Amiodarone did not reduce mortality in severe congestive heart failure
ACP J Club. 1995 Mar-April;122:33. doi:10.7326/ACPJC-1995-122-2-033
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• Editorial: Applying the findings of clinical trials to individual patients
Doval HC, Nul DR, Grancelli HO, et al. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet. 1994 Aug 20;344:493-8.
To study whether low-dose amiodarone reduced mortality in patients with severe congestive heart failure (CHF).
Randomized controlled trial with 2-year follow-up.
26 hospitals in Argentina.
516 patients (mean age 59 y, 81% men) with severe, stable CHF (approximately 20% New York Heart Association class II, 50% class III, and 30% class IV) treated with low-sodium diet, diuretics, digitalis, and vasodilators who were not taking antiarrhythmic medications and who had systolic myocardial dysfunction (2 of chest radiograph cardiothoracic ratio of > 0.55, ejection fraction ≤ 0.35, and end-diastolic echocardiographic diameter ≥ 3.2 cm/m2 body surface area). Exclusion criteria were amiodarone treatment or an ischemic event in the previous 3 months; concomitant serious disease; mitral or aortic stenosis; atrioventricular conduction disorder; or history of sustained ventricular tachycardia or ventricular fibrillation. Follow-up was 96%.
260 patients were allocated to amiodarone, 600 mg/d for 2 weeks and then 300 mg/d for 2 years. 256 patients received usual care only.
Main outcome measures
2-year mortality. Secondary end points were sudden death, death caused by progressive heart failure, and hospitalization for CHF.
A difference in mortality appeared after 3 to 4 months and was maintained. At 2 years, no difference existed in mortality in patients assigned to amiodarone compared with those assigned to usual care (P = 0.06) (Table). When mortality was combined with hospitalizations for CHF, patients assigned to amiodarone had fewer events than those who were assigned to usual care (P = 0.002) (Table).
Low-dose amiodarone did not reduce 2-year mortality in patients with stable severe congestive heart failure.
Source of funding: Roemmers Argentina Laboratory (amiodarone).
For article reprint: Dr. H.C. Doval, GESCIA, Malvinas Argentinas 740, Capital Federal, Argentina CP 1406. FAX 54-11-4981-3881.
Table. Amiodarone vs usual care in severe congestive heart failure (CHF)*
|Outcomes at 2 y||Amiodarone||Usual care||RRR (95% CI)||NNT (CI)|
|Mortality||34%||41%||19% (-1 to 36)||Not significant|
|Mortality plus CHF hospitalization||46%||58%||21% (7 to 34)||8 (5 to 24)|
*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.
During the past decade, major advances in the treatment of heart failure have occurred. Angiotensin-converting enzyme inhibitors reduce morbidity and mortality. Digoxin prevents clinical deterioration and alleviates symptoms; its effects on mortality are being assessed. Despite these advances, heart failure remains a major health problem. We need new treatments that further reduce morbidity and mortality.
Should amiodarone be one of these treatments? Doval and colleagues show that amiodarone improved functional status and reduced the combined end point of hospital admissions and total mortality. Mortality benefits appear to have been caused by reductions in both progressive heart failure and sudden death. Although these findings are impressive, the control group in this trial did not receive placebo. Patients and providers were aware of treatment status, which may have led to variations in management between patients receiving amiodarone and those assigned to usual care. The investigators stopped the trial before the planned recruitment was completed, which could have led to an inflated estimate of treatment effect.
2 placebo-controlled, double-blind trials have evaluated amiodarone for moderate-to-severe heart failure (1, 2). Neither found reductions in mortality with amiodarone. The difference between these results and those of Doval and colleagues could have been caused by factors other than chance, the difference in the double-blind design, or Doval and colleagues' decision to stop early. For example, the trial by Nicklas and colleagues (2) was too small to detect meaningful mortality differences, and the 674 patients in the Veterans Affairs trial (1) had different causes of heart failure, slightly less severe failure, higher ejection fractions, and slightly higher doses of amiodarone than the patients in the trial by Doval and colleagues.
In summary, little evidence is available that shows the efficacy of amiodarone in heart failure. The available data are confusing, without simple explanations for seemingly conflicting results. Given this state of affairs, clinicians should not routinely prescribe amiodarone for their patients with left ventricular dysfunction.
Cynthia Mulrow, MD
Audie L. Murphy Memorial Veterans HospitalSan Antonio, Texas, USA
2. Nicklas JM, McKenna WJ, Stewart RA, et al. Prospective, double-blind, placebo-controlled trial of low-dose amiodarone in patients with severe heart failure and asymptomatic frequent ventricular ectopy. Am Heart J. 1991;122:1016-21.