Amiodarone reduced ventricular fibrillation or arrhythmic death in MI with frequent ventricular premature depolarizations
ACP J Club. 1997 Sep-Oct;127:30. doi:10.7326/ACPJC-1997-127-2-030
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• Companion Abstract and Commentary: Amiodarone reduced arrhytmic death but not cardiac death in patients with MI and depressed left ventricular function
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• Correction: Amiodarone reduced ventricular fibrillation or arrhythmic death in MI with frequent ventricular premature depolarizations
• Review: Class II (β-blockers) and class III (amiodarone) antiarrhythmic agents reduce mortality in acute myocardial infarction
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 Mar 8;349:675-82.
To assess the effect of amiodarone on the risk for resuscitated ventricular fibrillation (RVF) or arrhythmic death in survivors of a myocardial infarction (MI) with frequent or repetitive ventricular premature depolarizations (VPDs).
Randomized, double-blind, placebo-controlled trial with mean 1.79-year follow-up.
36 acute-care hospitals in Canada.
1202 patients > 19 years of age (mean age 64 y, 82% men) who had had an acute MI within the previous 6 to 45 days and had frequent (≥ 10/h) or repetitive (≥ 1 run of ventricular tachycardia) VPDs. Exclusion criteria were contraindications to amiodarone, need for antiarrhythmic therapy or tricyclic antidepressants, concurrent severe disease, or factors that made study participation impractical.
606 patients were allocated to amiodarone, a loading dose of 10 mg/kg daily for 2 weeks followed by a maintenance dose of 300 to 400 mg daily for 3.5 months, then 200 to 300 mg daily for 4 months, and then 200 mg for 5 to 7 days/wk for 16 months. 596 patients were allocated to placebo.
Main outcome measures
The primary outcome was RVF or arrhythmic death. The secondary outcomes were arrhythmic, cardiac, and all-cause mortality.
By efficacy and intention-to-treat (ITT) analysis, RVF or arrhythmic death occurred less often in patients in the amiodarone group compared with those in the placebo group (P = 0.016 and P = 0.029, respectively) (Table). Arrhythmic death, cardiac mortality, and all-cause mortality (P = 0.129) (Table) did not differ between the treatment groups.
Amiodarone reduced the incidence of ventricular fibrillation or arrhythmic death among survivors of myocardial infarction with frequent or repetitive ventricular premature depolarizations.
Sources of funding: Medical Research Council of Canada and Sanofi Winthrop.
For article reprint: Dr. J.A. Cairns, Faculty of Medicine, University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. FAX 604-822-6061.
Table. Amiodarone vs placebo†
|Outcome at 2 years||Amiodarone EER||Placebo CER||RRR (95% CI)||ARR |EER-CER| (CI)|
|RVF or arrhythmic death (ITT analysis)||4.5%||6.9%||34.3% (1.9 to 66.8)||2.4% (-1.7 to 6.5)|
|Efficacy analysis||3.3%||6.0%||45.3% (11.0 to 79.6)||2.7% (0 to 5.4)|
|All-cause mortality (ITT analysis)||9.4%||11.4%||17.6% (-14.9 to 40.9)||2.0% (-1.4 to 5.5)|
†ITT = intention-to-treat; RVF = resuscitated ventricular fibrillation. Other abbreviations defined in Glossary; RRR, ARR, and CI supplied by the author.
Physicians desire adjunctive drugs to prolong life in survivors of acute MI, especially those with poor left ventricular function. Of the strategies evaluated to date, adrenergic receptor blockade and angiotensin-converting enzyme (ACE) inhibition clearly improve survival (1). However, some strategies that were thought to promote electrical stability (e.g., sodium-channel blockers) actually shorten life (2), even in low-risk patients. Earlier studies suggested that high-risk patients might benefit from antiarrhythmic therapy with amiodarone. Besides prolonging the ventricular refractory period, amiodarone has adrenergic blocking and anti-ischemic actions. These 2 trials, the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) and the European Myocardial Infarct Amiodarone Trial (EMIAT), show that the outcome of treatment with amiodarone is complex and not readily predictable.
CAMIAT focused on patients with frequent ventricular ectopy, and EMIAT focused on patients with left ventricular dysfunction. In CAMIAT, the primary outcome measure was arrhythmic death or RVF and the results were assessed using a 1-tailed t-test. Patients withdrew at high and unequal rates, 36% of patients in the amiodarone group and 25% in the placebo group, possibly confounding the results. In the ITT analysis, amiodarone did not show a statistically significant decrease in total mortality or nonarrhythmic cardiac mortality. Taken together, these factors weaken the authors' conclusion that amiodarone produces "a clinically important reduction in arrhythmic death and RVF." Although the design of EMIAT was better, the trial's 33% increase in nonarrhythmic death, which may have been caused by amiodarone, offset the 35% reduction in risk for arrhythmic death. 42 (CAMIAT) and 44 (EMIAT) patients would need to be treated to prevent 1 arrhythmic death.
The 2 trials remind us of the weakness of arrhythmic death as an outcome measure. Although committees try to distinguish arrhythmic or sudden death from other types of cardiac death, assessments using these end points fail because sudden death and arrhythmic death overlap but are not identical. Some sudden deaths are caused by ventricular arrhythmia, but others are caused by re-infarction, pulmonary embolism, and bradycardia, for example (3). Inconsistency between committees in classifying deaths (4) also hampers systematic review. Therefore, the objective end point, total mortality, remains clinically the most useful.
The results of CAMIAT and EMIAT show that, unlike other antiarrhythmic drugs, amiodarone does not shorten life. Although these trials suggest that amiodarone decreases arrhythmic death, it failed to decrease total mortality in both trials. The clinical effectiveness of amiodarone in prolonging life after MI therefore remains unproved. To evaluate whether amiodarone decreases total mortality requires a larger, more costly trial, or in the interim, a meta-analysis of current trials. Physicians must also weigh the substantial adverse effects of amiodarone against any apparent benefit. The evidence does not justify the routine use of amiodarone in survivors of MI who have left ventricular dysfunction or asymptomatic ventricular arrhythmias.
On average, only half of the patients in these trials were receiving β-adrenergic blockers and ACE inhibitors, although these drugs are proven to increase survival (1). Instead of considering amiodarone to lower the risk for arrhythmic death, physicians should confidently prescribe a β-adrenergic blocker or an ACE inhibitor to survivors of MI where appropriate.
Vernon M. Oh, MD
National University HospitalRepublic of Singapore
Vernon M. Oh, MD
National University HospitalRepublic of Singapore