Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Amiodarone did not prolong survival or reduce sudden death in congestive heart failure

ACP J Club. 1996 Jan-Feb;124:15. doi:10.7326/ACPJC-1996-124-1-015


Source Citation

Singh SN, Fletcher RD, Fisher SG, et al. for the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med. 1995 Jul 13;333:77-82. [PubMed ID: 7539890]


Abstract

Objective

To evaluate the effectiveness of amiodarone in reducing overall mortality in patients with congestive heart failure (CHF) and asymptomatic ventricular arrhythmias.

Design

Randomized, double-blind, placebo-controlled trial with median 45-month follow-up.

Setting

24 centers in the United States.

Patients

674 patients (mean age 66 y, 99% men) who had CHF, cardiac enlargement, ≥ 10 ventricular premature beats/h, and left ventricular ejection fraction (LVEF) ≤ 40%. Exclusion criteria were women of child-bearing age; myocardial infarction within the previous 3 months; symptomatic ventricular arrhythmia; history of aborted sudden cardiac arrest or sustained ventricular tachycardia; uncontrolled thyroid disease; need for antiarrhythmic therapy; prolongation of QRS interval ≥ 180 ms or of QTc interval ≥ 500 ms; a serious disease likely to be fatal within 3 years; or symptomatic hypotension or systolic blood pressure < 90 mm Hg.

Intervention

336 patients were assigned to amiodarone, 800 mg/d for 14 days, then to 400 mg/d for 50 weeks, and then to 300 mg/d until the end of the study. 338 patients were assigned to placebo.

Main Outcome Measures

Overall mortality, sudden death from cardiac causes, LVEF, and ventricular arrhythmias.

Main Results

Analysis was by intention to treat. 131 patients (39%) assigned to amiodarone died compared with 143 patients {P = 0.38*} (Table). The overall actuarial survival at 2 years was 69.4% (CI 64.2% to 74.6%) in the amiodarone group and 70.8% (CI 65.7% to 75.9%) in the placebo group (P = 0.60). At 2 years, the rate of sudden death was 15% in the amiodarone group compared with 19% in the placebo group (P = 0.43). Patients in the amiodarone group had a greater improvement in LVEF at 6 months than did those in the placebo group (33.7% vs 29.2%, P < 0.001). Patients in the amiodarone group also had a lower frequency of ventricular arrhythmias other than symptomatic ventricular tachycardia. 40% of patients assigned to amiodarone and 33% of patients assigned to placebo were withdrawn or lost to follow-up (27% and 23% related to side effects, respectively).

Conclusion

In patients with congestive heart failure and asymptomatic ventricular arrhythmias, amiodarone was effective in suppressing arrhythmias and improving ventricular function, but it did not reduce sudden death or prolong survival.

Sources of funding: Department of Veterans Affairs Cooperative Studies Program of the Medical Research Service; Sanofi Winthrop Recherche; Wyeth-Ayerst Laboratories.

For article reprint: Dr. S.N. Singh, Division of Cardiology, Veterans Affairs Medical Center 1E301, 50 Irving Street, NW, Washington, DC 20422, USA. FAX 202-745-8184.

*Numbers calculated from data in article.


Table. Amiodarone to reduce sudden death in congestive heart failure*

Outcomes at 2 y EER CER RRR (95% CI) NNT
Overall mortality 39% 42% 7.8% (-11 to 23) Not significant
Sudden death 15% 19% 21% (-10 to 44) Not significant

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Many clinicians who treat patients with heart failure have held high hopes for amiodarone, a drug with anti-ischemic, antiarrhythmic, and afterload reduction effects. Although a few small, relatively short trials failed to show substantive effects of amiodarone on heart failure morbidity and mortality, a large trial from Argentina (1) showed that amiodarone decreased mortality caused by both sudden death and pump failure. Why, then, the mostly negative results in the Veterans Affairs (VA) trial by Singh and colleagues?

To be sure, several differences exist between the Argentinean trial and the VA trial. Most patients continued to receive the assigned therapy in the single-blind Argentinean trial, whereas the VA trial had numerous withdrawals and dropouts that, when combined, were greater among patients taking amiodarone than among those taking placebo (40% vs 33%, P = 0.03). The Argentinean trial included many younger women with severe heart failure that often had nonischemic causes; the VA participants were mostly older men with ischemic heart disease. Subset analyses of the VA trial suggest that persons with nonischemic causes of heart failure are more likely to benefit from amiodarone, whereas those with ischemic causes may require multipronged therapy with lipid-lowering, antithrombotic, and vasodilating agents.

Regardless of the reasons that underlie the seemingly disparate results, amiodarone should not be routinely used in persons with heart failure. Clinicians should implement proven therapies, such as angiotensin-converting enzyme inhibitors and β-blockers given in adequate doses.

Cynthia Mulrow, MD, MSc
Robert Chilton, DO
Audie L. Murphy Memorial Veterans HospitalSan Antonio, Texas, USA


Reference

1. Doval HC, Nul DR, Grancelli HO, et al. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet. 1994;334:493-8.