title: 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. The CAST and CAPS Investigators.
abstract: OBJECTIVE
  This study was undertaken to determine the characteristics of worsening ventricular arrhythmia during antiarrhythmic drug titration.
  
  
  BACKGROUND
  Proarrhythmia is an evolving concept in cardiology. Its definition, incidence and clinical significance in various patient settings require refinement.
  
  
  METHODS
  The impact of early proarrhythmia was analyzed in 3,840 patients in the Cardiac Arrhythmia Suppression Trial (CAST).
  
  
  RESULTS
  Drug therapy did not affect the incidence of new, sustained but nonfatal ventricular tachycardia (placebo 0.5%, active drug 0.4%). Nevertheless, there was a threefold increase in arrhythmic death (placebo 0.5% vs. active drug 1.6%). The incidence of increased ventricular premature depolarizations was equivalent (3% to 5%) for the three study drugs and indistinguishable from that seen with placebo. 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 premature depolarizations occurred with the first drug, they were much more likely also to be present with the second drug (for example, 42% vs. 5%, p < 0.001). Increased ventricular premature depolarizations during initiation of therapy independently predicted increased risk of subsequent arrhythmic death (independent relative risk 2.34, p = 0.0053) in the absence of continued antiarrhythmic drug therapy.
  
  
  CONCLUSIONS
  The overall incidence of early worsening of arrhythmia in the present study was low. In the absence of placebo control, the incidence of proarrhythmia will be overestimated. Increased ventricular premature depolarizations had characteristics that suggest they often represent spontaneous variability rather than proarrhythmia. The main finding is that markedly increased ventricular premature depolarizations during drug titration predict long-term increased risk of arrhythmic death in this patient population despite absence of long-term antiarrhythmic drug therapy.
authors.affiliation: University of Calgary, Alberta, Canada.
authors.forename: D G
authors.initials: DG
authors.lastname: Wyse
authors.forename: J
authors.initials: J
authors.lastname: Morganroth
authors.forename: R
authors.initials: R
authors.lastname: Ledingham
authors.forename: P
authors.initials: P
authors.lastname: Denes
authors.forename: A
authors.initials: A
authors.lastname: Hallstrom
authors.forename: L B
authors.initials: LB
authors.lastname: Mitchell
authors.forename: A E
authors.initials: AE
authors.lastname: Epstein
authors.forename: R L
authors.initials: RL
authors.lastname: Woosley
authors.forename: R
authors.initials: R
authors.lastname: Capone
mesh_terms: D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology*; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016019:Survival Analysis; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents