Clinical Review & Education

JAMA Cardiology | Review

Optimal Medical Therapy for Known

Coronary Artery Disease
A Review
Raymond J. Gibbons, MD; Todd D. Miller, MD

IMPORTANCE This review examines the current state-of-the-art optimal medical therapy
(OMT) for patients with known coronary artery disease. This therapy, which is sometimes
labeled as secondary prevention, is effective in preventing recurrent events and is
recommended by the American College of Cardiology Foundation/American Heart
Association guidelines. Optimal medical therapy is of recognized public health benefit.

OBSERVATIONS The available evidence from broad patient populations, contemporary

randomized trials, and multiple recent studies with pharmacy records indicates that the
delivery of OMT is far from ideal. We suggest approaches for quality improvement, including
better patient education, the increased use of interventions that are known to improve
compliance, and the use of performance measures focused on long-term OMT in outpatient
care.

CONCLUSIONS AND RELEVANCE Improvement in the delivery of OMT to patients with Author Affiliations: Mayo Clinic,
coronary artery disease is one possible step to help the United States reduce the recently Rochester, Minnesota.
reported increase in death rate from heart disease. Corresponding Author: Raymond J.
Gibbons, MD, Department of
Cardiovascular Medicine, Mayo Clinic,
JAMA Cardiol. doi:10.1001/jamacardio.2017.2249 200 1st St SW, Rochester, MN 55905-
Published online July 12, 2017. 0001 (gibbons.raymond@mayo
.edu).

C
onsider a 48-year-old man who presents to your office for
3-month follow-up of coronary artery disease (CAD) risk fac-
tors. He has followed your instructions and is walking 2.4
km in 30 minutes almost every day. He is following a more prudent
diet and has lost 5 kg. His blood pressure and cholesterol levels have
improved from his previous values. He does not smoke and does not
have diabetes.
However, the patient describes an episode of severe chest dis-
comfort, diaphoresis, and dyspnea 3 weeks ago that lasted for sev-
eral hours. He did not seek medical attention. He felt tired for the
next few days but is now back to normal.
An electrocardiogram shows new inferior Q waves that were not
present previously. On an exercise single-photon emission com-
puted tomography study, the patient has normal exercise toler-
ance, normal hemodynamic response, and no electrocardiogram
changes or chest pain. The images show a fixed inferior defect that
measures 15% of the left ventricle. Ejection fraction is 54% with hy-
pokinesia of the inferior wall.
You inform the patient that his history, change in electrocardio-
gram, and exercise single-photon emission computed tomography
study indicate that his chest pain from 3 weeks ago was likely an in-
ferior myocardial infarction (MI). You recommend that he continue
with his regular exercise program and his prudent diet. What medi-
cal therapy should you recommend for him?
The purpose of this review is to summarize the current state-
of-the-art optimal medical therapy (OMT) for this asymptomatic pa-
tient with CAD. It will specifically focus on medical therapy that is
effective in preventing recurrent events, ie, secondary prevention.
It will highlight recent developments that are pertinent to OMT, sum-
marize the published data indicating how inconsistently OMT is de-
livered in broad populations, review the experience in several re-
cent randomized trials, and suggest potential approaches for quality
improvement.
OMT for Secondary Prevention
The major class I American College of Cardiology Foundation (ACCF)/
American Heart Association (AHA) guideline recommendations re-
garding antiplatelet therapy, lipid-lowering therapy, blockers, an-
giotensin-converting enzyme (ACE) inhibitors, angiotensin receptor
blockers (ARBs), antihypertensive therapy, and aldosterone antago-
nists are summarized in the Table.1-4 Most of these recommenda-
tions are based on randomized trials (level of evidence A). They are
generally far less controversial than recommendations for antiplate-
let therapy or lipid treatment for primary prevention in patients with-
out established CAD. With the exception of blockers and dual an-
tiplatelet therapy, most of these recommendations are for lifelong
therapy, as such patients are presumed to be at increased risk for
cardiac events indefinitely.
After the publication of their secondary prevention treatment
guidelines, the ACCF and AHA published a controversial guideline

