologic Effects

Renin Angiotensin Aldosterone System Natriuretic Peptide System
Vasodilation Sodium excretion Decreased aldosterone release Decreased cellular growth Inhibition of sympathetic nervous system activity

Vasodilators
Nitroprusside Nitroglycerin or

Subset IV Subset III (Hypoperfusion) (Congestion and Hypoperfusion) Cold and Dry Cold and Wet 10 20
Low SVR

Natriuretic peptides
Nesiritide

30
High SVR

Vasoconstriction Sodium retention Increased aldosterone release Increased cellular growth Increased sympathetic nervous system activity

Adapted from Nohria A et al. JAMA. 2002; 287:628-40.

VMAC Trial: Design

Vasodilatation in the Management of Acute CHF
3-hour placebo-controlled period
randomization stratification catheterized (n=246) eligible patient (n=489) noncatheterized (n=243) nitroglycerin (n=60) placebo (n=62) nesiritide fixed-dose (n=62) nesiritide adjustable-dose (n=62) nesiritide fixed-dose (n=92) nesiritide adjustable-dose (n=62) nitroglycerin (n=92) Mean Observed Value (mm Hg)

VMAC Trial
Primary endpoint: PCWP through 3 hours
Nesiritide
30 29 28 27 26 25 24 23 22 21 20 19 18 15 m 30 m BL 1h 2h 3h

Active-controlled treatment period

Nitroglycerin

Placebo

nitroglycerin (n=83) placebo (n=80) nesiritide fixed-dose (n=80)

nitroglycerin (n=124)

nesiritide fixed-dose (n=119)

Time

time zero

3 hours

VMAC Investigators. JAMA. 2002; 287:1531-40.

Time

end of study drug

6 months

* p <0.05 nesiritide vs. placebo p <0.05 nesiritide vs. nitroglycerin

VMAC Investigators. JAMA. 2002; 287:1531-40.

Nesiritide: Mortality Assessment

Meta-analysis assessing mortality of nesiritide vs. control

NAPA Trial
Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery
Design: Multicenter, randomized, placebo-controlled study Population: Undergoing coronary artery bypass graft (CABG) surgery requiring cardiopulmonary bypass, left ventricular ejection fraction (LVEF) < 40% Treatment: Intravenous nesiritide versus placebo for 24-96 hr Endpoints: Change in SCr and glomerular filtration rate (GFR) Change in urine output (UOP) at 24 hr Mean ICU/CCU and hospital LOS
CCU = coronary care unit Hebeler RF Jr et al. 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke. 2006 May 9.

3 trials: NSG-Efficacy, VMAC, PROACTION End point 30-day mortality Nesiritide (n = 485) 7.2 % Control (n = 377) 4% p value 0.059

Study limitations

3 heterogeneous trials Not designed to assess mortality Nesiritide doses greater than labeled doses Hypothesis-generating rather than conclusive
Sackner-Bernstein JD et al. JAMA. 2005; 293:1900-5.

Author conclusion

NAPA Trial: Design

Nesiritide* + standard care Nesiritide (n=141) Time (hrs) = 279 CABG patients
mitral valve procedure 0 24 96

NAPA Trial: Results

Endpoint* Peak SCr increase (mg/dL) All subjects Subjects with baseline SCr >1.2 mg/dL All subjects 0.15 (n=141) 0.02 (n=29) -10.8 (n=141) -0.2 (n=29) 0.34 (n=138) 0.48 (n=33) -17.2 (n=138) -9.1 (n=33) <0.001 0.001 Nesiritide Placebo p value

sia t he es on An ucti d In

Surgery

ICU/CCU

Floor / telemetry

h sc Di

ar

ge

Follow-up Day 30

Maximum decrease in GFR (mL/min/1.73 m2) 0.001 0.003

Placebo (n=138)

Time (hrs) = 0

24

96

Placebo* + standard care

*Administered for 24-96 hours (no bolus); nesiritide dose 0.01 mcg/kg/min Hebeler RF Jr et al. 7th Scientific Forum. 2006 May 9.

