Update in Cardiology

Congestive Heart Failure

Five notable advances occurred in this area in the past year. The first is the finding of the efficacy of exercise therapy, and the other four concern drug treatment with digoxin, amlodipine, carvedilol, and amiodarone.

Exercise Was Effective Treatment for Congestive Heart Failure

Keteyian SJ, Levine AB, Brawner CA, Kataoka T, Rogers FJ, Schairer JR, et al. Exercise training in patients with heart failure. A randomized, controlled trial. Ann Intern Med. 1996; 124:1051-7.

Left ventricular volume and stroke volume increase in anyone who exercises. Muscle arterioles also dilate during exercise, and oxygen is delivered and extracted more efficiently. Once fitness improves, heart rate, blood pressure, sympathetic tone, and exercise-induced platelet activation also improve. For these reasons, most cardiologists recommend exercise for patients with congestive heart failure. Only about one third of eligible patients are actually enrolled in cardiac rehabilitation programs, however, and only about one third of primary care physicians mention exercise to patients with congestive heart failure. Keteyian and colleagues assessed the benefit of exercise training in patients with heart failure caused by left ventricular systolic dysfunction.

In a clinical trial, 40 men with compensated congestive heart failure were randomly assigned to formal exercise training or usual care. All had resting ejection fractions of 35% or less, were clinically classified as belonging to New York Heart Association class II or class III, and had had no change in medications in the 30 days before study entry. Persons in the experimental group participated in a program consisting of three exercise sessions per week for 24 weeks. Each training session lasted 43 minutes and was considered to be moderate to vigorous in intensity. The dropout rate was about 25% in both groups.

At the end of the study, men in the exercise group had a mean increase (±SD) in exercise duration of 2.8 ± 0.6 minutes (about a 25% increase) compared with 0.5 ± 0.5 minutes in the control group. Peak heart rate increased by 10 ± 4 beats/min in the exercise group and decreased by 2 ± 4 beats/min in the control group. Oxygen consumption, peak ventilation, and peak power all increased (P < 0.05) in the exercise group. Among the exercisers, heart rate during submaximal exercise decreased over time. Perhaps the most interesting finding was that 85% of the improvement in peak oxygen consumption occurred during the first half of the experiment.

In the past few years, at least five other randomized trials and many other reports have focused on exercise in patients with congestive heart failure [1]. There seem to be no heart-related contraindications to exercise training in patients with stable heart failure caused by left ventricular systolic dysfunction. Almost all major heart failure centers now include exercise as standard therapy. For physicians outside these centers, a simple and effective plan is to enroll patients with congestive heart failure into cardiac rehabilitation programs, as would be done with patients who had had myocardial infarction.

Digoxin Decreased Hospitalizations

The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. 1997; 336:525-33.

During the 1970s, the use of digoxin fell out of favor for various reasons. First, and most important, little evidence showed that this 200-year-old drug was beneficial for patients who had congestive heart failure but were in sinus rhythm. Second, digoxin recipients often developed symptoms of toxicity. Third, the 1970s saw the introduction of new vasodilator drugs, which were shown to be effective in the treatment of congestive heart failure.

Finally, the Digitalis Investigation Group sought to test the efficacy of digoxin in patients with congestive heart failure who were in sinus rhythm. The investigators enrolled 6800 persons who had ejection fractions less than 45% and were in normal sinus rhythm. All received usual treatment with angiotensin-converting enzyme inhibitors plus diuretics; they were then randomly assigned to receive placebo or digoxin (median dosage, 0.25 mg/d). Main outcome measures were mortality and hospitalization, and mean follow-up was 37 months.

Mortality rates were unaffected by use of digoxin; 34.8% of digoxin recipients and 35.1% of placebo recipients died. In the digoxin group, a trend toward fewer deaths from heart failure was seen and the rate of hospitalizations was reduced by 6% (number needed to treat [NNT] to prevent one hospitalization, 36 over 37 months of treatment). Toxicity was more common in the digoxin group (11.9% compared with 7.9% in the placebo group) (number needed to harm [NNH], 33 over 37 months of treatment).

