Outpatient Management of Survivors of

Acute Coronary Syndromes

Coronary artery disease (CAD) continues to grow in prevalence as the
incidence of atherosclerotic risk factors (diabetes, hypertension, dyslipidemia)
escalates. Acute coronary syndromes (ACS) occur when an atherosclerotic plaque
in a coronary artery ruptures, activating clot formation, which suddenly and
critically reduces coronary blood flow. The result can be reversible myocardial
ischemia, ischemia with small amounts of myocardial necrosis (non-ST elevation
myocardial infarction) or large areas of frank (ST elevation) myocardial infarction
(MI). Earlier recognition of ACS, achieved through public education, has
combined with more effective initial therapy to reduce mortality, leaving an ever-
increasing population of ACS survivors in need of long-term outpatient care.

Depending upon their specific ACS manifestation, survivors are at variable

but elevated risk for a host of adverse cardiac events as consequences of the ACS
episode itself, and at increased risk for recurrent coronary episodes. Post-ACS
management therefore has 2 general goals: limitation of late complications (total
cardiovascular mortality, sudden cardiac death, arrhythmias, stroke, late heart
failure) and reduction in recurrent clinical coronary events. This latter group can be
further divided into reducing atherosclerotic burden or stabilizing existing plaques,
and lowering the probability of coronary thrombus formation (and subsequent
ischemia or infarction) should plaque rupture occur. Many interventions have been
identified by randomized trials to reduce risk, while others that have less robust
supporting evidence are generally considered advisable by experts in the field.
Recommendations in this article are based upon evidence-based guidelines and
expert opinion panels (see References), and trials that have modified these
recommendations after publication.

Key Questions

In deciding on the optimal post-ACS regimen for any individual patient,

several key pieces of data are needed.

• First, did the patient undergo coronary intervention including coronary

stenting, and if so, was this a drug-eluting or bare metal stent?

• Was there evidence, either by angiography or noninvasive coronary testing,

that the patient has residual ischemia?

• What are the patient’s new baseline left ventricular ejection fraction (LVEF),
blood pressure, and fasting lipid profile?

• Does the patient refrain from tobacco use, exercise regularly, and adhere to
an anti-atherogenic diet?

• Is the patient diabetic?

It may be necessary for the office practitioner to obtain updated information to

answer these questions. Particularly following large infarcts, plasma lipids may
demonstrate lower low-density lipoprotein (LDL) and higher triglyceride (TG)
levels during the index hospitalization, as a nonspecific response to systemic
inflammation. These values typically return to baseline about 6 weeks after an
ACS. High-density lipoproteins (HDL) are somewhat less sensitive to acute
nonspecific changes. Due to reversible myocardial dysfunction (stunning),
measured LVEF early after ACS may be lower than the patient’s new baseline, and
repeat assessment at 6 to 8 weeks is a more reliable indicator of residual systolic
function.1 Patients treated acutely without coronary angiography or intervention
may have had only low-level exercise testing before discharge; in these cases,
maximal stress testing, usually with noninvasive imaging (echo or myocardial
scintigraphy) and using pharmacologic stress in patients unable to exercise to
maximal heart rate for any reason, should be performed at about 6 weeks from
discharge.1

Medication Therapy

Several drug classes have been shown to reduce one or more post-ACS
adverse cardiac events, whether mortality, reinfarction, need for revascularization,
hospital readmission, stroke, cardiac arrest, or late heart failure. Note that listed
doses are study-derived targets; initial doses and titration schedules will depend
upon clinical variables (heart rate, blood pressure, heart failure severity).