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 Clinical Review & Education Review
Table. ACCF/AHA Class I Recommendations for Risk Reduction in
Patients With Known Arteriosclerotic Cardiovascular Disease
Medication Class I Recommendations
Aspirin, 75-162 mg daily, is recommended in all patients
with coronary artery disease unless contraindicated (level of
evidence: A)
Clopidogrel, 75 mg daily, is recommended as an alternative
for patients who are intolerant of or allergic to aspirin (level
Antiplatelet of evidence: B)
agents
In patients with ACS who are treated with medical therapy
alone and treated with DAPT, clopidogrel or ticagrelor should
be continued for at least 12 mo (level of evidence: B)
In patients treated with DAPT, a daily aspirin dose of 81 mg
(range, 75-100 mg) is recommended (level of evidence: B)
Angiotensin-converting enzyme inhibitors should be started
and continued indefinitely in all patients with left ventricular
ejection fraction 40% and in those with hypertension,
diabetes, or chronic kidney disease, unless contraindicated
Renin- (level of evidence: A)
angiotensin-
aldosterone Use of aldosterone blockers in post-MI patients without
significant renal dysfunction or hyperkalemia is
system
blockers recommended in patients who are already receiving
therapeutic doses of an angiotensin-converting enzyme
inhibitor and blocker, who have a left ventricular ejection
fraction 40%, and who have either diabetes or heart failure
(level of evidence: A)
Blocker therapy should be used in all patients with left
ventricular systolic dysfunction (ejection fraction 40%)
with heart failure or prior MI, unless contraindicated (level of
Blockers evidence: A)
Blocker therapy should be started and continued for 3 y in
all patients with normal left ventricular function who have
had MI or ACS (level of evidence: C)
High-intensity statin therapy is recommended for patients
who are 75 y and have no safety concerns (level of
evidence: A)
Statin therapy
Moderate intensity of statin therapy is recommended for
patients >75 y or who have safety concerns (level of
evidence: A)
ACCF indicates American College of Cardiology Foundation; ACS, acute
coronary syndromes; AHA, American Heart Association; DAPT, dual antiplatelet
therapy; MI, myocardial infarction.
on lipid-lowering therapy.5 The controversy surrounding this guide-
line focused on its recommendations for the use of statins in pa-
tients without known CAD. In the present patient with known CAD,
the lipid-lowering therapy guideline recommends the use of a high-
intensity statin (atorvastatin or rosuvastatin) in patients 75 years or
younger on the basis of previously published randomized trials.5
More recent relevant published evidence has not yet been con-
sidered in the ACCF/AHA guideline process. The SPRINT trial6 es-
tablished the benefit of stricter blood pressure targets in patients
with known CAD or patients who are at high risk for cardiac events.
In the SPRINT trial, blockers were the preferred antihypertensive
therapy in patients with previous cardiac events.6
What is the Overall Public Health Benefit of OMT
for Secondary Prevention?
The Centers for Disease Control and Prevention published an analy-
sis examining the factors that contributed to reduced cardiovascu-
lar mortality between 1980 and 2000.7 The management of hyper-
tension and hyperlipidemia and antiplatelet therapy following
cardiovascular events accounted for 11% of the reduction in cardio-
vascular mortality, which was comparable to the 10% reduction in
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Optimal Medical Therapy for Known Coronary Artery Disease
Figure 1. Optimal Care in Minnesota
100 100
Optimal care
Patient population
Patient Population, in Thousands
80 80
Optimal Care, %
60 60
40 40
20 20
0 0
2007 2008 2009 2010 2011 2012 2013
Year
The proportion of patients receiving optimal care between 2007 and 2013 in
Minnesota and the patient population, in thousands, is reported. The increasing
patient population reflects the increasing use of complete electronic medical
record extraction.
mortality that could be attributed to better acute care of acute coro-
nary syndromes.7 Thus, OMT for secondary prevention is generally
accepted, recommended in clinical practice guidelines, and has a
demonstrable, important public health benefit.
OMT in Broad Populations
Although single-center studies from Duke University8 and Mayo
Clinic9 have reported improvement in the use of aspirin, block-
ers, and statins between 1995 and 2008, use of ACE inhibitors is per-
sistently lower than the other 3 drug classes. These studies are lim-
ited by patient selection and referral bias.
Minnesota had a consistent state standard for the optimal treat-
ment of patients with established CAD from 2004 to 2013,10 which
required a low-density lipoprotein (LDL) cholesterol level of less than
130 mg/dL (to convert to millimoles per liter, multiple by 0.0259),
blood pressure of less than 140/90 mm Hg (or <130/80 mm Hg be-
fore 2010), daily aspirin or antiplatelet medication (unless allowed
contraindications or exceptions), and no tobacco use. This all-or-
none performance measure, as advocated by the Institute of Medi-
cine, is publicly reported for outpatient practices.11 This concept has