Digoxin did not seem to extend life in these patients. It did, however, seem to decrease the rate of hospitalization, which is an important outcome in an era of cost containment. Moreover, previous clinical trials have shown that digoxin increases exercise tolerance and quality of life [2, 3]. If used carefully so that adverse effects are minimized, digoxin appears to be an important drug in patients who have congestive heart failure and are in sinus rhythm.

Amlodipine Was Safe in Patients with Congestive Heart Failure

Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med. 1996; 335:1107-14.

Because treatment with calcium-channel blockers has been shown to worsen heart failure in patients with advanced left ventricular dysfunction, physicians have come to avoid these drugs in patients with congestive heart failure. However, amlodipine, a second-generation calcium-channel blocker commonly used to treat angina, has not shown these adverse affects in patients with congestive heart failure. Packer and colleagues therefore directly assessed the long-term effect of amlodipine on morbidity and mortality among patients with advanced congestive heart failure.

The authors recruited 1153 patients with ejection fractions less than 30% into a clinical trial. Patients were randomly assigned to receive either amlodipine (5 to 10 mg/d) or placebo for 6 to 33 months. Randomization was stratified according to the cause of left ventricular dysfunction: either coronary artery disease or nonischemic dilated cardiomyopathy. Therapy with usual medications was continued; these medications did not differ between groups.

Mortality rates were 33% in the amlodipine group and 38% in the placebo group. Among patients with ischemic heart disease, mortality did not differ between groups. However, among patients with nonischemic cardiomyopathy, amlodipine therapy reduced the risk for death by 46% (P < 0.001; NNT, 11). Peripheral edema and pulmonary edema occurred slightly more often in amlodipine recipients.

If necessary, amlodipine can apparently be used with relative safety to treat angina or hypertension in patients with severe congestive heart failure. A second trial, known as PRAISE-2 (Prospective Randomized Amlodipine Survival Evaluation 2), is now in progress to further evaluate the possible beneficial role of amlodipine in prolonging survival among patients with nonischemic cardiomyopathy.

A β-Blocker Improved Outcomes of Congestive Heart Failure

Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996; 334:1349-55.

β-blockers are another class of drugs that are effective against angina. Like most calcium-channel blockers, they have been difficult to use in patients with congestive heart failure because of their negative effect on contractility. In selected patients with congestive heart failure, however, β-blockers have been used successfully, presumably because they block excessive activity of the sympathetic nervous system. Carvedilol is a nonselective β-receptor antagonist that also blocks α-1 receptors. Unlike other β-blockers, carvedilol also exerts antioxidant effects.

Packer and colleagues set up a clinical trial to assess the safety and efficacy of carvedilol in increasing survival and limiting hospitalization in patients with congestive heart failure. A total of 1094 patients with ejection fractions of 35% or less were assigned to one of four treatment protocols on the basis of exercise capacity. The patients were further stratified by severity of heart failure and were then randomly assigned to receive carvedilol (titrated up to a target dosage of 25 to 50 mg twice daily) or placebo. Background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant.

The study was stopped early because carvedilol was found to significantly affect survival; this effect exceeded all conventional criteria used to stop clinical trials. Table 1 shows the results of the study: Carvedilol treatment was associated with a large decrease in the risk for death from progressive heart failure and in the risk for sudden death. The most common adverse effect was dizziness, which occurred in 33% of the treated patients and 20% of those receiving placebo (NNH, 8).

The beneficial effect of carvedilol on survival was consistent in all evaluated subgroups. However, Packer and colleagues point out that their findings should be interpreted with caution. For example, during the 6 months of the study, only 53 patients in this very ill group died. Moreover, because carvedilol has unique effects, the study findings cannot be generalized to all β-blockers. Studies of the use of several other β-blockers for congestive heart failure are now under way.

Amiodarone Did Not Prolong Life

Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med. 1995; 333:77-82.

Patients with congestive heart failure and ventricular arrhythmia, particularly brief runs of ventricular tachycardia, have poor survival. Until the late 1980s, it was assumed that drug therapy that suppressed ventricular arrhythmias would prolong life. Unfortunately, the opposite has proven to be the case so far [4]. Amiodarone was first used in the 1960s in France for patients with angina and was eventually shown to have unique antiarrhythmic properties. It entered the United States in 1985 as an orphan drug because its patent had run out. Amiodarone is undoubtedly the most effective drug for converting atrial fibrillation to sinus rhythm, but it can be difficult to use for two reasons: Its half-life is long (approximately 30 days), and it has numerous serious adverse effects. However, it is extremely effective in suppressing ventricular arrhythmias.