Subjects with baseline SCr >1.2 mg/dL

*Mean change in SCr and GFR through discharge or hospital day 14, whichever came first

Hebeler RF Jr et al. 7th Scientific Forum. 2006 May 9.

NAPA Trial: Results (cont)

Parameter UOP in 24 hr (mL) Postoperative SCr increase > 0.5 mg/dL (%) LOS (days) Nesiritide 2926 7 Placebo 2350 23 p Value <0.001 <0.001

Optimizing Chronic Therapy

9.1

11.4

0.043

Hebeler RF Jr et al. 7th Scientific Forum. 2006 May 9.

IMPACT-HF Trial
Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure
Screening hospitalized patients LVEF < 40%, hospitalized for ADHF Randomization n=363 Pre-discharge initiation carvedilol 3.125 mg bid Follow-up at 60 days
All patients were treated with other HF therapy, including angiotensin-converting enzyme (ACE) inhibitors, at the J physicians discretion.

IMPACT-HF Trial: Results

Predischarge (n=185 ) 91.2* 3.2 21.7 23.8 Post-discharge at MD Discretion (n=178 ) 73.4 4.5 25.3 27.0

Endpoint Treatment with -blocker (%) Death (%) Rehospitalization (%) Death or rehospitalization (%)

Physician discretion postdischarge (2 weeks) Initiation of any -blocker

*p<0.0001; all other differences nonsignificant

Gattis WA et al. Am Coll Cardiol. 2004; 43:1534-41.

Gattis WA et al. J Am Coll Cardiol. 2004; 43:1534-41.

IMPACT-HF Trial: Serious Adverse Effects

Endpoint Withdrawal of -blocker (%) Withdrawal hypotension (%) Withdrawal bradycardia (%) Withdrawal HF worse (%) Hospital LOS (days)
All differences nonsignificant. Gattis WA et al. J Am Coll Cardiol. 2004; 43:1534-41.

Predischarge (n=185 ) 10 1.6 1.6 0.5 5

Post-discharge at MD Discretion (n=178 ) 11 0.6 0 1.7 5

Pharmacist Role

PHARM Trial
Freedom from Death or NF HF

1.5

Pharmacist in Heart Failure Assessment Recommendation and Monitoring

UC- Usual care I - Intervention

PHARM Trial: Death or Readmission

100%
Control Intervention

82%

% of Patients

75% 59% 50% p<0.05 24% p<0.01 29%

0.5

OR 0.218 (0.06-0.625), p=0.0048

0

25%

60

120

180 Time (days)

240

300

360
0%

NF HF = nonfatal heart failure Gattis WA et al. Arch Intern Med. 1999; 159:1939-45. Death alone p=0.48

Readmission

Death or Readmission

Gattis WA et al. Arch Intern Med. 1999; 159:1939-45.

ADHERE Registry: Conforming to HF Performance Indicators

All Hospitals (n=223) Discharge instructions (%) Left-ventricular function tests (%) Discharge ACEinhibitor Rx (%) Smoking cessation counseling (%) 31.5 84.2 71.9 45.5 Academic Hospitals (n=67) 22.1 86.3 75.4 41.5 Non-Academic Hospitals (n=156) 35.5 83.3 70.4 47.2 p value <0.001 0.03 0.007 0.14

Patient Selection and Treatment

Pulmonary Capillary Wedge Pressure (mmHg) 15-18 mmHg Cardiac Index (L/min/m2) 5 4 3 2.2 L/min/m2 2 1 Subset I (Normal) Warm and dry Subset II (Congestion) Warm and wet

Subset IV Subset III (Hypoperfusion) (Congestion and hypoperfusion) Cold and dry Cold and wet 10 Inotropes 20 30

81,142 hospital admissions for ADHF. ADHERE Registry Report Q2 2002 (7/1/02-12/31/03) of 233 U.S. hospitals. Fonarow GC et al. Arch Intern Med. 2005; 165:1469-77.

