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Therapeutics

Amlodipine did not increase morbidity or mortality rates in severe heart failure

ACP J Club. 1997 Mar-Apr;126:30. doi:10.7326/ACPJC-1997-126-2-030


Source Citation

Packer M, O'Connor CM, Ghali JK, et al., for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996 Oct 10;335:1107-14.


Abstract

Objective

To evaluate the long-term effect of amlodipine on morbidity and mortality in patients with advanced chronic heart failure.

Design

Randomized, double-blind, placebo-controlled trial with a median follow-up of 13.8 months. Randomization was stratified by the cause of the left ventricular dysfunction (coronary artery disease or nonischemic dilated cardiomyopathy).

Setting

Clinical centers throughout the United States.

Patients

1153 patients (mean age 65 y, 76% men) who had dyspnea or fatigue at rest or on minimal exercise and a left ventricular ejection fraction of < 30% (New York Heart Association class IIIB or IV) despite treatment with digoxin, diuretics, and an angiotensin-converting enzyme (ACE) inhibitor. Exclusion criteria included uncorrected primary valvular disease; active myocarditis; constrictive pericarditis; history of cardiac arrest; sustained ventricular tachycardia or fibrillation in the previous year; unstable angina or acute myocardial infarction in the previous month; cardiac revascularization or stroke in the previous 3 months; and severe pulmonary, renal, or hepatic disease. No patients were lost to follow-up.

Intervention

571 patients were assigned to amlodipine, 5 mg/d for 2 weeks. The dosage was then increased to 10 mg/d (if tolerated) for the remainder of the study. 582 patients were assigned to matching placebo.

Main outcome measures

The primary end point was all-cause mortality and hospitalization for major cardiovascular events (acute pulmonary edema, severe hypoperfusion, acute myocardial infarction, or ventricular arrhythmia).

Main results

A primary fatal or nonfatal event occurred in 222 patients (39%) in the amlodipine group compared with 246 patients (42%) in the placebo group (relative risk reduction [RRR] 9%, 95% CI -10% to 24%, P = 0.31). 190 patients (33%) in the amlodipine group died from all causes compared with 223 patients (38%) in the placebo group (RRR 16%, CI -2% to 31%, P = 0.07). Treatment with amlodipine did not affect the primary outcomes among patients with ischemic heart disease: 45% of patients in both treatment groups had a fatal or nonfatal event, and 40% in both groups died. Among patients with nonischemic dilated cardiomyopathy, fatal or non-fatal events were reduced in the amlodipine group (28% vs 37%, P = 0.04) as was death from all causes (18% vs 31%, P = 0.001).

Conclusion

Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure and may prolong survival in patients with nonischemic cardiomyopathy.

Source of funding: Pfizer Central Research.

For article reprint: Dr. M. Packer, Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. FAX 212-305-7439.


Commentary

Current management of congestive cardiac failure relies heavily on ACE inhibitors, but these drugs are not well tolerated in as many as 20% of patients (1). Calcium channel blockers have anti-ischemic effects that may benefit patients with heart failure secondary to coronary artery disease (2), but some calcium antagonists (particularly first-generation drugs) also produce myocardial depression and subsequent clinical deterioration (2).

Packer and colleagues aimed to determine the long-term influence of amlodipine, a second-generation drug, on morbidity and mortality. Their large, well-conducted trial included patients with severe refractory cardiac failure—more than 99% of whom were receiving concomitant therapy with digitalis, diuretics, and ACE inhibitors. Amlodipine had no detrimental effects in patients with cardiac failure. Of potential interest is that a subgroup analysis of patients with heart failure secondary to nonischemic cardiomyopathy indicated that treatment with amlodipine has significant benefits. This is consistent with the results of animal studies that have shown the beneficial effects of calcium antagonists in cardiomyopathy (3).

This study establishes the safety of amlodipine for the treatment of angina and hypertension in patients with advanced left ventricular dysfunction. Whether amlodipine should be used for the treatment of heart failure in patients without these associated cardiovascular conditions is a question that is being addressed by a trial now in progress.

Gillian Leng, MD
University of EdinburghEdinburgh, Scotland, UK


References

1. De Vries RJ, Quere M, Lok DJ, et al. Comparison of effects on peak oxygen consumption, quality of life and neurohormones of felodipine and enalapril in patients with congestive heart failure. Am J Cardiol. 1995; 76:1253-8.

2. Elkayam U, Shotan A, Mehra A, Ostrzega E. Calcium channel blockers in heart failure. J Am Coll Cardiol. 1993;22(Suppl A): 139A-44A.

3. Garrett JS, Wilkman-Coffelt J, Sievers R, Finkbliner WE, Parmley WW. Verapamil prevents the development of alcoholic dysfunction in hamster myocardium. J Am Coll Cardiol. 1987;9:1326-31.