In a clinical trial, Singh and colleagues evaluated the effect of amiodarone on the survival of patients with congestive heart failure and asymptomatic but frequent and complex ventricular arrhythmias. They enrolled 674 patients with congestive heart failure (ejection fraction ≤ 40%), cardiac enlargement, and at least 10 premature ventricular contractions per hour. The patients were randomly assigned to receive amiodarone or placebo and were followed for a median of 45 months.

Although amiodarone significantly suppressed ventricular arrhythmias while increasing left ventricular ejection fraction by 42%, 2-year survival rates were 69.4% for amiodarone recipients and 70.8% for placebo recipients. Amiodarone did not reduce the rate of sudden death or improve overall mortality, although mortality tended to be lower in patients with nonischemic cardiomyopathy. This trial therefore underscores the fact that suppression of ventricular arrhythmias does not increase survival.

The manufacturer of amiodarone will soon launch a marketing campaign aimed at primary care physicians. As mentioned above, the drug is excellent in maintaining sinus rhythm in patients who cannot tolerate atrial fibrillation, but its side effects require careful monitoring. Patients should be seen every 3 to 6 months for evaluation for signs of dyspnea or thyroid disease. A thyroid-stimulating hormone test and chest radiography should be done annually. Patients receiving warfarin need close short-term monitoring because amiodarone markedly increases prothrombin time in such patients. The drug also increases levels of digoxin and procainamide.

Acute Ischemic Heart Disease

In 1996, another possible trigger of acute myocardial infarction-sexual activity-was found not to be a major risk factor, and an antioxidant vitamin decreased the frequency of nonfatal infarctions but not death.

Sexual Activity Seemed Safe

Muller JE, Mittleman MA, Maclure M, Sherwood JB, Tofler GH. Triggering myocardial infarction by sexual activity. Low absolute risk and prevention by regular physical exertion. Determinants of Myocardial Infarction Onset Study Investigators. JAMA. 1996; 275:1405-9.

Evidence suggests that some factors can trigger the onset of acute myocardial infarction. Heavy physical exertion by otherwise sedentary persons is one trigger, but physical conditioning seems to minimize exertion as a risk factor [5]. Anger is another trigger, and aspirin has been shown to blunt that risk [6]. Many physicians and patients have wondered whether sexual activity is a trigger for acute myocardial infarction. (It has been estimated that sexual intercourse requires about the same amount of work as climbing two flights of stairs.) Muller and colleagues therefore sought to determine the relative risks for nonfatal myocardial infarction triggered by sexual activity in the general population and in patients known to have previously had coronary heart disease.

A total of 1774 patients in 45 hospitals were interviewed a median of 4 days after having a myocardial infarction. Data were gathered on potential triggers that occurred just before myocardial infarction and during the previous year. Special attention was given to patients who were known to have had coronary heart disease before the index myocardial infarction. The main outcome measure was the relative risk for nonfatal myocardial infarction after sexual activity.

Of the 858 sexually active patients, 9% reported engaging in sexual activity in the 24 hours before myocardial infarction and 3% reported activity within 2 hours of symptom onset. The odds ratio, expressed as relative risk, for triggering the onset of myocardial infarction in patients with a history of angina (2.1 [95% CI, 0.8 to 5.8]) or myocardial infarction (2.9 [CI, 1.3 to 6.5]) was not greater than that seen in patients without previous cardiac disease. Sexual activity was a likely contributor to the onset of myocardial infarction in only 0.9% of cases, and regular physical exertion was found to be inversely associated with risk.

Although sexual activity can trigger the onset of myocardial infarction, the relative risk is low and the absolute risk increase caused by sexual activity is extremely small (1 chance in a million for healthy persons). The relative risk is not increased in patients with a history of cardiac disease. The finding that regular exercise can reduce whatever small risk exists provides further evidence of the benefit of exercise to cardiovascular health.

