Amiodarone Post MIEurope
ABSTRACT & COMMENTARY
The European infarct amiodarone trial (EMIAT) was conducted between 1990 and 1995 in a consortium of 64 European hospitals. All patients who suffered documented myocardial infarction (MI) between November 30, 1990, and October 30, 1995, in the participating hospitals were surveyed. Eligible patients included those who were between 18 and 75 years of age and who had a left ventricular ejection fraction of 40% or less, as determined by multiple gated nuclear angiography (MUGA). The MUGA had to be performed within 5-21 days after infarction. During the study period, there were 32,633 MIs in the participating hospitals. A total of 7565 patients underwent MUGA scanning. Of these, 3255 had ejection fractions of 40% or less. Fourteen hundred eighty-six of these patients were eventually randomized to receive either amiodarone (800 mg qd ´ 14 days, 400 mg qd ´ 14 weeks, then 200 mg qd) or matched placebo. Patients were seen at regular intervals. The primary end point of the study was all-cause mortality. Secondary end points of cardiac mortality, arrhythmic death, and arrhythmic death plus resuscitated cardiac arrest were reviewed by a validation committee. The primary analysis used was on an intention-to-treat basis, but an on-treatment analysis was also performed in which data were censored three months after permanent discontinuation of the study drug.
The baseline characteristics of the two patient groups were roughly similar, but there were minor imbalances in ejection fraction, New York Heart Association functional class, and history of prior MI that tended to favor the placebo-treated patients.
There was no difference in all-cause mortality between the two treatment groups (risk ratio, 0.99; P = 0.96). This was true even after patients were grouped by ejection fraction. Although there was a reduction in the number of deaths classified as arrhythmic in the amiodarone therapy group, there were more deaths from nonarrhythmic cardiac or noncardiac causes that balanced the overall mortality.
During the trial, 38.5% of patients in the amiodarone group discontinued study medication. A lower percentage (21.4%) of the placebo group patients also discontinued medication. Abnormalities in thyroid function and photosensitivity were the most frequent reasons for discontinuation. There were, however, three cases of fatal pulmonary toxicity among the amiodarone patients.
There was no significant difference in concomitant drug therapy between the two groups. However, there was a strong tendency toward a favorable interaction between use of beta-blockers in addition to amiodarone and mortality.
Julian et al conclude that EMIAT "does not support the systematic prophylactic use of this regimen of amiodarone in survivors of myocardial infarction. Nevertheless, amiodarone therapy does lead to a reduction in arrhythmic death with no proarrhythmic effect, only a few minor side effects, and a neutral effect on total mortality." (Julian DG, et al. Lancet 1997;349:667-674.)
COMMENT BY JOHN P. DiMARCO, MD, PhD
Survivors of an acute MI have been the subject of numerous studies using antiarrhythmic drugs as primary prophylaxis against sudden death. Studies using drugs that primarily affect fast sodium channels showed that these drugs increased mortality even if spontaneous ventricular premature beats, a marker of risk for death, were suppressed (Teo, et al. JAMA 1993;270:1589-1595). Studies using beta adrenergic blockers have shown benefit, but the search for a more effective antiarrhythmic intervention continued. In the last 15 years, amiodarone has become recognized as the most consistently effective antiarrhythmic drug in patients with sustained ventricular arrhythmias. Several smaller studies have shown benefit in groups of post-infarction patients (BASIS. J Am Coll Cardiol 1990;16:1711-1718; Polish Trial. J Am Coll Cardiol 1992;20:1056-1062). EMIAT and a Canadian trial also reported in this issue of Lancet were planned as large, well-controlled studies to confirm these observations.
The EMIAT investigators chose ejection fraction as their marker of post-infarction risk. Ejection fraction has been shown to be a powerful predictor of mortality in virtually all studies, and unlike ventricular ectopy, it is reliably and reproducibly measured. However, the event rate using an ejection fraction of 40% as the entry criterion gave a mortality rate of only approximately 6% at one year and 10% at two years.
Only a minor, insignificant decrease in total mortality was observed in the group that received amiodarone. Although it is tempting to focus on the decrease in arrhythmic death, total mortality must be the end point in any trial designed to improve survival after infarction. There are far too many uncertainties involved in assigning cause of death for any other standard to apply. The trivial decrease in total mortality reported here, therefore, is insufficient to justify the expense and risks of minor and major toxicity seen during long-term therapy with amiodarone. Although better identification, using a panel of predictors of risk, of those who will actually go on to die would help target those most likely to benefit from antiarrhythmic therapy, such an approach would fail to identify the majority of deaths, and it is uncertain whether any drug would benefit this highest risk group.