a simple rationale, eg, a patient who is receiving antiplatelet therapy
and has well-controlled cholesterol and blood pressure is not being
optimally treated if he or she continues to use tobacco.11,12 This Min-
nesota standard does not include ACE inhibitors as it was estab-
lished before publication of a key systematic evidence review.13 The
state standard underwent reassessment in 2013 because of the pub-
lication of the ACCF/AHA lipid-lowering guidelines. After Minneso-
tas initial adoption in 2004, this measure was broadened to in-
clude patients with confirmed peripheral vascular disease or previous
stroke.12,14 The performance for this broader measure improved from
a statewide average of 32.6% in 2007 to 50.0% in 2013 (Figure 1).14
The REGARDS study15 analyzed 30 239 community-dwelling in-
dividuals recruited between 2003 and 2007 and was designed to
be balanced on race/ethnicity and sex. There were 3167 partici-
pants with a self-reported history of MI, percutaneous coronary in-
tervention (PCI), or coronary artery bypass grafting. The propor-
jamacardiology.com
 Optimal Medical Therapy for Known Coronary Artery Disease
tion who met individual goals for aspirin use, blood pressure control
(<130/85 mm Hg), LDL cholesterol level (<100 mg/dL), and non-
smoking status ranged from 57% to 85%. Only 16% met all 3 aspi-
rin, blood pressure, and LDL cholesterol goals.
Survey data from the EUROASPIRE I, II, and III studies showed
that uncontrolled hypertension (140/90 mm Hg) was constant at
approximately 60% over time in patients with established CAD (pre-
vious MI, PCI, or coronary artery bypass grafting).16 Lipid-lowering
therapy improved over time but only to 48% in women and 60%
in men. Data from EUROASPIRE IV showed that 75% of patients re-
ceived some lipid-lowering therapy after MI, but only 35% re-
ceived a high-intensity statin.17
The PURE study18 reported the use of 4 medications (aspirin,
blockers, statins, and ACE inhibitors or ARB) following MI. In 3 de-
veloped countries (ie, Sweden, United Arab Emirates, and the United
Kingdom), 3 or more drugs were delivered to only 50% of the pa-
tients. The performance in less developed countries was worse.
OMT in Randomized Trials
Recent randomized trials of the treatment of CAD have empha-
sized the importance of OMT. The COURAGE trial set ambitious goals
for LDL cholesterol level (<85 mg/dL), systolic blood pressure (<130
mm Hg), and diastolic blood pressure (<85 mm Hg).19 At 5-year fol-
low-up, a relatively high percentage of patients met the individual
goals. However, at 1 year, only 46% patients without diabetes met
all 3 goals of not smoking, an LDL cholesterol level of less than 100
mg/dL, and a systolic blood pressure of less than 130 mm Hg.20
Optimal medical therapy in individuals with diabetes included a
fourth goal comprising a hemoglobin A1C goal of less than 7% (to con-
vert to proportion of total hemoglobin, multiply by 0.01), which was
only met by 48% of the patients at 1 year. Blood pressure control in
patients with diabetes was less successful. As a result, only 18% of
patients with diabetes met all 4 goals for OMT at 1 year.20
SubsequenttrialsinthemanagementofCADhavehadlowerrates
of success. In the SYNTAX trial,21 OMT, defined as antiplatelet therapy,
a statin, an ACE inhibitor or ARB, and a blocker, was delivered to less
than half of the patients at baseline and generally declined with time.
Patients who received OMT had fewer adverse events.
The BARI-2D22 and FREEDOM23 trials, which were restricted to
patients with diabetes, met their goal of a hemoglobin A1C level of
less than 7% in only about half of their patients and all 4 goals for
OMT in less than 25% of their patients.20
In the Dual Antiplatelet Therapy Study,24 11 648 patients who
had undergone coronary stenting and completed 12 months of dual
antiplatelet therapy were randomly assigned to dual antiplatelet
therapy for an additional 18 months. Optimal medical therapy, de-
fined as a statin, an ACE inhibitor or ARB, and a blocker was pres-
ent in 7363 patients (63.2%) at randomization. They had lower rates
of MI and major adverse cardiovascular or cerebrovascular events
over the next 18 months compared with patients not receiving OMT.
Investigators of the ART trial25 randomized patients to bilat-
eral vs single internal mammary artery grafts. At 5 years, the use of
aspirin was 88.9%; blockers, 76.2%; statins, 89%; and ACE inhibi-
tors or ARB, 73.4%. These rates were higher than those reported for
the COURAGE,19 SYNTAX,21 or BARI-2D22 trials. The authors did not
report the rate of OMT (all 4 drug classes) at 5 years.
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Review Clinical Review & Education
Figure 2. Full Adherence to Medication in the MI FREE Trial
50
Usual
40 Free
Adherence, %
30
20
10
0
ACE Inhibitor -Blocker Statin Drug All 3
or ARB Class
Drug Class
Full adherence in the MI FREE trial was defined as greater than 80% usage
according to pharmacy records. Full adherence at 1 year after myocardial
infarction for angiotensin-converting enzyme (ACE) inhibitors or angiotensin
receptor blockers (ARBs), blockers, and statins was less than 35% for each
individual drug class. All 3 were used 9% of the time. When the drugs were
