[Methodology in clinical trials of anti-arrhythmia agents in ventricular arrhythmias. Analysis and perspective following results of the CAST study].

The results of the Cardiac Arrhythmia Suppression Trial (CAST) have not finished modifying the methodology and strategy of development of new antiarrhythmic agents for the treatment of ventricular arrhythmias. The demonstration of a dissociation between a proved antiarrhythmic effect and increased mortality in coronary patients treated with encainide or flecainide, means that, in this situation, antiarrhythmic efficacy cannot be considered to be a substitute criterion of therapeutic benefit. The consequences of these results are as follows: in phase II, the dose-effect relationships should be studied in patients with chronic ventricular extrasystole without ischemic heart disease. This model is sufficiently predictive for the selection of the dosage to be tested in phase III; in phase III, studies of benign ventricular arrhythmias, antiarrhythmic efficacy is demonstrated by ambulatory ECG recordings. If these studies include patients with ischemic heart disease, the patients must be placed on betablocker therapy and the benefits in terms of reduction of mortality have to be shown by controlled trials versus placebo. In malignant life-threatening arrhythmias, open clinical trials may be performed using provocative electrophysiological studies. The inclusion of patients with implanted automatic defibrillator devices could constitute control groups for the placebo group. The future of antiarrhythmic agents for the treatment of ventricular arrhythmias greatly depends on the search for criteria of severity of arrhythmias and the validation of intermediate criteria of efficacy.