Laan, Michael J. Holroyde, Igor Singer and Craig M. Pratt
Daljit S. Tatla, Johannes Brachmann, Robert J. Myerburg, David S. Cannom, Michael van der
Paul Dorian, Martin Borggrefe, Hussein R. Al-Khalidi, Stefan H. Hohnloser, Jose M. Brum,
Tachyarrhythmias in Patients With an Implantable Cardioverter Defibrillator
Placebo-Controlled, Randomized Clinical Trial of Azimilide for Prevention of Ventricular
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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2004;110:3646-3654; originally published online November 8, 2004;
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Placebo-Controlled, Randomized Clinical Trial of Azimilide
for Prevention of Ventricular Tachyarrhythmias in Patients
With an Implantable Cardioverter Defibrillator
Paul Dorian, MD; Martin Borggrefe, MD; Hussein R. Al-Khalidi, PhD; Stefan H. Hohnloser, MD;
Jose M. Brum, MD; Daljit S. Tatla, PhD; Johannes Brachmann, MD; Robert J. Myerburg, MD;
David S. Cannom, MD; Michael van der Laan, MD; Michael J. Holroyde, PhD; Igor Singer, MD;
Craig M. Pratt, MD; on Behalf of the SHock Inhibition Evaluation with azimiLiDe (SHIELD) Investigators
Background—Although implanted cardioverter defibrillators (ICDs) effectively treat sustained ventricular
tachyarrhythmias, up to 50% of ICD recipients eventually require concomitant antiarrhythmic drug therapy to prevent
symptomatic arrhythmia recurrences and hence reduce the number of device therapies.
Methods and Results—A total of 633 ICD recipients were enrolled in a randomized, double-blind, placebo-controlled
study to evaluate the effect of daily doses of 75 or 125 mg of azimilide on recurrent symptomatic ventricular
tachyarrhythmias and ICD therapies. Total all-cause shocks plus symptomatic ventricular tachycardia (VT) terminated
by antitachycardia pacing (ATP) were significantly reduced by azimilide, with relative risk reductions of 57% (hazard
ratio [HR]?0.43, 95% CI 0.26 to 0.69, P?0.0006) and 47% (HR?0.53, 95% CI 0.34 to 0.83, P?0.0053) at 75- and
125-mg doses, respectively. The reductions in all-cause shocks with both doses of azimilide did not achieve statistical
significance. The incidence of all appropriate ICD therapies (shocks or ATP-terminated VT) was reduced significantly
among patients taking 75 mg of azimilide (HR?0.52, 95% CI 0.30 to 0.89, P?0.017) and those taking 125 mg of
azimilide (HR?0.38, 95% CI 0.22 to 0.65, P?0.0004). Five patients in the azimilide groups and 1 patient in the placebo
group had torsade de pointes; all were successfully treated by the device. One patient taking 75 mg of azimilide had
severe but reversible neutropenia.
Conclusions—Azimilide significantly reduced the recurrence of VT or ventricular fibrillation terminated by shocks or ATP
in ICD patients, thereby reducing the burden of symptomatic ventricular tachyarrhythmia. (Circulation. 2004;110:3646-
Key Words: drugs ? cardioversion ? defibrillation ? antiarrhythmia agents ? tachycardia
life compared with antiarrhythmic drug therapy (or no anti-
arrhythmic drug therapy) in patients at risk for sustained
ventricular tachyarrhythmias.1–4However, many patients
with an ICD have ventricular tachyarrhythmias that may
cause transiently disabling symptoms and may lead to painful
ICD shocks. In patients implanted with defibrillators after
sustained ventricular tachyarrhythmias, quality of life im-
proves in many but not in those who require multiple ICD
therapies.5Over time, 30% to 50% of ICD recipients receive
antiarrhythmic drug therapy to prevent symptomatic
tachyarrhythmias and to reduce the number of device thera-
mplanted cardioverter defibrillators (ICDs) effectively
treat sustained ventricular arrhythmias and thereby prolong
pies.6–8Moreover, defibrillator therapies often occur in
clusters, which suggests that the recurrence of ventricular
tachyarrhythmias is not randomly distributed in time.9–11
See p 3624
No antiarrhythmic drug is currently approved by regulatory
agencies in North America or Europe for use in ICD
recipients. The range of currently available antiarrhythmic
drugs for this indication is limited, particularly because of
adverse effects. Drugs with class I action are contraindicated
in patients with coronary artery disease or left ventricular
dysfunction.12Although sotalol, a drug with class III and
?-blocking action, has been shown to be effective as an
Received October 1, 2004; revision received October 18, 2004; accepted October 19, 2004.
From the Division of Cardiology, St. Michael’s Hospital (P.D.), Toronto, Ontario, Canada; Klinikum Mannheim (M.B.), Universtatsklinikum,
Mannheim, Germany; Health Care Research Center (H.R.A.-K., J.M.B., D.S.T., M.J.H.), Procter & Gamble Pharmaceuticals, Cincinnati, Ohio; J.W.
Goethe University (S.H.H.), Department of Cardiology, Division of Electrophysiology, Frankfurt, Germany; Landkrankenhaus Coburg (J.B.), II
Medizinische Klinik, Coburg, Germany; University of Miami School of Medicine (R.J.M.), Miami, Fla; Los Angeles Cardiology Associates (D.S.C.), Los
Angeles, Calif; Procter & Gamble Pharmaceuticals (M.v.d.L.), Egham, United Kingdom; Methodist Medical Center (I.S.), Peoria, Ill; and The Methodist
DeBakey Heart Center and the Section of Cardiology, Baylor College of Medicine (C.M.P.), Houston, Tex.
Presented in part at the 77th Scientific Sessions of the American Heart Association, New Orleans, La, November 7–10, 2004.
Correspondence to Dr Paul Dorian, St. Michael’s Hospital, 30 Bond St, Toronto, Ontario M5B 1W8, Canada. E-mail email@example.com
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000149240.98971.A8
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