provided for free (light blue bars), there was a slight improvement in drug use,
but all 3 drugs were still only used 12% of the time at 1 year after myocardial
infarction (arrow). Adapted using data from Choudhry et al26 with permission
from Massachusetts Medical Society.
OMT in Studies With Pharmacy Records
Most of the evidence summarized thus far relied on medical rec-
ords or patient reports, rather than pharmacy records. Studies that
have used pharmacy records generally show much poorer results
of medication adherence. In the United States, the MI-FREEE study26
examined the potential value of providing statins, blockers, and
ACE inhibitors or ARB to insured non-Medicare patients at the time
of discharge. Full adherence was defined as evidence from phar-
macy records that the drugs had been taken 80% of the time over
the next year. The best full adherence for any single medication was
for statins, but full adherence over 1 year was still less than 40%
(Figure 2). Adherence with all 3 medications at 1 year was only 12%
when patients were given the medications for free.
A study of 292 residents of Olmsted County, Minnesota,27 with
incident MI from 1997 to 2006 and available prescription data from
a specific employer-sponsored health plan reported 3-year indi-
vidual medication continuation rates of less than 50% for statins,
blockers, and ACE inhibitors or ARB. A larger study from British Co-
lumbia, Canada, that used pharmacy records reported similarly dis-
appointing results for medical therapy following MI.28 Patients who
survived an MI were usually prescribed a blocker, a statin, and an
ACE inhibitor or ARB. However, by 1 year, both men and women, re-
gardless of age, were taking all 3 drugs less than 50% of the time.
Doll et al29 used the ACTION RegistryGet With the Guidelines
and Part D prescription filling data to study medication adherence
over 1 year after MI in 17 419 Medicare patients, of whom 4674 were
also eligible for Medicaid. Adherence to 4 medications ( blocker,
statin, ACE inhibitor or ARB, and platelet inhibitors) was 36.4% in
the dual-eligible patients and 30% in the Medicaid-only patients.
These 4 studies highlight the importance of pharmacy records in the
complete ascertainment of patient compliance.
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 Clinical Review & Education Review
Box. Approaches for Quality Improvement in Optimal
Medical Therapy
Patient Education
Access to electronic medical records
Shared decision making
Discussions with physicians about adherence
Discharge contracts
Interventions to Improve Compliance
Cardiac rehabilitation
Blister packs
Systems approaches using pharmacy records
Synchronized prescription refills
Polypill
Measurement
Minnesota Community Measures
National Quality Forum
Approaches for Quality Improvement
What approaches might potentially improve the delivery of OMT in
patients with known CAD (Box)?
Adherence is affected by multiple factors including socioeco-
nomic status, health care systems, and the patients condition and
therapy, which are beyond the scope of this review.30 Interven-
tions to address racial and ethnic disparities in control of hyperten-
sion have been reviewed elsewhere.31 We will focus on simple mea-
sures for practicing clinicians and health care systems.
Better patient education should be the cornerstone of quality
improvement. Many medical centers now provide patients with on-
line access to their electronic medical records. Health care profes-
sionals should document the proven benefits of OMT in their notes
and encourage their patients to review their records without the time
constraints and emotional stress of the actual medical visit so that
they can fully understand the importance of OMT.
Shared decision making in the management of CAD is critical. One
study reported that most patients who underwent PCI for stable an-
gina believed that the procedure would reduce MI and death, even
though a minority of the referring cardiologists and interventional car-
diologists agreed.32 These data suggest that patients overestimate the
benefits of stenting. National registry data indicate that many pa-
tients are not receiving OMT before or after PCI.33 Although patient
preferences, comorbidities, and adverse drug effects34,35 may re-
duce the use of OMT, patients should understand that OMT will re-
duce MI and death. Patients should be questioned about their adher-
ence to OMT; such discussions are currently uncommon.36 Decision
aids that help to promote meaningful conversations and shared de-
cision making should be encouraged.37 A study has shown success
when such an aid is used in explaining the value of statins.38
The American College of Cardiology conducted a Guidelines Ap-
plied in Practice project involving 33 Michigan hospitals, which in-
cluded a standard discharge contract to encourage long-term pa-
tient adherence to evidence-based medications.39 This contract
educated patients about their condition, encouraged them to par-
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Optimal Medical Therapy for Known Coronary Artery Disease
ticipate in their own care, provided instructions on taking medica-
tions, and helped establish goals for cholesterol levels, smoking ces-
