Significance of Classifying Antiarrhythmic Actions Since the Cardiac Arrhythmia Suppression Trial

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Abstract
The Cardiac Antiarrhythmic Suppression Trial (CAST) showed flecainide and encainide induced excess mortality compared with placebo. Labeling drugs as Class 1C is based on clinical observations, comprising measurements of the electrocardiographic parameters QRS, H‐V and J‐T intervals and of effective refractory period (ERP) as follows: 1—(QRS) wide, 2—(HV) long, 3—(ERP) unchanged, 4—(JT) unchanged. In vitro electrophysiology helped to explain the clinical findings. Flecainide and encainide rendered Na channels as nonconducting, but F and E were only slowly released from the channels after repolarization. At any given drug concentration, a proportion of total channels were eliminated, and the steady‐state proportion increased at rising heart rate. It is not proven that the properties that lead to classification of a drug as 1C were those that caused excess deaths in the CAST. The proarrhythmic tendency of 1C drugs can be reduced by beta‐blockade, and the mechanisms of adrenergic arrhythmogenicity are discussed. Propafenone is both a 1C drug and a beta‐blocker, and its pharmacologic profile is reviewed to illustrate how it resembles and differs from flecainide and encainide. Some features of the CAST are assessed with particular reference to the extent to which conclusions drawn from the results may be justifiably extrapolated to other drugs classified as 1C.