When is Drug Therapy Warranted to Prevent Sudden Cardiac Death?

Summary

Sudden arrhythmic death is an important contributor to the mortality rate in patients with cardiac disease, accounting for over 450 000 deaths per year in the USA alone. About 80% of such patients, particularly those survivors of acute myocardial infarction with low ventricular ejection fractions, have coronary artery disease. The remainder have cardiomyopathy or valvular disease and the common denominator in all these subsets of patients is the association with complex and frequent premature ventricular contractions (PVCs). The most common mechanism of death is ventricular tachycardia (VT) deteriorating into ventricular fibrillation (VF); the initiating factor is a PVC (the trigger mechanism). Thus, if an effective antiarrhythmic (? antifibrillatory) regimen could be identified, these subsets of patients clearly constitute targets for mortality reduction by pharmacological suppression.

The question that has arisen is whether suppression of PVCs will reduce the incidence of sudden death (the PVC hypothesis). The alternative approach is to modify the arrhythmogenic substrate in the ventricle by eliminating the source of ischaemia, extirpating the ectopic focus, dividing re-entry circuits, or pharmacologically prolonging the refractory period so that VT does not deteriorate into VF (the antifibrillatory approach).

Whether sudden death in postinfarct survivors could be reduced has been the subject of study. These patients are at high risk of sudden death or reinfarction, the risk being greatest in those with a low ventricular ejection fraction, continuing myocardial ischaemia and asymptomatic high density and complex PVCs. Numerous trials have been performed to determine whether β-blockers, calcium antagonists and antiarrhythmic agents reduce the incidence of sudden death and reinfarction in survivors of myocardial infarction. β-Blockers remain the only agents which, when given prophylactically, have been found to reduce the incidence of sudden death and reinfarction (by 18 to 45% in the first 2 years after infarction). The reduced incidence of sudden death appears to be associated with a reduction in VF, but not in PVCs. A meta-analysis of data from trials with calcium antagonists found that these drugs either had no effect or tended to increase mortality (by an average of 6%), indicating that an effect on ischaemia alone is unlikely to be the sole mechanism mediating the effect of β-blockers. The divergent effects of β-blockers and calcium antagonists are unexplained, but may be partly due to a lack of a significant bradycardiac effect of calcium antagonists. There were no differences in effect between different calcium antagonists. A meta-analysis of pooled data from trials involving class Ia and Ic antiarrhythmic agents indicated that agents acting via depression of cardiac conduction are either devoid of effect or produce a modest increase in mortality. In the Cardiac Arrhythmia Suppression Trial (CAST), the newer more potent class I agents (flecainide and encainide) were used to determine whether the suppression of PVCs in the survivors of acute infarction reduces mortality. Although flecainide and encainide suppressed PVCs by over 80%, they increased mortality by 364%, undoubtedly due to a marked proarrhythmic effect. Whether these data can be extrapolated to all class I agents is uncertain, but the overall results indicate the inherent difficulties with the PVC hypothesis. They also suggest that in patients with recurrent VT and/or VF, class I agents generally chosen on the basis of electrophysiological testing or Holter monitoring may either have no impact on mortality or may possibly increase it. This issue requires critical reappraisal. Preliminary data with class III antiarrhythmic agents suggest that, in addition to β-blockers, these agents (especially amiodarone) have the potential to reduce mortality in survivors of myocardial infarction. Data from ongoing trials suggest that, in the prevention of sudden death in survivors of acute infarction and possibly in other high risk patients, the focus must shift from antiarrhythmic agents that delay conduction to β-blockers and agents with antifibrillatory activity resulting from a prolongation of the refractory period.