Diuretics or Vasodilators Nitroprusside Nitroglycerin or Natriuretic Peptides Nesiritide

Dobutamine Milrinone Adapted from Nohria A et al. JAMA. 2002; 287:628-40.

Conclusions
ADHF is associated with significant morbidity and mortality and consumes a considerable portion of overall healthcare expenditures. Maintaining the neurohormonal balance is instrumental to preventing ADHF. Limited literature supports therapies currently being used to manage ADHF. It is critical to understand the underlying process (wet/dry, cold/warm) in ADHF to best select optimal drug therapy. Pharmacists are instrumental in preventing and managing ADHF.

Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
References
1. Abraham WT, Adams KF, Fonarow GC et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005; 46:57-64. Adams KF, Lindenfeld J, Arnold JMO et al. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006; 12:10-38. American Heart Association, American Stroke Association. Heart disease and stroke statistics2006 update. Dallas: American Heart Association; 2006. Available at: http://www.americanheart.org/downloadable/heart/1135358648580551026_HS_Stats06book.pdf. Accessed July 18, 2006. Cohn JN, Goldstein SO, Greenberg BH et al. A dose-dependent increase in mortlity with vesnarinone among patients with severe heart failure: Vesnarinone Trial Investigators. N Engl J Med. 1998; 339:1810-6. Costanzo MR, Heywood JT, De Marco T et al. Impact of renal insufficiency and chronic diuretic therapy on outcome and resource utilization in patients with acute decompensated heart failure. Poster presented at the American College of Cardiology 2004 scientific sessions; New Orleans, LA: 2004 March. Costanzo MR et al. Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD). Presented at the American College of Cardiology annual meeting; Atlanta, GA: 2006 Mar 14. Cuffe MS, Califf RM, Adams KF Jr et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002; 287:1541-7. DiDomenico RJ, Park HY, Southworth MR et al. Guidelines for acute decompensated heart failure treatment. Ann Pharmacother. 2004; 38:649-60. Dies F, Krell MJ, Whitlow P et al. Intermittent dobutamine in ambulatory outpatients with chronic cardiac failure. Circulation. 1986; 74:II-38. Emerman C, DeMarco T, Costanzo MR et al. Impact of intravenous diuretics on the outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE Registry. J Card Fail. 2004; 10(Suppl 4):S116-7 (A368). Fonarow GC, Adams KF, Abraham WT et al. Risk stratification for in-hospital mortality in acutely decompensated heart failure classification and regression tree analysis. JAMA. 2005; 293:572-80. Fonarow GC, Yancy CW, Heywood JT (for the ADHERE Scientific Advisory Committee, Study Group, and Investigators). Adherence to heart failure quality-of-care indicators in US hospitals. Arch Intern Med. 2005; 165:1469-77.

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Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
13. Gattis WA, Hasselblad V, Whellan DJ et al. Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study. Arch Intern Med. 1999; 159:1939-45 Gattis WA, OConnor CM, Gallup DS et al. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACTHF) trial. J Am Coll Cardiol. 2004; 43:1534-41. Hampton JR, van Veldhuisen DJ, Kleber FX et al. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure: Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators. Lancet. 1997; 349:971-7. Hebeler RF Jr, Oz MC. Effect of perioperative nesiritide administration on postoperative renal function and clinical outcomes in patients undergoing cardiothoracic surgery. Poster presented at 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke; Washington, DC: 2006 May 9. Maisel AS, Krishnaswamy P, Nowak RM et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002; 347:161-7. McBride BF, White CM. Acute decompensated heart failure: a contemporary approach to pharmacotherapeutic management. Pharmacotherapy. 2003; 23:997-1020. Nohria A, Lewis E, Stevenson LW. Medical management of advanced heart failure. JAMA. 2002; 287:628-40. OConnell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant. 1994; 13:S107-S12. OConnor CM, Gattis WA, Uretsky BF et al. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advancd heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1999; 138(1 Pt 1):78-86. Packer M, Carver JR, Rodeheffer RJ et al. Effect of oral milrinone on mortality in severe chronic heart failure: The PROMISE Study Research Group. N Engl J Med. 1991; 325:1468-75. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002; 287:1531-40. Sackner-Bernstein JD, Kowalski M, Fox M et al. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005; 293:1900-5. Shah M, Ali V, Lamba S et al. Pathophysiology and clinical spectrum of acute congestive heart failure. Rev Cardiovasc Med. 2001; 2(Suppl 2):S2-6.