Beta-blockers are a mainstay of postinfarction therapy, reducing mortality

(particularly sudden death), recurrent coronary events, angina, and blood pressure.
Selection of individual drugs within the class is based upon the presence or
absence of LV dysfunction. Early post-MI studies excluded patients with
significant heart failure and demonstrated that timolol (10 mg twice a day [BID]),
propranolol (80-120 mg three times a day [TID]), and metoprolol (100 mg BID)
reduced post-MI events. More recently, carvedilol (25 mg BID) was shown to have
a similar benefit in patients with heart failure and reduced LVEF early after an MI,
as was time-release metoprolol (200 mg daily) when started several months later in
such patients with moderate heart failure. At target doses, little difference in beta-2
effects is seen among these drugs. Although likely that other beta blockers afford
such protection, and a possibility exists for no measurable benefit in patients with
small troponin elevations, normal LV function, and complete revascularization, an
evidence-based approach suggests prescription of carvedilol for early post-MI
patients with LV dysfunction and either metoprolol, timolol, or propranolol for
those with normal LV function. Contraindications include moderate-severe
reactive airway disease, symptomatic bradycardia, heart block greater than first
degree (without implanted pacemaker present), and hypotension.

Angiotensin-converting enzyme inhibitors (ACEi) reduce mortality and late

heart failure when started orally early (first 24 hours after ACS presentation) in
nonhypotensive patients without other contraindications (severe renal impairment,
hyperkalemia, known adverse reaction to ACEi in past). The protective effects of
several ACEi (captopril 50 mg TID, enalapril 10 mg BID, ramipril 5 mg BID,
trandolapril 4 mg daily) in patients with significant systolic heart failure following
acute MI have been well documented, as have those of enalapril (10 mg BID) in
patients with a mildly depressed LVEF but no clinical heart failure. Additionally,
several studies of the ability of ACEi to reduce cardiac events in patients without
LV dysfunction included large subgroups (50%-65%) of patients who had suffered
previous ACS. In these cohorts, high-risk patients showed improved outcomes
with ramipril 10 mg daily, and low-to-moderate risk patients with perindopril 8 mg
daily. Benefits were reflected in composite endpoints of cardiovascular death,
resuscitated cardiac arrest, or stroke, depending upon the specific study and risk
population examined.
 Angiotensin receptor blockers (ARB) are recommended in ACEi-intolerant
patients with LVEF <40% and clinical evidence of heart failure. Valsartan 160 mg
BID and candesartan 32 mg have been studied with outcomes generally
comparable with ACEi. One trial suggested an additional benefit of adding an
ARB (candesartan) to an ACEi in this population, but this single study requires
further validation before combined therapy can be considered a standard of care. It
should be noted that, in limited studies thus far, patients with LVEF >40% showed
no demonstrable benefit from ARB therapy. Contraindications to ARBs are similar
to those of ACEi, although some frequent side effects (eg, cough) are decidedly
less frequent with ARBs.

Aldosterone receptor antagonists (ARA) have been studied in 2 distinct

populations: patients with distant MI and moderate to severe heart failure
(spironolactone 25 mg daily); and patients with recent ACS, LVEF <40%, and
clinical signs of heart failure (eplerenone 25-50 mg daily). In both trials, combined
endpoints (including all-cause mortality and re-hospitalization) were reduced.
Contraindications include baseline hyperkalemia (K >5 mEq/L) and significant
azotemia (creatinine >2.5 mg/dL). ARAs have been added to ACEi in both trials,
and to ACEi or ARB plus beta-blockers with eplerenone. Caution should be
exercised when prescribing ARAs to any patient at increased risk for
hyperkalemia.

Lipid-lowering therapy with HMG-Co-A reductase inhibitors (“statins”)

