- Email: [email protected]
Outpatient Management of Survivors of Acute Coronary Syndromes
The American Journal of Medicine (2007) 120, 12-15
UPDATE IN OFFICE MANAGEMENT
AJM Theme Issue: Cardiology
Outpatient Management of Survivors of Acute Coronary Syndromes Stephen A. Geraci, MD,a,b Nancy D. Stubbs, NPb a
Department of Medicine, University of Mississippi School of Medicine, Jackson; bMedical Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Miss. ABSTRACT More patients are both suffering and surviving acute coronary syndromes. After hospital discharge, a host of interventions, including medications, therapeutic lifestyle changes, revascularization, and electrophysiologic devices improve quality of life and survival. Evidence-based management requires the general internist to have a working knowledge of these interventions and to identify patients whose outcomes would benefit from subspecialty referral. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Myocardial infarction; Ischemic heart disease; Therapy; Prevention; Review
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. PostACS 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.
Requests for reprints should be addressed to Stephen A. Geraci, MD, Medical Service (111), G.V. (Sonny) Montgomery VAMC, 1500 E. Woodrow Wilson Drive, Jackson, MS 39216. E-mail address: [email protected].
●
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.05.029
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 drugeluting 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?
Geraci and Stubbs
Post-ACS Outpatient Management
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. Highdensity 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.1,2 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.3 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.3 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.3 Contraindications include moderatesevere 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
13 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.1 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.1 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.1 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.1 Valsartan 160 mg BID and candesartan 32 mg have been studied with outcomes generally comparable with ACEi.1 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.1 It should be noted that, in limited studies thus far, patients with LVEF ⬎40% showed no demonstrable benefit from ARB therapy.1 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).4 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.5 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
14 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.6 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.7 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.8 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.1,2 Clopidogrel (75 mg daily) has clear indications now for all ACS manifestations, including those receiving medical management, thrombolytic therapy, or primary coronary stenting.1,2 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).2 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.1 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.1 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.2,4 They are poor antihypertensives and, when used alone, have failed to demonstrate reduction in any major
The American Journal of Medicine, Vol 120, No 1, January 2007 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).1 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.1,2 In the presence of residual symptomatic heart failure, loop diuretics are typically indicated to control excess volume and help lower blood pressure.4 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.4 In the absence of other compelling indications, the patient without heart failure should receive additional treatment with a thiazidetype 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.9 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.1 Abstinence from tobacco is essential, and every effort and tool available should be employed to help patients stop smoking.1,2 Diets low in sodium, saturated fat, and cholesterol (replaced by monoand poly-unsaturated fats), high in dietary fiber and complex carbohydrates, and devoid of excess calories remain most commonly recommended in patients with atherosclerosis.1 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.
Geraci and Stubbs
Post-ACS Outpatient Management
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.1,2 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).4 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).4 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-
15 blockers, angiotensin antagonists, statins and other lipidlowering 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.
References 1. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction), 2004. Available at: www.acc.org/clinical/guidelines/stemi/ index.pdf. 2. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina), 2002. Available at: http://www.acc.org/clinical/ guidelines/unstable/unstable.pdf. 3. Stubbs ND, Geraci SA. Outpatient management of patients after acute coronary syndromes: treatment goals and clinical parameters to reduce mortality and recurrent events. Am J Nurse Pract. 2006;10:11-22. 4. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005;46:1-82. 5. Grundy SM, Cleeman JI, Merz NB, 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;110:227-239. 6. Jacobson TA, Zimmerman FH. Fibrates in combination with statins in the management of dyslipidemia. J Clin Hypertens. 2006;8:35-41. 7. Executive Summary of the 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). JAMA. 2001;285:2486-2497. 8. Kris-Etherton PM, Harris WS, Appel LJ for the Nutrition Committee. AHA scientific statement: fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757. 9. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;289:2560-2572.
UPDATE IN OFFICE MANAGEMENT
AJM Theme Issue: Cardiology
Outpatient Management of Survivors of Acute Coronary Syndromes Stephen A. Geraci, MD,a,b Nancy D. Stubbs, NPb a
Department of Medicine, University of Mississippi School of Medicine, Jackson; bMedical Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Miss. ABSTRACT More patients are both suffering and surviving acute coronary syndromes. After hospital discharge, a host of interventions, including medications, therapeutic lifestyle changes, revascularization, and electrophysiologic devices improve quality of life and survival. Evidence-based management requires the general internist to have a working knowledge of these interventions and to identify patients whose outcomes would benefit from subspecialty referral. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Myocardial infarction; Ischemic heart disease; Therapy; Prevention; Review
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. PostACS 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.
Requests for reprints should be addressed to Stephen A. Geraci, MD, Medical Service (111), G.V. (Sonny) Montgomery VAMC, 1500 E. Woodrow Wilson Drive, Jackson, MS 39216. E-mail address: [email protected].
●
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.05.029
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 drugeluting 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?
Geraci and Stubbs
Post-ACS Outpatient Management
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. Highdensity 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.1,2 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.3 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.3 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.3 Contraindications include moderatesevere 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
13 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.1 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.1 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.1 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.1 Valsartan 160 mg BID and candesartan 32 mg have been studied with outcomes generally comparable with ACEi.1 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.1 It should be noted that, in limited studies thus far, patients with LVEF ⬎40% showed no demonstrable benefit from ARB therapy.1 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).4 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.5 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
14 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.6 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.7 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.8 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.1,2 Clopidogrel (75 mg daily) has clear indications now for all ACS manifestations, including those receiving medical management, thrombolytic therapy, or primary coronary stenting.1,2 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).2 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.1 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.1 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.2,4 They are poor antihypertensives and, when used alone, have failed to demonstrate reduction in any major
The American Journal of Medicine, Vol 120, No 1, January 2007 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).1 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.1,2 In the presence of residual symptomatic heart failure, loop diuretics are typically indicated to control excess volume and help lower blood pressure.4 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.4 In the absence of other compelling indications, the patient without heart failure should receive additional treatment with a thiazidetype 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.9 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.1 Abstinence from tobacco is essential, and every effort and tool available should be employed to help patients stop smoking.1,2 Diets low in sodium, saturated fat, and cholesterol (replaced by monoand poly-unsaturated fats), high in dietary fiber and complex carbohydrates, and devoid of excess calories remain most commonly recommended in patients with atherosclerosis.1 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.
Geraci and Stubbs
Post-ACS Outpatient Management
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.1,2 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).4 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).4 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-
15 blockers, angiotensin antagonists, statins and other lipidlowering 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.
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