title: Time to arrhythmic, ischemic, and heart failure events: exploratory analyses to elucidate mechanisms of adverse drug effects in the Cardiac Arrhythmia Suppression Trial.
abstract: In this study we investigated the time to the first arrhythmic, ischemic, or failure event for encainide-flecainide and moricizine versus their respective placebo comparison groups in the Cardiac Arrhythmia Suppression Trial. The purpose was to explore possible mechanisms for the excessive deaths associated with active therapy that have been previously reported. Differences were noted between the active drugs. In particular, encainide-flecainide appeared to convert an ischemic event into death in more cases and more promptly than moricizine. However, the excessive deaths noted on encainide-flecainide were as likely to occur subsequent to a failure event as an ischemic event; for both encainide-flecainide and moricizine, the vast majority of excess deaths appeared to be the result of an increase in arrhythmia events without any protective effect of the drug. We were unable to identify any specific mechanism to explain the adverse effect of encainide and flecainide.
authors.affiliation: Clinical Trial Center, University of Washington, Seattle 98105, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Hallstrom
authors.forename: J L
authors.initials: JL
authors.lastname: Anderson
authors.forename: M
authors.initials: M
authors.lastname: Carlson
authors.forename: R
authors.initials: R
authors.lastname: Davies
authors.forename: H L
authors.initials: HL
authors.lastname: Greene
authors.forename: J M
authors.initials: JM
authors.lastname: Kammerling
authors.forename: D W
authors.initials: DW
authors.lastname: Romhilt
authors.forename: H J
authors.initials: HJ
authors.lastname: Duff
authors.forename: M
authors.initials: M
authors.lastname: Huther
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D004311:Double-Blind Method; D016700:Encainide / Q000009:adverse effects; D005424:Flecainide / Q000009:adverse effects; D006333:Heart Failure / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D016293:Moricizine / Q000009:adverse effects; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D017202:Myocardial Ischemia / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D016293:Moricizine; D005424:Flecainide; D016700:Encainide