Therapy for Patients with HF and CAD

Aspirin. In patients with stable CAD, unstable angina or acute MI, treatment with aspirin 81-325 mg daily provides a 25% to 30% reduction in all-cause mortality, MI, and stroke.95 In a retrospective review of the Studies of Left Ventricular Dysfunction (SOLVD) trial, antiplatelet use (mostly aspirin) was associated with 28% reduction in all-cause mortality and HF death or hospitalizations.96 Despite conflicting data about aspirin reducing the benefits of ACE inhibitors,96,97 all patients with CAD and HF should receive 75-325 mg aspirin daily in absence of contraindications. Recent studies suggest that higher doses may be associated with increases in drug interactions and bleeding, so 75 to 81 mg is recommended. (See Section 7, Recommendations 7.33-7.38.)

In the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial, patients with symptomatic heart failure, LV dysfunction, and no atrial fibrillation, were randomized to aspirin 162 mg/day, clopidogrel 75 mg/day, or open-label warfarin to achieve an international normalized ratio (INR) of 2.5 to 3.98 The primary endpoint of the study was the composite of all-cause mortality, non-fatal MI, and non-fatal stroke. The majority of patients had an ischemic etiology of heart failure, although the study population was not limited to patients with CAD. There were no statistically significant differences in the primary endpoint for warfarin versus aspirin, for clopidogrel versus aspirin, or for warfarin versus clopidogrel.98

Clopidogrel. In patients admitted for unstable angina/non ST-elevation MI (STEMI), treatment with clopidogrel in addition to aspirin was associated with an 18% reduction in the incidence of HF.99 All patients admitted with ACS and non-ST elevation treated medically without stenting should be given clopidogrel 300 mg, followed by 75 mg daily for at least 1 month and ideally for up to 1 year in addition to aspirin.100 Patients with STEMI should be treated with clopidogrel or prasugrel, according to the 2009 STEMI/percutaneous coronary intervention (PCI) Focused Update Recommendations.101

Warfarin. Although warfarin is an acceptable alternative to antiplatelet agents when necessary for CAD, its effectiveness may be due to the large number of HF patients with atrial fibrillation. It was not superior to aspirin in the WATCH trial.100 See Section 7 for more information.

In a study of patients with stable CAD and few other risk factors, treatment with the ACE inhibitor perindopril was associated with a 20% reduction in cardiovascular mortality, new MI, or sudden death.102 HF hospitalizations were reduced by 39%. In a population at high risk for CAD, but without overt HF, treatment with ramipril was associated with a 22% reduction in cardiovascular mortality, new MI, or stroke.103 The incidence of HF was reduced by 23% and HF hospitalizations by 12%. ACE inhibitors should be routine therapy in patients at high-risk for CAD and in patients with established CAD.

Four major trials proved the favorable effects of prophylactic ACE inhibition in reducing HF, HF hospitalizations and mortality after an acute MI.104-107 In patients with a recent MI, with or without symptoms of HF, ACE inhibitors should be started early (within 24 hours) and continued indefinitely.108

The first trial to show a survival benefit for ACE inhibitors in patients with chronic HF, of whom the majority had underlying CAD, was the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial. This trial was conducted in New York Heart Association (NYHA) class IV patients who were randomized to receive enalapril or placebo.20 At the end of the study (20 months), patients treated with enalapril had a significant 27% reduction in total mortality, the primary end point. It appeared that enalapril had no effect on sudden death, but decreased mortality from progressive HF by 50%. After CONSENSUS, the SOLVD Treatment trial examined the effect of enalapril in patients with mild to moderate HF.109 Enalapril decreased all-cause mortality by 16%, mortality caused by progressive HF by 22%, and the combined point of death or hospitalizations for worsening HF by 26% compared with placebo. In the SOLVD Prevention trial of patients with asymptomatic LV dysfunction, enalapril reduced the total number of deaths and cases of HF by 29%.22 Taken together, these studies provide for the recommendation that ACE inhibitors should be administered to all patients with asymptomatic LV systolic dysfunction or with signs and symptoms of HF.

In patients with stable CAD, treatment with beta blockers is associated with a reduction in the number and duration of ischemic episodes, mortality or hospitalization.110 Retrospective analyses of two large beta blocker trials demonstrated reduced mortality with beta blockers, especially in high-risk subsets.111,112 In the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial of 1959 patients with a proven acute MI and LVEF <=40%, with or without symptoms of HF, carvedilol reduced the number of deaths by 23%, a benefit attained on top of treatment with ACE inhibitors, antiplatelet agents, and statins.58 There was no difference between carvedilol and placebo in the number of patients meeting the primary endpoint of all-cause mortality or hospital admissions. In all patients with a history of MI, regardless of LVEF, beta blockers should be used acutely and continued indefinitely. In studies of patients with chronic HF, more than 65% of whom had underlying CAD, use of bisoprolol, carvedilol, or metoprolol succinate was associated with a uniform 34% reduction in all-cause mortality and 20% to 25% reduction in hospitalizations.16,113,114 In the Australia-New Zealand study of patients with ischemic cardiomyopathy and LVEF <45%, carvedilol reduced the risk of all-cause mortality or any hospitalization by 26%.115 Based on the results from available studies, beta blockers should be routinely prescribed to all patients with asymptomatic LV dysfunction and stable HF caused by LV systolic dysfunction.

