The coming of age of the class III antiarrhythmic principle: retrospective and future trends.

Antiarrhythmic drug therapy is in a state of continuous flux. In the last decade or so, numerous experimental and clinical studies have revealed that drugs that act by delaying conduction, while markedly suppressing ventricular arrhythmias, have the proclivity to increase mortality in subsets of patients with significant cardiac disease. The adverse impact on mortality was confirmed by placebo-controlled randomized trials as well as meta-analysis of smaller randomized clinical trials. The latter indicated that beta blockers exert a beneficial effect on mortality. Benefit from drugs that lengthen repolarization, especially drugs that have the additional property of blocking sympathetic excitation, was also seen in relatively small numbers of patients. Sotalol and amiodarone fell into this category of antiarrhythmic drugs. There were 2 major consequences that stemmed from the results of these trials. First, the endpoint of clinical trials shifted to total mortality from surrogates such as defined degree of suppression of ventricular arrhythmias. Second, concern regarding increases in mortality produced by class I drugs engendered a shift in favor of drugs that prolong repolarization. Such a shift was bolstered by the growing body of data that established the efficacy of sotalol and amiodarone as potent agents for the control of life-threatening ventricular arrhythmias. They were both found to be superior to class I agents. The perception that the critical factor that mediates their efficacy is the homogeneous prolongation of repolarization has led to the synthesis and characterization of so-called pure class III agents, which include d-sotalol and other lKr blockers such as dofetilide, sematilide, E-4031, and almokalant, among numerous others. The increase in mortality produced by d-sotalol in patients with myocardial infarction and lowered ejection fraction and in patients with and without heart failure has led researchers to question how to design future antiarrhythmic molecules. In the search for an ideal antifibrillatory agent, should emphasis be placed on simple molecules such as pure class III agents or on those with more complex profiles, such as sotalol and amiodarone, which exhibit antiadrenergic actions and the ability to prolong cardiac repolarization? The available data are in favor of the latter approach.