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Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
26. Uretsky BF, Jessup M, Konstam MA et al. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure: lack of benefit compared with placebo. Enoximone Multicenter Trial Group. Circulation. 1990; 82:774-80. Vinson JM, Rich MW, Sperry JC et al. Early readmission of elderly patients with congestive heart failure. J Am Geriatr Soc. 1990; 38:1290-5. Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet. 1990; 336:1-6. Yusuf SF. Inotropic agents increase mortality in patients with congestive heart failure. Circulation. 1990; 82:III-673.

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Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
Self-Assessment Questions
1. Which of the following is the most significant contributor to the cost of heart failure management? a. b. c. d. Medication. Transplantation. Outpatient care. Hospitalization.

2. Which of the following are involved in the neurhormonal imbalance that occurs in heart failure? a. b. c. d. Reduction in vascular impedance or resistance. Increase in sodium and water retention. Reduction in B-type natriuretic peptide (BNP) level. Reduction in tachycardia.

3. What is the most common cause of worsening heart failure? a. b. c. d. Failure to seek care. Inappropriate prescribing. Inadequate discharge planning. Noncompliance with diet and medication.

4. Which of the following signs and symptoms is consistent with low cardiac output? a. b. c. d. Increased serum creatinine. Orthopnea. Ascites. Rales.

5. Which of the following BNP concentrations is consistent with an unlikely diagnosis of acute decompensated heart failure (ADHF)? a. b. c. d. 50 pg/mL. 500 pg/mL. 5000 pg/mL. 50,000 pg/mL.

6. A patient is hospitalized for ADHF with a systolic blood pressure of 100 mmHg, blood urea nitrogen of 55 mg/dL, and a serum creatinine of 4.2 mg/dL. Which of the following percentages most closely corresponds to the in-hospital risk of mortality for this patient? a. b. c. d. 2%. 5%. 15%. 20%.

Acute Decompensated Heart Failure: Review of Pathophysiology and Key Clinical Trials
7. Which of the following therapies directly improves contractility in patients with ADHF? a. b. c. d. Diuretics. Inotropes. Vasodilators. Natriuretic peptides.

8. Which of the following statements regarding diuretic therapy in patients with ADHF is true? a. b. c. d. Many well-controlled studies support the positive impact of i.v. diuretics on outcomes. Intravenous diuretics have a limited adverse effect profile. Diuretic resistance rarely occurs. Retrospective studies suggest a negative impact of intravenous diuretics on outcome.

9. Compared with diuretics, ultrafiltration has been shown to result in a. b. c. d. Greater net fluid and weight loss. Greater hypokalemia. Greater need for vasoactive therapy. Greater reduction in dyspnea score.

10. All of the following are concerns regarding the use of inotropic therapy in patients with ADHF except a. b. c. d. Arrhythmia. Increased mortality. Lack of response to milrinone in patients receiving -blocker therapy. Neurohormonal activation.

11. Compared with nitroglycerin, nesiritide has been demonstrated to reduce which of the following parameters a. b. c. d. Symptoms as reported by patient. Symptoms as reported by physician. Pulmonary capillary wedge pressure through 24 hours. Pulmonary capillary wedge pressure through 48 hours.

12. Controversy has arisen regarding nesiritides effect on which of the following outcomes? a. b. c. d. Mortality at 30 days. Hospital readmission within 180 days. Hemodynamic parameters within 12 hours. Length of stay for initial hospitalization.

13. Initiating -blocker therapy before discharge for patients hospitalized with ADHF has been demonstrated to a. b. c. d. Increase length of stay. Increase outpatient treatment with a -blocker. Increase the number of readmissions within 60 days. Increase the total hospitalization cost.