Amiodarone Post MI Canada
ABSTRACT & COMMENTARY
Synopsis: The results of CAMIAT must be considered disappointing to those who hoped that amiodarone would be a simple yet highly effective way to decrease mortality in myocardial infarction survivors.
Source: Cairns JA, et al. Lancet 1997;349:675-682.
The canadian amiodarone myocardial infarction Trial (CAMIAT) enrolled 1202 patients from 36 Canadian hospitals during the period between June 1990 and November 1995. Patients were eligible for enrollment 6-45 days after their infarction if they manifested an average of 10 ventricular premature depolarizations (VPDs) per hour or at least one run of nonsustained ventricular tachycardia on a 24-hour ambulatory recording. Ejection fraction was not a criterion for entry. Eligible patients who agreed to participate were randomized to receive either amiodarone (10 mg/kg/d ´ 2 weeks, then 400 mg/d) or matched placebo tablets. Follow-up ambulatory monitors were obtained at four and eight months in all patients, and the amiodarone dose could be reduced if arrhythmia suppression was documented. The primary end point of the study was the composite end point of resuscitated ventricular fibrillation (VF) or arrhythmic death. Cardiac death and all-cause mortality were secondary end points. The minimum follow-up time was one year. The primary analysis was performed using only patients on prescribed therapy or within three months of its permanent discontinuation. An intention-to-treat analysis was also reported. Cairns et al presumed potential benefit; therefore, only a one-sided test of significance was used.
The randomized groups were similar in age (mean, 64 years) and gender distribution (82% male). Other clinical factors were also evenly matched. Left ventricular function and coronary anatomy were not reported. Amiodarone resulted in arrhythmia suppression in 84% of patients, but there was spontaneous resolution in 35% of the placebo group at four months. Early study drug discontinuation was seen in 36.4% of the amiodarone patients and in 25.5% of the placebo patients. In both groups, presumed side effects were responsible for two-thirds of the discontinuations.
In the analysis of patients on therapy, amiodarone reduced the estimated risk of resuscitated VF or arrhythmia death from 6.0% to 3.3%. In this analysis, total mortality was decreased from 5.4% per year to 4.4% per year. Only the analysis for resuscitated VF and arrhythmia death achieved a P value of less than 0.05 in the intention-to-treat analysis. For resuscitated VF and arrhythmic death, the reduction was from 3.7% per year to 2.3% per year (P = 0.029) and for total mortality, from 6.4% per year to 5.2% per year (P = 0.13). Age over 70 years, diabetes, heart failure, and history of pulmonary edema with the index myocardial infarction (MI) were predictors of recurrent arrhythmias. Patients not taking beta-blockers or diltiazem, those who had not received thrombolytics with their infarction, and those receiving digoxin had higher event rates. The authors conclude from their data that post-MI patients who are able to tolerate amiodarone will have a decreased risk of arrhythmic death or aborted cardiac arrest.
COMMENT BY JOHN P. DiMARCO, MD, PhD
Although the authors’ final conclusion was positive, the results of CAMIAT must be considered disappointing to those who hoped that amiodarone would be a simple yet highly effective way to decrease mortality in MI survivors. Despite entering over 1200 patients, there was only an absolute 1.2% reduction in yearly mortalitya difference that did not achieve statistical significance. Given the drug’s known potential for toxicity, it is difficult to recommend its use in asymptomatic patients after infarction. Several aspects of the trial, however, deserve comments.
The authors selected ventricular ectopy as their marker for post-infarction risk, but the control group two-year mortality estimate was only 11%. In EMIAT, an ejection fraction cut-off was used, and the two-year control-group mortality was slightly higher at 14%. Any antiarrhythmic intervention post MI is likely to have significant cost and/or morbidity. It is therefore important to concentrate on very high-risk groups. A study group that had both the EMIAT and CAMIAT type markers, ejection fraction below 40% and some marker of risk for arrhythmia (e.g., a positive signal averaged ECG, abnormal heart rate variability, inducible ventricular tachycardia, or ventricular ectopy) would be a potential group for such a study. Unless the two-year event rate is greater than 20%, it will be difficult to show any improvement with therapy. However, by making the selection criteria highly specific, sensitivity will be lost and the impact on overall post-infarction mortality will be decreased.
CAMIAT should also be an example of why an intention-to-treat analysis should be standard in studies on mortality reduction. We can never be sure that patients in the two groups discontinued therapy for the same reasons and that they were at similar risks for death off therapy. Different patterns of discontinuation might create imbalances not present after the initial randomization and lead to at least quantitatively erroneous conclusions.
Several other aspects of CAMIAT deserve comment. CAMIAT used a primary end point of arrhythmic events. It should now be standard that total mortality be the primary event in such a trial since classification of the mechanism of death is often uncertain. CAMIAT also used a one-sided test of significance. Given the relatively low event rate and the known risks of all antiarrhythmic therapies, a two-sided test would have been preferable. Finally, interaction of study drug with concomitant therapy continues to be a problem in analyzing trials. Although a favorable interaction between amiodarone therapy and beta-blockers was noted, the reason for this interaction remains obscure.