Cumulative Experience of Azimilide-Associated Torsades de Pointes Ventricular Tachycardia in the 19 Clinical Studies Comprising the Azimilide Database

• Published in: Journal of the American College of Cardiology 2006-08, Vol.48 (3), p.471-477
• Main Authors: Pratt, Craig M., Al-Khalidi, Hussein R., Brum, Jose M., Holroyde, Michael J., Schwartz, Peter J., Marcello, Stephen R., Borggrefe, Martin, Dorian, Paul, Camm, A. John
• Format: Article
• Language: English
• Subjects: Aged; Anti-Arrhythmia Agents - administration & dosage; Anti-Arrhythmia Agents - adverse effects; Anti-Arrhythmia Agents - therapeutic use; Arrhythmias, Cardiac - drug therapy; Arrhythmias, Cardiac - physiopathology; Biological and medical sciences; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Clinical trials; Confidence intervals; Databases, Factual; Dose-Response Relationship, Drug; Drug therapy; Electrocardiography; Female; Heart; Heart attacks; Heart rate; Humans; Hydantoins; Imidazolidines - administration & dosage; Imidazolidines - adverse effects; Imidazolidines - therapeutic use; Logistics; Male; Medical sciences; Middle Aged; Mortality; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - therapeutic use; Studies; Time Factors; Torsades de Pointes - chemically induced
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2006.04.075

Cumulative Experience of Azimilide-Associated Torsades de Pointes Ventricular Tachycardia in the 19 Clinical Studies Composing the Azimilide Database Craig M. Pratt, Hussein R. Al-Khalidi, Jose M. Brum, Michael J. Holroyde, Peter J. Schwartz, Stephen R. Marcello, Martin Borggrefe, Paul Dorian, A. John Camm, on behalf of the Azimilide Trials Investigators Azimilide dihydrochloride is a class III antiarrhythmic possessing Ikr and Iks channel-blocking properties. The entire azimilide database was assessed for its incidence, temporal characteristics, and risk factors associated with torsades de pointes (TdP) (incidence 1%, 95% confidence interval 0.78 to 1.35). Oral azimilide (75 to 125 mg/day) was taken by 5,375 patients in 19 clinical trials. The 56 cases of TdP in azimilide-treated patients were dose related and tended to occur earlier with an azimilide-loading regimen. Significant risk factors were increasing age, female gender, diuretic use, and lack of aspirin use, similar to sotalol and dofetilide. A distinctive temporal profile is described, as well as a low azimilide-associated TdP risk in patients with a low left ventricular ejection fraction, even in women. The purpose of this study was to assess the incidence, temporal characteristics, and risk factors associated with azimilide-associated torsades de pointes (TdP) ventricular tachycardia. Azimilide dihydrochloride is a class III antiarrhythmic drug possessing Ikr and Iks channel-blocking properties. Oral azimilide (75 to 125 mg/day) was taken by 5,375 patients in 19 clinical trials conducted at 775 international centers. Of 3,964 patients in double-blind studies, 1,427 had a history of atrial fibrillation or other supraventricular arrhythmia, 510 had an implantable cardioverter-defibrillator, and 2,027 were post-myocardial infarction patients with a left ventricular ejection fraction ≤35%. The TdP occurred in 56 patients assigned to azimilide, was dose-related, and tended to occur earlier with an azimilide-loading regimen. Forty-three percent of TdP patients had a QT interval corrected by Bazett’s formula, for heart rate, (QTc) ≥500 ms at the time of or before the TdP occurrence. Significant risk factors using logistic regression were increasing age, female gender, diuretic use, and lack of aspirin use. Azimilide-associated TdP has characteristics and risk factors similar to other Ikr blockers. However, there is a distinctive temporal profile. The TdP events are not concentrated in the first week.