Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator

Baylor College of Medicine, Houston, Texas, United States
Circulation (Impact Factor: 14.43). 01/2005; 110(24):3646-54. DOI: 10.1161/01.CIR.0000149240.98971.A8
Source: PubMed


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.
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.
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.

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    • "Azimilide is an investigational Class III antiarrhythmic agent that blocks both the rapid (IKr) and slow (IKs) components of the delayed rectifier cardiac potassium current. It causes prolongation of the atrial and ventricular action potential duration and refractory period [36]. As such, azimilide has demonstrated action against both supraventricular and ventricular arrhythmias. "
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    ABSTRACT: Ventricular arrhythmias, including ventricular fibrillation (VF) and sustained ventricular tachycardia (VT), are the principal causes of sudden cardiac death in patients with structural heart disease. While coronary artery disease is the predominant substrate associated with the development of VT, these arrhythmias are known to occur in a variety of disorders, including dilated cardiomyopathy, valvular and congenital heart disease, and cardiac ion channelopathies such as the long QT syndrome. In a minority of patients, VT occurs in the absence of structural heart disease. Despite the established mortality benefit of the implantable cardioverter defibrillator (ICD) in patients at risk of lethal arrhythmias, recurrent VT/VF events continue to be a source of morbidity and impaired quality of life in such patients. Antiarrhythmic therapy is indicated in select patients to treat symptomatic VT episodes, to reduce the incidence of ICD shocks, and potentially to improve quality of life and reduce hospitalizations related to cardiac arrhythmia. The primary adverse effects of antiarrhythmic medications are related to both cardiac and extracardiac toxicity, including the risk of proarrhythmia. Current drug therapy for ventricular arrhythmia has been limited by suboptimal efficacy in many patients, resulting in recurrent VT/VF events, and by drug toxicity or intolerance leading to discontinuation in a large percentage of patients. Amiodarone and sotalol are the principal agents used in the chronic treatment of VT. In addition, dronedarone and dofetilide, agents approved for the treatment of atrial fibrillation, and ranolazine, an antianginal agent, have been demonstrated to be protective against ventricular arrhythmia in small clinical studies. Finally, advances in basic electrophysiology have uncovered new molecular targets for the treatment of ventricular arrhythmia, and pharmacologic agents directed at these targets may emerge as promising VT treatments in the future. The roles of these current and emerging therapies for the treatment of VT in humans will be summarized in this review.
    Preview · Article · Jun 2013
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    • "One comparison of dofetilide and d,l-sotalol reported that withdrawals for adverse events were equal (19% and 26%, respectively) and that the risks of ventricular proarrhythmia were equal during acute titration (4.5% and 3.1%, respectively) and during follow-up (4.9% and 7.7%, respectively) [51]. Three RCTs found adverse events to occur equally with azimilide and placebo [51] [52] [58] except for severe neutropenia (0.9% versus 0.2%, respectively; P ¼ .01) [58]. "
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    ABSTRACT: Antiarrhythmic drug therapy, broadly defined, is the mainstay of treatment and prevention of ventricular tachycardia (VT)/ventricular fibrillation (VF), which can lead to sudden death. This article evaluates the evidence for and appropriate use of class I antiarrhythmic drugs, class III antiarrhythmic drugs, beta-blockers, nondihydropyridine calcium-channel blockers, statins, angiotensin enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, and digoxin for antiarrhythmic benefits in patients who have a propensity for VT/VF and therefore are at risk of sudden death.
    Preview · Article · Sep 2008 · Cardiology Clinics
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    • "One side effect of ICD therapy is the painful shock needed to terminate the life-threatening tachycardias. Different studies showed a reduction of the ICD therapy by an additional antiarrhythmic therapy [10-14]. "
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    ABSTRACT: Many patients with ICD receive different antiarrhythmic drugs (e.g. sotalol, amiodarone, beta-blockers) because of ventricular or atrial tachycardias. These drugs can cause AV-block or chronotropic incompetence resulting in a higher percentage of ventricular pacing. We analyzed in a retrospective study the impact of DDD(R) versus VVI(R) mode on subjective (NYHA classification) and objective parameters [brain natriuretic peptide (BNP), 6 minute walk test, echocardiography] in 12 of 120 patients (age 60.2 +/- 11.2 years; 10 males, 2 females) who needed an upgrading of a single to a dual chamber ICD. The ICD had to be upgraded because of chronotropic incompetence in all patients with signs of progressing heart failure. Data were collected in VVI(R)-pacing and after 6 and 12 months in DDD(R)-pacing with a long AV-interval and AV hysteresis to reduce ventricular pacing. The 6 minute walk test (392.4 +/- 91.4 vs. 324.6 +/- 93.3 m, P < 0.001), NYHA-classification (1.4 +/- 0.3 vs. 2.6 +/- 0.8, P < 0.0001), BNP (234.1 +/- 73.5 vs. 410.4 +/- 297.0 pg/ml, P < 0.001), left ventricular ejection fraction (49.8 +/- 9.6 vs. 36.5 +/- 10.9 %, P < 0.0001) and A-wave (73.6 +/- 13.7 vs. 41.0 +/- 14.0 cm/sec, P < 0.0001) improved with DDD(R)-pacing after 12 months. The ventricular pacing decreased (84.2 +/- 18.1 vs. 1.1 +/- 1.7 %, P < 0.0001) after 12 months by DDD(R)-pacing with long AV-interval (220.0 +/- 10.4 ms) and AV hysteresis. Our data show a superiority of DDD(R) mode versus VVI(R) mode regarding subjective and objective parameters as NYHA-classification, BNP, 6 minute walk test, left ventricular ejection fraction and left ventricular endsystolic volume after 12 months. The improvements seem to depend on the reduction of ventricular pacing with advanced atrial contraction. But only a small number of patients needed the upgradation.
    Full-text · Article · Jul 2006 · Indian pacing and electrophysiology journal
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