Vitamin E Had Mixed Effects

Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ, et al. Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996; 347:781-6.

Acute coronary artery syndromes seem to be precipitated by the rupture of lipid-rich plaques that line the coronary artery walls. Several factors lead to rupture, which then exposes the circulating blood to underlying thrombogenic elements. By this process, the thrombus that occludes the vessel is created. One hypothesis is that macrophage-mediated oxidation of low-density lipoprotein (LDL) has a central role in atherogenesis, and some have postulated that antioxidant agents might blunt the cascade that leads to thrombus formation.

Stephens and colleagues tested the hypothesis that treatment with vitamin E (α-tocopherol) reduces subsequent risk for myocardial infarction and cardiovascular death in patients known to have coronary artery disease. A total of 2002 patients with abnormal angiograms were entered into a clinical trial in which they were randomly assigned to receive vitamin E (400 to 800 IU/d) or placebo. They were followed for a mean of 17 months.

Vitamin E therapy was associated with a significant reduction in the risk for the combined end point of cardiovascular death and nonfatal myocardial infarction (relative risk reduction, 47%; NNT, 38) and the single end point of nonfatal myocardial infarction (relative risk reduction, 76%; NNT, 36). However, no difference was seen in overall mortality between groups.

Vitamin E therapy given for approximately 1 year thus seems to be associated with a major reduction in the occurrence of nonfatal myocardial infarction in patients known to have coronary artery disease. Another study of antioxidants (specifically, β-carotene) [7] was highlighted in the 1997 Update in General Internal Medicine [8]; this study also showed no differences in mortality.

Several other trials using vitamin E or vitamin C are under way. Retrospective, observational studies have suggested that vitamin E may be beneficial. The conclusion is still unclear. For now, however, many cardiologists recommend vitamin E for their patients with ischemic heart disease in an attempt to prevent further events.

Primary Angioplasty Was Usually Not Superior to Thrombolysis

Every NR, Parsons LS, Hlatky M, Martin JS, Weaver WD. A comparison of thrombolytic therapy with primary coronary angioplasty for acute myocardial infarction. Myocardial Infarction Triage and Intervention Investigators. N Engl J Med. 1996; 335:1253-60.

When a coronary artery is occluded, the ischemic area starts in the subendocardium and then, over 3 to 4 hours, extends to the epicardium. By 12 hours, much of the infarction is complete. The timing of these events explains why so much emphasis has been placed on attempts to open the coronary artery as quickly as possible. The obvious question is how best to do this: with thrombolytic drugs or coronary angioplasty? A few small clinical trials have suggested that angioplasty provides better short-term outcomes, but these trials have been limited to major academic centers.

Every and colleagues compared short-term and long-term mortality in patients in community hospitals who underwent angioplasty with mortality in patients given thrombolytic drugs. Patients were selected from the Myocardial Infarction Triage and Intervention Project registry from a cohort of 12 331 consecutive patients admitted with myocardial infarction to 19 Seattle hospitals between 1988 and 1994. A total of 1050 patients had primary angioplasty, and 2095 received thrombolytic therapy. Because of the potential for selection bias, the analysis included subgroups that consisted of patients who were eligible only for thrombolysis, high-risk patients, and patients treated with primary angioplasty at hospitals with a high volume of cardiac care.

No difference in short-term or long-term (3-year) mortality was seen between the two groups (5.6% for the angioplasty group compared with 5.5% for the thrombolysis group). Rates of procedures and costs were lower in patients treated with thrombolytic therapy both at the time of hospital discharge and 3 years later: These patients had 30% fewer coronary angiographies, 15% fewer angioplasties, and 13% lower total cost.

A previous study [9] showed that patients with myocardial infarction of the anterior wall have better outcomes with angioplasty. On the basis of the available information, our current recommendation is that angioplasty should be the preferred approach if a patient with evidence of anterior-wall infarction is admitted to a high-volume cardiac center where angioplasty is immediately available. Otherwise (that is, in most cases), thrombolytic therapy would probably be the treatment of choice. The evidence on “rescue angioplasty,” used if thrombolysis fails, is contradictory. If pain continues after thrombolysis, a sensible approach is to use angiography and to consider angioplasty or emergency coronary artery bypass grafting.

