Review: Class II (β-blockers) and class III (amiodarone) antiarrhythmic agents reduce mortality in acute myocardial infarction
ACP J Club. 1994 May-June;120:75. doi:10.7326/ACPJC-1994-120-3-075
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Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. An overview of results from randomized controlled trials. JAMA. 1993 Oct 6;270:1589-95.
To evaluate, using meta-analysis, the effectiveness of prophylactic antiarrhythmic drug therapy in reducing mortality in patients with acute myocardial infarction (MI).
Relevant citations were identified using MEDLINE and by searching the references of retrieved articles. Additional articles were identified by consulting other investigators and pharmaceutical industry scientists.
All randomized controlled trials, published or unpublished, of antiarrhythmic agents in MI with mortality as an outcome measure were included. Crossover trials that did not allow clear attribution of mortality to active treatment or control and trials with comparison of ≥ 2 antiarrhythmic agents without a placebo control group were excluded.
Data on mortality for all randomized patients and the antiarrhythmic agent used were extracted. Investigators were contacted for data on patients excluded after randomization. Data were combined using the Yusuf-Peto adaptation of the Mantel-Haenszel method.
138 trials (involving 98 000 patients) met the selection criteria. In 59 trials, 660 deaths occurred among 11 712 patients (5.6%) assigned to class I agents compared with 571 deaths among 11 517 control patients (5.0%) (P = 0.03) (Table). The class I agents evaluated among the 59 trials were quinidine, procainamide, disopyramide, imipramine, moricizine, lidocaine, tocainide, phenytoin, mexiletine, aprindine, encainide, and flecainide. In 55 trials, 1464 patients died among 26 973 (5.4%) allocated to receive β-blockers (class II agents) compared with 1727 deaths in 26 295 control patients (6.6%) (P = 0.001) (Table). In 8 trials evaluating the effectiveness of amiodarone (a class III agent), 77 of 778 patients (10%) allocated to receive active treatment died compared with 101 of 779 control patients (13%) (P = 0.03) (Table). In 24 trials, 982 deaths occurred among 10 154 patients (10%) allocated to receive calcium channel blockers (a class IV agent) compared with 949 deaths in 10 188 control patients (9%) (P > 0.2) (Table).
Class I antiarrhythmic agents increase the risk for death in patients given these agents during or after acute myocardial infarction. Mortality is reduced with class II agents (β-blockers) and with amiodarone, a class III agent. No benefit is shown with calcium channel blockers, a class IV agent.
Source of funding: Not stated.
For article reprint: Dr. K.K. Teo, Division of Cardiology, University of Alberta, 2C2 Walter Mackenzie Centre, Edmonton, Alberta T6G 2R7, Canada.
Table. Mortality rates for prophylactic antiarrhythmic drug therapy vs control in acute myocardial infarction*
|Treatment||No. of studies||Control rates||RRI (95% CI)||NNH (CI)|
|Class I agents||59||5%||13% (1 to 26)||152 (77 to 2107)|
|Class IV agents (calcium channel blockers)||24||9%||4% (-5 to 13)||Not significant|
|RRR (CI)||NNT (CI)|
|Class II agents (β-blockers)||55||7%||18% (12 to 24)||85 (69 to 124)|
|Class III agent (amiodarone)||8||13%||26% (3 to 46)||30 (17 to 294)|
*Abbreviations defined in Glossary; RRI, RRR, NNH, NNT, and CI calculated from odds ratios in article.
Prophylactic antiarrhythmic treatment after MI was recently addressed in several reviews and meta-analyses, but the broad scope of the review by Teo and colleagues makes it particularly useful. The update on β-adrenergic and calcium channel blockers is warranted after several recent, larger trials. The overview adheres to the Vaughan-Williams classification of antiarrhythmic agents. Many drugs, however, are not easily classified (e.g., moricizine) and others have multiple electrophysiologic effects (e.g., calcium channel blockers).
Most of the 138 trials involved asymptomatic persons. Some included higher-risk patients only, typically with depressed left ventricular function or ventricular ectopy. Others tested the "arrhythmia suppression hypothesis": the assumption that reducing ventricular ectopy would translate into reduced sudden death. As the authors note, this assumption has been disproved, particularly by the Cardiac Arrhythmia Suppression Trials. Patients with sustained or symptomatic ventricular arrhythmias, however, are not covered by this overview and represent a special subset of the post-MI patient cohort. Current, generally accepted strategies in these patients include antiarrhythmic treatment guided by electrophysiologic testing, automatic defibrillator implantation, or "empiric" antiarrhythmic drugs, generally a class III agent. These strategies in symptomatic persons are being compared in ongoing trials.
Secondary prevention after acute MI includes other measures, such as antiplatelet and anticoagulant drugs, ACE inhibitors, cholesterol lowering, and smoking cessation; consideration of antiarrhythmic agents should be placed into this context. β-blockers have long been considered a high priority. Class I agents are not indicated and rate-slowing calcium channel blockers are weak alternatives to β-blockers, and then only when heart failure is absent. Although promising, the data are insufficient to support amiodarone or devices for general, prophylactic use; trials under way will help determine their value.
The more recent CAMIAT (1) and EMIAT (2) trials reported prevention of sudden cardiac death with prophylactic use of amiodarone in high-risk patients. Two meta-analyses (3, 4) reported a small but statistically significant reduction in all-cause death and more substantial reductions in sudden cardiac death with amiodarone after MI and in patients with congestive heart failure.
Steven Borzak, MD
Henry Ford HospitalDetroit, Michigan, USA
1. 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.
2. Julian DG, Camm AJ, Frangin G, et al., for the European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet. 1997;349:667-74.
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.