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

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

doi:10.1093/europace/eur120

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

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

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1148-56
Number of pages	9
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
Volume	13
Issue number	8
DOIs	https://doi.org/10.1093/europace/eur120
Publication status	Published - Aug 2011
Externally published	Yes

Keywords

Adult
Aged
Anti-Arrhythmia Agents/administration & dosage
Atrial Fibrillation/drug therapy
Azabicyclo Compounds/administration & dosage
Carbamates/administration & dosage
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

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10.1093/europace/eur120

Cite this

Rónaszéki, A., Alings, M., Egstrup, K., Gaciong, Z., Hranai, M., Király, C., Sereg, M., Figatowski, W., Bondarov, P., Johansson, S., Frison, L., Edvardsson, N., & Berggren, A. (2011). Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously. 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, 13(8), 1148-56. https://doi.org/10.1093/europace/eur120

Rónaszéki, Aladár ; Alings, Marco ; Egstrup, Kenneth et al. / Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously. In: 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. 2011 ; Vol. 13, No. 8. pp. 1148-56.

@article{7a017ae7335b4a5f9b5eddab8b7ab26e,

title = "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.",

keywords = "Adult, Aged, Anti-Arrhythmia Agents/administration & dosage, Atrial Fibrillation/drug therapy, Azabicyclo Compounds/administration & dosage, Carbamates/administration & dosage, 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",

author = "Alad{\'a}r R{\'o}nasz{\'e}ki and Marco Alings and Kenneth Egstrup and Zbigniew Gaciong and Mari{\'a}n Hranai and Csaba Kir{\'a}ly and Matyas Sereg and Wlodzimierz Figatowski and Patrik Bondarov and Susanne Johansson and Lars Frison and Nils Edvardsson and Anders Berggren",

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month = aug,

doi = "10.1093/europace/eur120",

language = "English",

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pages = "1148--56",

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Rónaszéki, A, Alings, M, Egstrup, K, Gaciong, Z, Hranai, M, Király, C, Sereg, M, Figatowski, W, Bondarov, P, Johansson, S, Frison, L, Edvardsson, N & Berggren, A 2011, 'Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously', 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, vol. 13, no. 8, pp. 1148-56. https://doi.org/10.1093/europace/eur120

Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously. / Rónaszéki, Aladár; Alings, Marco; Egstrup, Kenneth et al.
In: 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, Vol. 13, No. 8, 08.2011, p. 1148-56.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously

AU - Rónaszéki, Aladár

AU - Alings, Marco

AU - Egstrup, Kenneth

AU - Gaciong, Zbigniew

AU - Hranai, Marián

AU - Király, Csaba

AU - Sereg, Matyas

AU - Figatowski, Wlodzimierz

AU - Bondarov, Patrik

AU - Johansson, Susanne

AU - Frison, Lars

AU - Edvardsson, Nils

AU - Berggren, Anders

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Anti-Arrhythmia Agents/administration & dosage

KW - Atrial Fibrillation/drug therapy

KW - Azabicyclo Compounds/administration & dosage

KW - Carbamates/administration & dosage

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Female

KW - Heart Conduction System/drug effects

KW - Humans

KW - Injections, Intravenous

KW - Male

KW - Middle Aged

KW - Placebo Effect

KW - Torsades de Pointes/drug therapy

KW - Treatment Outcome

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DO - 10.1093/europace/eur120

M3 - Article

C2 - 21561900

SN - 1099-5129

VL - 13

SP - 1148

EP - 1156

JO - 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

JF - 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

IS - 8

ER -

Rónaszéki A, Alings M, Egstrup K, Gaciong Z, Hranai M, Király C et al. Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously. 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. 2011 Aug;13(8):1148-56. doi: 10.1093/europace/eur120

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

Abstract

Keywords

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