In patients with stable CAD, nitrates improve exercise tolerance and time to onset of angina.116 An overview of small studies of nitrates in acute MI from the pre-thrombolytic era suggested a 35% reduction in mortality rates,117 although 2 trials formally tested this hypothesis in patients with suspected acute MI and failed to confirm this magnitude of benefit.118,119 There was no difference in survival in the 14% of patients with HF at baseline in the Fourth International Study of Infarct Survival (ISIS-4) trial, nor was there a difference in the new cases of HF in Gruppo Italiano per lo Studio della Sopravvivenza nell-infarto Miocardio (GISSI-3) study. Nitrates did not decrease the rate of re-infarction, but they decreased the rate of post-infarct angina in GISSI-3, in which nitrates in combination with lisinopril also decreased all-cause mortality by 17%. The difference was mainly attributable to the lower numbers of deaths and cases with LVEF <=35%. Nitrates are well tolerated in acute MI and appear safe to use early in acute MI for symptomatic relief of angina or for reduced LVEF. Patients with CAD, HF, and anginal symptoms should be considered for therapy with nitrates in addition to beta blockers.

Although all calcium antagonists have anti-ischemic properties, a meta-analysis of 16 trials that used immediate-release and short-acting nifedipine in patients with MI and unstable angina reported a dose-related excess mortality.120 First-generation calcium antagonists, such as diltiazem and nifedipine, were found to exacerbate HF or increase mortality in patients after MI with pulmonary congestion or an LVEF <40%.121 An alternative consideration regarding the worsening of heart failure in early calcium channel blocker trials is reflex neurohormonal activation. It is possible that the earlier-generation calcium channel blockers would not have proved deleterious if they had been investigated on a background of ACE inhibitors and beta blockers. Amlodipine does not have clinically significant negative inotropic effects, and it has not been associated with the deleterious effects seen with earlier drugs in this class. Although one trial of amlodipine in patients with advanced HF produced a 9% reduction in the combined risk of fatal and nonfatal events and decreased the risk of all-cause mortality by 16%, these reductions were not statistically significant overall or for patients with ischemic heart disease.15 Amlodipine had no effect on the frequency of worsening HF associated with hospitalizations or the rate of MI, but the amlodipine group had a higher incidence of pulmonary and leg edema, as well as renal failure.15 Based on available data, first-generation calcium channel blockers should not be used in patients with CAD, HF and LVEF <40%. Amlodipine or felodipine could be used in these patients to manage angina or hypertension if beta blockers or nitrates are not tolerated.122,123

Despite advances in medical therapy, patients with severe CAD and symptomatic reduced LVEF have poor outcomes when treated medically.14,16,17,20,30-36,58,59,102-109,113,114,124,125 Although revascularization for patients with CAD and HF seems the logical approach because restoration of blood flow may improve LV function and possibly survival,73,74 there are no randomized controlled trials comparing revascularization with medical therapy to improve outcomes in patients with HF, demonstrated myocardial viability, and an LVEF <35%. Revascularization of viable myocardial segments could provide benefit by improving contractility or by preventing additional myocardial remodeling.126,127 Myocardial viability has been assessed by PET, single-photon emission computed tomography (SPECT), dobutamine echocardiography, and MRI. Registry and cohort studies provide some data for this group of patients. These data suggest that exercise capacity and HF symptoms improve after revascularization and the improvement is related to the amount of abnormal but viable myocardium.126,128,129 Improvement in LVEF also is directly related to the amount of viable myocardium.128,130 Finally, in non-randomized, observational studies, revascularization has been associated with improved survival compared to medical therapy in patients with myocardial viability and an LVEF <35%.69,128

The results of medical therapy for both HF and CAD have improved markedly. It is impossible to estimate whether revascularization in well-treated HF patients will improve survival or clinical course. As a result, prospective randomized trials of revascularization in addition to optimal medical therapy compared to optimal medical therapy alone in patients with CAD, depressed LV systolic function, and symptoms of HF are necessary. At present, two such studies are underway.50,51 In the interim, when PCI or surgical intervention is considered, the decision should be made in the context of the patient's functional status, prognosis, and surgical risk. See Section 10, recommendation 10.1 for further information.