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Therapeutics

Low-dose amiodarone led to fewer cardiac deaths and serious arrhythmics in patients surviving myocardial infarction who had contraindications to β-blockers

ACP J Club. 1993 May-June;118:74. doi:10.7326/ACPJC-1993-118-3-074


Source Citation

Ceremuzynski L, Kleczar E, Krzeminska-Pakula M, et al. Effect of amiodarone on mortality after myocardial infarction: a double-blind, placebo-controlled, pilot study. J Am Coll Cardiol. 1992 Nov 1;20:1056-62.


Abstract

Objective

To determine, in a pilot study, whether low-dose amiodarone reduces 1-year total and cardiac mortality in patients surviving acute myocardial infarction (MI) who have contraindications to β-blockers.

Design

1-year, randomized, double-blind, placebo-controlled trial.

Setting

8 medical school hospitals in Poland.

Patients

Patients were assessed 5 to 7 days after admission and were eligible if they were < 75 years old; had a confirmed MI based on history, electrocardiographic alterations, and laboratory values; and had contraindications to β-blockers (heart failure, bronchial asthma, treated diabetes, or peripheral artery disease with claudication). Patients were excluded if they lived far away or had a variety of cardiovascular conditions (including atrial fibrillation or the need for antiarrhythmic drugs). 6249 patients were screened and 613 were studied (mean age 59 y, 425 men). Follow-up was complete.

Intervention

305 patients were assigned to amiodarone. The initial dose was 800 mg/d for 7 days, and then 400 mg/d, 6 d/wk for 12 months. The dose could be reduced for heart rates < 55 beats/min and was stopped if the rate fell to < 50, any type of heart block developed, the QT interval was > 0.5 seconds, or a new MI or significant pulmonary symptoms occurred. 308 patients were assigned to placebo.

Main outcome measures

Total and cardiac mortality, arrhythmias, and adverse effects. Patients were examined at 15 clinic visits during the study year.

Main results

Patients in the amiodarone group had fewer cardiac deaths { P = 0.046}*, fewer serious ventricular arrhythmias { P < 0.001}*, and more adverse effects { P < 0.001}* (Table). No difference existed between the groups for total mortality. At the end of the study, 103 patients assigned to amiodarone and 79 assigned to placebo had stopped their medications. 10 of the 19 cardiac deaths in the amiodarone group occurred after the drug was stopped.

Conclusion

Among patients with myocardial infarction who had contraindications to β-blockers, amiodarone treatment led to fewer cardiac deaths and serious arrhythmias, and more adverse effects.

Source of funding: In part, Polish government.

For article reprint: Dr. L. Ceremuzynski, Department of Cardiology, Postgraduate Medical School, Szpital Grochowski 04-073, Grenadierow 51/59, Warsaw, Poland. FAX 48-22-257300.

* P values calculated from data in article.


Table. Amiodarone vs placebo at 1 year in patients surviving myocardial infarction who had contraindications to β-blockers†

Outcomes Amiodarone Placebo RRR (95% CI) NNT (CI)
Cardiac deaths 6% 11% 42% (0.8 to 66) 23 (12 to 1323)
Arrhythmias 8% 19% 61% (39 to 75) 9 (6 to 16)
Total death 7% 11% 36% (-8 to 62) Not significant
RRI (CI) NNH (CI)
Adverse effects 30% 10% 190% (102 to 321) 6 (4 to 8)

†Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from data in article.


Commentary

This is the first randomized trial to clearly show that an antiarrhythmic agent can reduce the incidence of sudden death after MI. Though Ceremuzynski and colleagues' interpretation of the results is appropriately conservative, a stronger case for therapeutic efficacy could have been made because half of the patients who discontinued treatment did not meet standard criteria for discontinuation, and half of the deaths in the treatment group occurred after stopping the drug. In contrast, class I antiarrhythmics such as encainide, flecainide, and moricizine were associated with an increased mortality in postinfarction patients studied in the Cardiac Arrhythmia Suppression Trial (CAST).

The potential effect of these results on North American clinical practice is unclear. The postinfarction risk assessment trials that counted premature ventricular contractions and measured left ventricular ejection fraction, as well as the β-blocker trials that showed a 25% reduction in subsequent mortality, are over a decade old. The natural history of postinfarction patients may be better now. Patients are now likely to be treated with antiplatelet, anticoagulant, thrombolytic, or angiotensin-converting enzyme inhibitor drugs. Atherosclerotic risk factors are rigorously controlled. Postinfarction ischemia is aggressively sought and often treated with coronary revascularization. A patent infarct artery may be associated with a normal signal-averaged electrocardiogram and an excellent long-term prognosis independent of drug therapy.

Despite the promise amiodarone has shown in this and other small trials, it is unlikely that amiodarone will be used nonselectively and chronically for secondary prevention. The cost and inconvenience of monitoring patients for amiodarone toxicity suggest that future trials with amiodarone should focus on high-risk patients (low ejection fraction with frequent pre-mature ventricular beats, occluded infarct artery, late potentials on signal-averaged electrocardiogram), perhaps using a lower dose and a limited treatment period.

Eric R. Bates, MD
University of MichiganAnn Arbor, Michigan, USA


Editorial Comment:

Since the publication of this study, 2 longer clinical trials (1, 2) and 2 systematic overviews have further evaluated the use of amiodarone after MI (3, 4). The European Myocardial Infarct Amiodarone Trial (1), and the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (2) did not show a reduction in all-cause mortality but did show a statistically significant reduction in arrythmic sudden death. The 2 meta-analyses (3, 4) evaluating the effectiveness of amiodarone showed an overall reduction in total mortality of about 13%, and a reduction in arrhythmic sudden death of about 29% in high-risk patients with recent MI or congestive heart failure receiving prophylactic amiodarone therapy.


References

1. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet. 1997;349:667-74.

2. Cairns JA, Connolly SJ, Roberts R, Gent M, for the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet. 1997;349:675-82.

3. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350:1417-24.

4. Sim I, McDonald KM, Lavori PW, Norbutas CM, Hlatky MA. Quantitative overview of randomized trials of amiodarone to prevent sudden cardiac death. Circulation. 1997;96:2823-9.