NEW INSIGHTS INTO THE DEFINITION AND MEANING OF PROARRHYTHMIA DURING INITIATION OF ANTIARRHYTHMIC DRUG-THERAPY FROM THE CARDIAC-ARRHYTHMIA SUPPRESSION TRIAL AND ITS PILOT-STUDY

Objectives. This study was undertaken to determine the characteristics of worsening ventricular arrhythmia during antiarrhythmic drug titrat ion. Background. Proarrhythmia is an evolving concept in cardiology. I ts definition, incidence and clinical significance in various patient settings require refinement. Methods. The impact of early proarrhythmi a was analyzed in 3,840 patients In the Cardiac Arrhythmia Suppression Trial (CAST). Results. Drug therapy did not affect the incidence of n ew, sustained but nonfatal ventricular tachycardia (placebo 0.5%, acti ve drug 0.4%). Nevertheless, there was a threefold increase in arrhyth mic death (placebo 0.5% vs. active drug 1.6%). The incidence of increa sed ventricular premature depolarizations was equivalent (3% to 5%) fo r the three study drugs and indistinguishable from that seen with plac ebo. Patients with increased ventricular premature depolarizations on the first drug tested had fewer at baseline (65 +/- 94 vs. 137 +/- 260 per hour; mean +/- SD) (p < 0.01), When increased ventricular prematu re depolarizations occurred with the first drug, they were much more l ikely also to be present with the second drug (for example, 42% vs. 5% , p < 0.001). Increased ventricular premature depolarizations during i nitiation of therapy independently predicted increased risk of subsequ ent arrhythmic death (independent relative risk 2.34, p = 0.0053) in t he absence of continued antiarrhythmic drug therapy. Conclusions. The overall incidence of early worsening of arrhythmia in the present stud y was low. In the absence of placebo control, the incidence of proarrh ythmia will be overestimated. Increased ventricular premature depolari zations had characteristics that suggest they often represent spontane ous variability rather than proarrhythmia. The main finding is that ma rkedly increased ventricular premature depolarizations during drug tit ration predict long term increased risk of arrhythmic death in this pa tient population despite absence of long term antiarrhythmic drug ther apy.