title: Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously.
abstract: OBJECTIVE
  AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR).
  
  
  RESULTS
  Patients with AF episodes of duration 3 h to 3 months were randomized in a 3:1 ratio to receive a maximum 30 min intravenous infusion of AZD1305 or matching placebo. The primary efficacy endpoint was the proportion of patients converting within 90 min of the start of infusion, after which patients who had not converted were to undergo direct current (DC) cardioversion. Four ascending AZD1305 dose groups were assigned sequentially, with dose rates of 50, 100, 130, and 180 mg/h. A total of 171 patients were randomized. Pharmacological conversion was achieved in 0 of 43 patients (0%) in the placebo group, and in 2 of 26 (8%; P= 0.14 vs. placebo), 8 of 45 (18%; P= 0.006), 17 of 45 (38%; P< 0.001), and 6 of 12 patients (50%; P< 0.001) in AZD1305 dose groups 1-4, respectively. Maximum QTcF (QT interval corrected according to Fridericia's formula) generally increased dose-dependently up to a plateau, although there was wide variation between patients. Two patients experienced torsade de pointes (TdP): one patient without symptoms in dose group 3, and one patient requiring DC defibrillation in dose group 4. Both patients recovered without sequelae.
  
  
  CONCLUSIONS
  AZD1305 was effective in converting AF to SR, but was associated with QT prolongation and TdP. The benefit-risk profile was judged as unfavourable and the AZD1305 development programme was discontinued.
  
  
  BACKGROUND
  http://clinicaltrials.gov identifier NCT00915356.
authors.affiliation: Department of Cardiology, Péterfy Hospital, Budapest, Hungary.
authors.forename: Aladár
authors.initials: A
authors.lastname: Rónaszéki
authors.forename: Marco
authors.initials: M
authors.lastname: Alings
authors.forename: Kenneth
authors.initials: K
authors.lastname: Egstrup
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Gaciong
authors.forename: Marián
authors.initials: M
authors.lastname: Hranai
authors.forename: Csaba
authors.initials: C
authors.lastname: Király
authors.forename: Matyas
authors.initials: M
authors.lastname: Sereg
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Figatowski
authors.forename: Patrik
authors.initials: P
authors.lastname: Bondarov
authors.forename: Susanne
authors.initials: S
authors.lastname: Johansson
authors.forename: Lars
authors.initials: L
authors.lastname: Frison
authors.forename: Nils
authors.initials: N
authors.lastname: Edvardsson
authors.forename: Anders
authors.initials: A
authors.lastname: Berggren
mesh_terms: D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001281:Atrial Fibrillation / Q000188:drug therapy*; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002219:Carbamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D016171:Torsades de Pointes / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents; D053961:Azabicyclo Compounds; D002219:Carbamates; C550721:tert-butyl (2-(7-(2-(4-cyano-2-fluorophenoxy)ethyl)-9-oxa-3,7-diazabicyclo(3.3.1)non3-yl)ethyl)carbamate