reduces virtually all cardiac events in the post-ACS patient as part of a
comprehensive secondary prevention program. Recommended lipid goals in this
population include LDL <70 mg/dL, HDL >40 mg/dL, and TG >150 mg/dL, with
the primary focus on LDL levels, based on 2 large studies of low-versus-high
intensity statin therapy. Earlier trials showed secondary prevention benefit from
less aggressive lipid lowering (pravastatin 40 mg, simvastatin 40 mg). While
intensive LDL lowering arms have typically included atorvastatin 80 mg once
daily, it remains unclear whether achieving similar LDL levels with other statins
(where possible) would afford the same benefit. While clinical trials have
demonstrated benefit from raising HDL with fibrates (gemfibrizol 600 mg BID) in
patients not receiving statin therapy, HDL-targeted therapy has not yet been
combined with high-dose statins to determine if benefits are additive and outweigh
risks from adverse drug interactions.1 Fenofibrate appears to cause less myositis
than gemfibrizol when combined with high-dose statins, but positive outcome
studies are lacking with this agent. Niacin (crystalline niacin 500-750 mg BID or
equivalent) is also effective at raising HDL and reducing TG levels, but careful
monitoring of hepatic transaminases should be performed when prescribed with
statins. Whether other LDL-lowering agents (ezetimibe, binding resins) have
similar outcome benefits to those of statins, or additional benefits when added to
statins, remains unclear. Fish oil (900 mg daily of combined omega-3
polyunsaturated fatty acids) appears to reduce combined atherosclerotic endpoints
in post-ACS patients when added to other standard therapies. This is very well
tolerated, and the benefit does not appear to track with a specific lipoprotein
change.

Antiplatelet therapy is a mainstay in reducing recurrent coronary events in

post-ACS patients. Aspirin, 81-162 mg once daily, should be prescribed for life in
all patients not strictly intolerant of the drug. Clopidogrel (75 mg daily) has clear
indications now for all ACS manifestations, including those receiving medical
management, thrombolytic therapy, or primary coronary stenting. The optimal
duration of clopidogrel therapy remains unclear and is in part driven by the initial
therapy received by the patient. At a minimum, non-ST elevation ACS survivors
treated medically should receive clopidogrel for 3 months (up to 1 year), patients
receiving bare metal stents for 4 weeks, and those with drug-eluting stents for 3-6
months (depending upon brand and eluted drug). The duration of clopidogrel
therapy remains a disputed topic at the time of this writing, and readers are
encouraged to seek information from regularly updated sources for further
guidance. Other antiplatelet medications (dipyridimole, oral glycoprotein IIb/IIIa
inhibitors) have no role in post-ACS management.

Although protracted outpatient therapy with low molecular weight heparins

are of no benefit to these patients, oral warfarin does afford some protection
against recurrent coronary events and is indicated primarily for patients with atrial
fibrillation, left ventricular aneurysms, and large anterior ST elevation MIs to
reduce the risk of stroke and peripheral embolization. Warfarin carries a higher
bleeding risk than either aspirin or clopidogrel and, when added to aspirin, does not
reduce coronary events more than aspirin alone.

Long-acting nitrates should be prescribed only as part of a combination

regimen in selected patients with heart failure (see below) or for patients with
symptomatic exertional angina. They are poor antihypertensives and, when used
alone, have failed to demonstrate reduction in any major clinical outcomes. When
prescribed, care should be taken to provide a 10- to 12-hour nitrate-free interval to
avoid tachyphylaxis. Transdermal nitroglycerin patches (12 hours daily) or oral
isosorbide mononitrate (dosed once each morning) are the simplest ways to avoid
nitrate tolerance.

Use of calcium channel blocking drugs (CCB) should in general be limited

to patients without heart failure or LV dysfunction who are intolerant of beta
blockers (verapamil), or have residual hypertension or angina despite other
therapies (amlodipine). Studies of CCBs have been variable, with many of those
showing benefit only in patients not receiving beta-blockers.

Although a combination of ACEi/ARB, beta-blockers, and ARA may be

sufficient to control hypertension, the blood pressure goal in post-ACS patients is
<130/85 mm Hg or <130/80 mm Hg in patients with diabetes or chronic kidney
disease. In the presence of residual symptomatic heart failure, loop diuretics are
typically indicated to control excess volume and help lower blood pressure.
Hydralazine 75 mg plus isosorbide dinitrate 40 mg, both three times a day, would
constitute third- or fourth-line therapy in African Americans with heart failure, or
whose blood pressure remains above goal despite ACEi/ARB and beta-blocker
therapy at target or maximum-tolerated doses. In the absence of other compelling
indications, the patient without heart failure should receive additional treatment
with a thiazide-type diuretic, then fourth- or fifth-line antihypertensive agents
(sympatholytics, calcium channel blockers) based upon expected side effects in the
individual patient already receiving evidence-based therapy. Therapeutic lifestyle
modifications (see below) are part of every antihypertensive regimen.

