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CLINICAL RESEARCH: HEART RHYTHM DISORDERS

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

Craig M. Pratt, MD, FACC^_*,_*, Hussein R. Al-Khalidi, PhD, Jose M. Brum, MD, Michael J. Holroyde, PhD, Peter J. Schwartz, MD, FACC, Stephen R. Marcello, MD, FACC, Martin Borggrefe, MD, FACC, Paul Dorian, MD, FACC^||, A. John Camm, MD, FACC^¶ on behalf of the Azimilide Trials Investigators

^_* Department of Cardiology, Methodist DeBakey Heart Center, Houston, Texas
Procter & Gamble Pharmaceuticals, Cincinnati, Ohio
Department of Cardiology, Policlinico S. Matteo, IRRCS, and University of Pavia, Pavia, Italy
Klinikum Mannheim, Universtatsklinikum, Mannheim, Germany
^|| Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada
^¶ Department of Cardiology, St. George's Hospital, London, England

Manuscript received November 23, 2005; revised manuscript received April 6, 2006, accepted April 11, 2006.

^_* Reprint requests and correspondence: Dr. Craig M. Pratt, The Methodist DeBakey Heart Center, 6565 Fannin Street, F1001, Houston, Texas 77030 (Email: cpratt{at}tmh.tmc.edu).

OBJECTIVES: 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.

BACKGROUND: Azimilide dihydrochloride is a class III antiarrhythmic drug possessing Ikr and Iks channel-blocking properties.

METHODS: 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%.

RESULTS: 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.

CONCLUSIONS: 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. The azimilide-associated TdP rate is 1% (95% confidence interval 0.78 to 1.35) and is not increased in patients with low left ventricular ejection fraction, even in women.

Abbreviations and Acronyms   AF = atrial fibrillation   ALIVE = Azimilide Post-Infarct Survival Evaluation   CI = confidence interval   EC = event committee   ECG = electrocardiogram   ICD = implantable cardioverter-defibrillator   JTc = JT interval corrected by Bazett's formula, for heart rate   LVEF = left ventricular ejection fraction   MI = myocardial infarction   QTc = QT interval corrected by Bazett's formula, for heart rate   SI = site investigator   SVA = supraventricular arrhythmias

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