Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT

Summary

Background

Ventricular arrhythmias are a major cause of death after myocardial infarction, especially in patients with poor left-ventricular function. Previous attempts to identify and suppress arrhythmias with various antiarrhythmic drugs failed to reduce or actually increase mortality. Amiodarone is a powerful antiarrhythmic drug with several potentially beneficial actions, and has shown benefit in several small-scale studies. We postulated that this drug might reduce mortality in patients at high risk of death after myocardial infarction because of impaired ventricular function, irrespective of whether they had ventricular arrhythmias.

Methods

The European Myocardial Infarct Amiodarone Trial (EMIAT) was a randomised double-blind placebo-controlled trial to assess whether amiodarone reduced all-cause mortality (primary endpoint) and cardiac mortality and arrhythmic death (secondary endpoints) in survivors of myocardial infarction with a left-ventricular ejection fraction (LVEF) of 40% or less. Intention-to-treat and on-treatment analyses were done.

Findings

EMIAT enrolled 1486 patients (743 in the amiodarone group, 743 in the placebo group). Median follow-up was 21 months. All-cause mortality (103 deaths in the amiodarone group, 102 in the placebo group) and cardiac mortality did not differ between the two groups. However, in the amiodarone group, there was a 35% risk reduction (95% CI 0–58, p=0·05) in arrhythmic deaths.

Interpretation

Our findings do not support the systematic prophylactic use of amiodarone in all patients with depressed left-ventricular function after myocardial infarction. However, the lack of proarrhythmia and the reduction in arrhythmic death support the use of amiodarone in patients for whom antiarrhythmic therapy is indicated.

Introduction

Ventricular arrhythmias are one of the main causes of death in survivors of acute myocardial infarction. The European Myocardial Infarct Amiodarone Trial (EMIAT) was conceived at the end of 1988, after many studies of antiarrhythmic drugs that block the sodium-channel (class I) showed no efficacy in the suppression of arrhythmias and prevention of death in survivors of myocardial infarction.1, 2, 3 Later, the Cardiac Arrhythmia Suppression Trials proved that in survivors of myocardial infarction at low risk of death, the suppression of ventricular extrasystoles with the sodium-channel-blocking drugs flecainide and encainide, and possibly moricizine, was associated with excess mortality.4, 5 Apart from β-adrenergic blocking agents, the only antiarrhythmic drug that showed any promise in the late 1980s was amiodarone, although the number of patients studied was too small to allow definite conclusions about the drug's effect on all-cause mortality.6, 7, 8 We, therefore, decided to conduct a large trial of amiodarone in survivors of myocardial infarction at increased risk of death.9, 10

Although the presence of frequent or complex ventricular arrhythmias is an independent risk factor for mortality after myocardial infarction,11, 12, 13 and most trials of antiarrhythmic drugs have used such ventricular arrhythmias as an entry criterion, there is no evidence that suppression of ventricular arrhythmias leads to a reduction in overall mortality. Moreover, the single most powerful independent predictor of mortality, including sudden death, is left-ventricular dysfunction.13, 14 Thus, we decided to adopt a different approach from the other trials by taking no account of the presence of symptomless arrhythmias and by choosing depressed left-ventricular ejection fraction (LVEF) as the main entry criterion. We expected that most patients with left-ventricular dysfunction would subsequently suffer from lethal arrhythmias, even if ventricular arrhythmias were not initially present. In addition to its antiarrhythmic properties, amiodarone has anti-ischaemic actions and does not aggravate heart failure, properties that may have an additional beneficial effect on survivors of myocardial infarction.

The aim of this randomised placebo-controlled double-blind trial was to assess the effect of amiodarone on all-cause mortality, cardiac mortality, and arrhythmic death in survivors of myocardial infarction with depressed left-venticular function.

EMIAT was a joint venture between the Working Group on Arrhythmias of the European Society of Cardiology and Sanofi Recherche.