Chronic Coronary Heart Disease

For most patients with multivessel coronary artery disease, primary angioplasty compares favorably with coronary artery bypass grafting (CABG) in community hospitals. Additional data reported in 1996 support previous studies that showed that decreasing cholesterol levels with statin drugs is effective secondary prevention.

Angioplasty Equaled Coronary Artery Bypass Grafting, Except in Diabetic Patients

Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization (BARI) Investigators. N Engl J Med. 1996; 335:217-25.

When angioplasty was introduced in 1977, it was used mainly for single-vessel coronary artery disease. With the improvement of technology and technique, indications for use of the procedure have broadened, and it is now commonly used in multivessel coronary artery disease. Because of the growth of both CABG and angioplasty, the National Heart, Lung, and Blood Institute set up a clinical trial to test the hypothesis that an initial revascularization strategy of angioplasty would compare favorably with CABG over 5 years in patients with multivessel disease and severe angina or ischemia.

A total of 1828 patients with multivessel disease were randomly assigned to undergo either CABG or angioplasty. The patients were then followed for a mean of 5.4 years. Results are shown in Table 2. The one subgroup that did better with CABG was diabetic patients; these patients had not been identified as a subgroup when the study was designed. The 5-year survival rate for diabetic patients was 80.6% with CABG and 65.5% with angioplasty (P = 0.003; NNT, 7).

Although mortality did not differ between the angioplasty and CABG groups, subsequent revascularization was often required for patients who underwent angioplasty. For nondiabetic patients, angioplasty is a reasonable alternative to CABG. Angioplasty was initially cheaper, but the costs of the two procedures did not substantially differ over 5 years because the angioplasty group required more repeated procedures.

Revascularization procedures are changing rapidly as stents and other nonsurgical technologies are being introduced. In addition, minimally invasive CABG is now available. New studies will make our current knowledge obsolete in just a few years.

Pravastatin Was Effective Even If Cholesterol Levels were “Average”

Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med. 1996; 335:1001-9.

New additional evidence supports the use of strategies for preventing further progression of disease in patients known to have coronary artery disease. Our knowledge of the clinical association between cholesterol reduction and risk for death is increasing. The 5-year Scandinavian Simvastatin Survival Study [10] showed the effectiveness of secondary prevention-decreasing elevated cholesterol levels in patients known to have coronary artery disease. The West of Scotland study [11] showed the benefit of using pravastatin to decrease elevated cholesterol levels in men not known to have coronary artery disease. In 1996, a third study provided evidence for an association that was implied by the first two.

In a 5-year clinical trial, Sacks and colleagues sought to determine whether the pharmacologic reduction of cholesterol levels with pravastatin would reduce the rate of fatal coronary heart disease or nonfatal myocardial infarction in patients who survived a myocardial infarction but had “average” cholesterol values (<240 mg/dL).

A total of 4159 patients who had had acute myocardial infarction but had plasma cholesterol levels less than 240 mg/dL (mean, 209 mg/dL) were randomly assigned to receive either pravastatin (40 mg/d) or placebo. All patients had LDL cholesterol levels of 115 to 174 mg/dL (mean, 139 mg/dL).

Table 3 shows the results of major outcomes. Pravastatin therapy decreased the mean LDL cholesterol level by 32% and maintained mean levels of about 98 mg/dL throughout the 5-year follow-up. The reduction in the rate of coronary events with pravastatin was greater in patients who had higher LDL cholesterol levels before treatment; little or no effect occurred among patients with a baseline level less than 125 mg/dL. The pravastatin group also had a 31% lower incidence of stroke (P = 0.03).

Reducing LDL cholesterol levels from average to low with pravastatin significantly reduced the rate of recurrent coronary events in patients with a history of myocardial infarction. The results suggest that an LDL cholesterol level of 125 mg/dL may be an approximate lower level above which LDL cholesterol exerts a clinically important influence.

Dr. Horn: University of Tennessee, 800 Madison Avenue, Memphis, TN 38163.

Dr. Roberts (Series Editor): Madrona Medical Group, 4370 Cordata Parkway, Bellingham, WA 98226-8075.