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Do antiarrhythmic drugs work? Some reflections on the implications of the Cardiac Arrhythmia Suppression Trial
1Department of Cardiology, Wadsworth VA Hospital, Los Angeles, CA 90073.
Insights
Antiarrhythmic drugs that delay cardiac conduction may increase mortality in heart attack survivors. Beta-blockers and amiodarone, which reduce adrenergic stimulation, show promise for reducing sudden cardiac death.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Significant advances in understanding cardiac arrhythmias and antiarrhythmic drugs exist.
- Doubt remains regarding the efficacy of antiarrhythmic agents in reducing mortality, except in specific patient groups.
Purpose of the Study:
- To evaluate the impact of antiarrhythmic drugs on mortality in patients with cardiac arrhythmias.
- To identify crucial determinants for mortality reduction in high-risk myocardial infarction survivors.
Main Methods:
- Analysis of the Cardiac Arrhythmia Suppression Trial (CAST) results.
- Meta-analysis of randomized antiarrhythmic trials in acute myocardial infarction survivors.
- Examination of beta-blockers and amiodarone effects, focusing on adrenergic attenuation.
Main Results:
- Class Ic antiarrhythmic agents, primarily delaying conduction, were found to increase mortality in acute infarction survivors.
- Beta-blockers are the only class shown to reduce sudden death in control trials, acting via beta-blockade and preventing ventricular fibrillation.
- Amiodarone shows potential for prolonging survival by controlling arrhythmias, with effects similar to beta-blockers in attenuating adrenergic stimulation.
Conclusions:
- Drugs delaying cardiac conduction may be deleterious in post-infarction patients.
- Focus should shift from PVC suppression to agents with antifibrillatory actions via sympathetic antagonism and those lengthening myocardial refractoriness.
- Beta-blockers and amiodarone offer insights into effective mortality reduction strategies through adrenergic attenuation.
Abstract:
Despite major advances in our understanding of the mechanisms of cardiac arrhythmias and how antiarrhythmic drugs appear to work, there remains much doubt whether these agents reduce arrhythmic mortality except in certain subsets of patients. The results of the Cardiac Arrhythmia Suppression Trial (CAST) have indicated that certain antiarrhythmic drugs not only "fail to work" but may substantially increase mortality. The effects of Class Ic agents in CAST and the meta-analysis of randomized antiarrhythmic trials in the survivors of acute infarction suggest that drugs that act primarily by delaying conduction are particularly deleterious in the survivors of acute infarction. Whether these data have a wide applicability in terms of all ventricular arrhythmias is unclear, but beta-blockers remain the only class of agents that in control trials have been shown to reduce sudden death. The effect appears to be related to beta-blockade and not to suppression of premature ventricular contractions (PVCs). Beta blockers appear to act by preventing ventricular fibrillation. It is reasonable to assume that PVC suppression per se is unlikely to produce a reduction in sudden death. Uncontrolled data with amiodarone suggests that it has the potential to prolong survival by controlling arrhythmias. The effects of amiodarone and beta blockers, both significantly attenuating adrenergic stimulation, provide pharmacologic probes to define the crucial determinants of efficacy of a compound for mortality reduction in high risk survivors of myocardial infarction. The focus must now shift from antiectopic and antiarrhythmic agents that delay conduction to those that exert antifibrillatory actions by sympathetic antagonism and those that exhibit the added property of lengthening myocardial refractoriness.