Therapeutic Lifestyle Changes

Regular aerobic exercise, including formal cardiac rehabilitation programs,

should be part of every patient’s long-term management. Besides reducing blood
pressure, helping to control obesity and its complications, and raising HDL levels,
a minimum of 120 minutes of moderate aerobic activity weekly in 3-4 sessions
(ideally, 20-30 min daily) improves the patient’s sense of well-being and hastens
return to normal activities. Abstinence from tobacco is essential, and every effort
and tool available should be employed to help patients stop smoking. Diets low in
sodium, saturated fat, and cholesterol (replaced by mono- and poly-unsaturated
fats), high in dietary fiber and complex carbohydrates, and devoid of excess
calories remain most commonly recommended in patients with atherosclerosis.
More specific diets (eg, Mediterranean) have shown mixed results when actual
food was not provided free to patients. “Trendy” diets, particularly those high in fat
and low in carbohydrates, have shown no long-term benefit in either
cardiovascular disease or weight reduction. Limited alcohol intake (1-2 servings
daily) raises HDL levels; however, excessive intake can elevate blood pressure and
produce other complications and should be discouraged.

Although a detailed review of diabetes management is beyond the scope of

this discussion, comprehensive risk factor modification includes aggressive
glycemic control, with goal hemoglobin A1C levels below 7.0 mg/dL using
combined drug, diet, and exercise therapy. Treatment of the metabolic syndrome
(central obesity, glucose intolerance/diabetes, high normal or elevated blood
pressure, elevated TG, low HDL) centers around weight, blood pressure, and lipid
management.

Cardiology Referral for Additional Interventions

Two groups of post-ACS patients routinely require subspecialty referral:

those with demonstrable residual ischemia and those with moderate-severe heart
failure (LVEF <35% and functional class III or IV symptoms) more than 1 month
following their coronary event.

Depending upon specific combinations of coronary lesions and left

ventricular function, revascularization (whether by percutaneous intervention or
bypass graft surgery) will improve long-term survival in many patients after ACS.
Because the decision as to the degree of revascularization possible and the
risk:benefit ratio of the available approaches depends on technical issues beyond
the scope of the primary care internist, consultative opinion from a general
cardiologist, interventional cardiologist, or cardiac surgeon is necessary in any
patient demonstrating post-event myocardial ischemia.

Patients more than 1 month out from their MI who have an LVEF <30%-
35% will enjoy a significant mortality reduction with placement of an internal
cardiac defibrillator (ICD). Similarly, patients with clinical heart failure (functional
class III or IV) and a wide (>120 ms) QRS can expect both symptomatic and
survival benefit following implantation of a biventricular pacemaker (cardiac
resynchronization therapy, or CRT). Some patients will need devices with both
capabilities. Therefore, patients who meet the clinical and noninvasive criteria for
consideration for ICD or CRT should be referred to a cardiac electrophysiologist
for further evaluation and therapy.

Conclusion

Major adverse cardiac events can be significantly reduced in patients

following an acute coronary syndrome. Beta-blockers, angiotensin antagonists,
statins and other lipid-lowering treatments, and antiplatelet therapy combine with
therapeutic lifestyle changes and atherosclerosis risk factor modification to help
patients live longer, with fewer symptoms and better quality of life. Aldosterone
inhibitors, hydralazine/nitrates, warfarin, and perhaps calcium channel blockers
add benefit in select subpopulations, as can revascularization and ICD/CRT. The
primary care provider should strive to reach recommended goals for blood
pressure, lipid levels, behavior, and medication doses to maximize benefit in
patients following ACS.