Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously.

Abstract

AIM:

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).

METHODS AND 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.

CLINICAL TRIAL REGISTRATION:

http://clinicaltrials.gov identifier NCT00915356.

• Authors: Aladár Rónaszéki, Marco Alings, Kenneth Egstrup, Zbigniew Gaciong, Marián Hranai, Csaba Király, Matyas Sereg, Wlodzimierz Figatowski, Patrik Bondarov, Susanne Johansson, Lars Frison, Nils Edvardsson, Anders Berggren
• Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology (Europace) Vol. 13 Issue 8 Pg. 1148-56 (Aug 2011) ISSN: 1532-2092 [Electronic] England
• PMID: 21561900 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Azabicyclo Compounds
• Carbamates
• tert-butyl (2-(7-(2-(4-cyano-2-fluorophenoxy)ethyl)-9-oxa-3,7-diazabicyclo(3.3.1)non3-yl)ethyl)carbamate

Topics

• Adult
• Aged
• Anti-Arrhythmia Agents (administration & dosage, adverse effects, pharmacokinetics)
• Atrial Fibrillation (drug therapy)
• Azabicyclo Compounds (administration & dosage, adverse effects, pharmacokinetics)
• Carbamates (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Heart Conduction System (drug effects)
• Humans
• Injections, Intravenous
• Male
• Middle Aged
• Placebo Effect
• Torsades de Pointes (drug therapy)
• Treatment Outcome