sation, diet, and exercise. Both the patient and their health care
professional were expected to sign the contract. This project re-
ported a 26% reduction in 30-day mortality and a 22% reduction
in 1-year mortality. Use of the discharge contract was significantly
associated with the reduction in 1-year mortality (odds ratio, 0.53;
95 CI%, 0.36-0.76; P = .006).39,40
A second important component of quality improvement ef-
forts should be specific interventions to improve patient compli-
ance. Cardiac rehabilitation programs following MI are underused
(<10% in some states).41,42 Such programs encourage exercise, em-
phasize the importance of compliance with evidence-based mea-
sures, and improve patient outcomes.43,44 Automatic referral pro-
grams can double participation rates.45 In 2017, the Million Hearts
Cardiac Rehabilitation Collaborative announced a road map to in-
crease participation from 20% to 70%.46
A randomized trial of patients with multiple medications found
that blister packs increased medical adherence for at least 8
months.47 We are not aware of any national data indicating how of-
ten such packs are available routinely or on request. However, our
clinical experience suggests that patients who have such packs are
among the most insistent that they are compliant with their medi-
cations, unless their pharmacist has made a mistake.
In integrated health systems where pharmacy records are avail-
able, adherence should be encouraged through system approaches.
Kaiser Permanente has reported that follow-up telephone calls and
letters to patients who do not fill their initial statin prescription within
3 weeks can significantly increase the rate of statin initiation within
1 year.48 In patients with hypertension, Kaiser Permanente has shown
that the use of a mail-order pharmacy decreases the rate of nonad-
herenceby43%.49 Otherstudieshaveshownthatbloodpressurecon-
trol can be improved by in-person visits with physician assistants50
and by biweekly telephone calls from a pharmacist.51 A 2016 random-
ized trial from Alberta, Canada,52 where the scope of practice al-
lowed for pharmacists is broader than in the United States, found that
pharmacist case-finding and intervention could significantly in-
crease the rate of attainment of risk factor goals over a follow-up of
3 months. A multifaceted intervention that included a pharmacist and
voice messaging improved compliance after hospital discharge.53 De-
layed follow-up after discharge should be discouraged, as it reduces
adherence.54 One small nonrandomized study reported that filling
multiple medication refills by mail order at the same time may im-
prove adherence.55 Two trials outside the United States have re-
ported increased adherence with the use of a polypill.56,57
A third component of quality improvement efforts must be mea-
surement. National performance measures have emphasized dis-
charge medications following MI, but not subsequent outpatient
compliance. The quality improvement in Minnesota over more than
a decade can be attributed to outpatient measurement and public
reporting. The cardiovascular mortality rate in Minnesota has de-
clined by 47% from 1990 to 2015.58 Although this decrease is cer-
tainly due to many factors, the improvement in secondary preven-
tion, and the increased patient and physician awareness that the
performance measure for optimal vascular care has inspired, have
likely contributed. Hospitalizations of patients with CAD in Minne-
sota have decreased by 3% per year over the last decade.54 The Min-
nesota optimal vascular care performance measure was ap-
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 Optimal Medical Therapy for Known Coronary Artery Disease Review Clinical Review & Education

proved by the National Quality Forum in 200914 and was reendorsed
in December 2016.59 Its use and public reporting in other data col-
lection systems should be encouraged.
Conclusions
Although the benefit of OMT for secondary prevention is well es-
tablished, the available data from broad patient populations and ran-
domized trials suggest incomplete delivery of this care. The goal of
all health care professionals who participate in the care of patients
with CAD should be to raise performance above its current level of
(at best) 50%. In 2017, the Centers for Disease Control and Preven-
tion announced that the death rate from heart disease increased from
2014 to 2015, reversing a long-term downward trend.60 We be-
lieve that more consistent delivery of OMT for secondary preven-
tion is 1 possible step that the nation can take to address this in-
crease in death rate from heart disease.

ARTICLE INFORMATION
Accepted for Publication: March 30, 2017.
Published Online: July 12, 2017.
doi:10.1001/jamacardio.2017.2249
Author Contributions: Both authors had full access
to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Both authors.
Acquisition, analysis, or interpretation of data: Both
authors.
Drafting of the manuscript: Gibbons.
Critical revision of the manuscript for important
intellectual content: Both authors.
Conflict of Interest Disclosures: Both authors
have completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
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