Dose Ranging Study of Celivarone With Amiodarone as Calibrator for the Prevention of Implantable Cardioverter Defibrillator Interventions or Death - ALPHEE

Description:

The current trial was a phase II dose-ranging trial to study the safety and efficacy of celivarone as compared with amiodarone and placebo in patients with cardiomyopathy and recent implantable cardioverter defibrillator (ICD) therapy. Celivarone is a new AAD with Vaughn Williams Class I-IV effects.

Hypothesis:

Celivarone would be superior to amiodarone and placebo in preventing ventricular tachycardia/ventricular fibrillation (VT/VF) triggered ICD interventions or sudden death.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • ICD patients with an LVEF of ≤40% AND one of the following criteria:
    • At least one ICD therapy for VT or VF in the previous month, OR
    • ICD implantation in the previous month for documented VT/VF

      Number of enrollees: 486
      Duration of follow-up: 2 years
      Mean patient age: 64.4 years
      Percentage female: 11%
      Ejection fraction: 29.1%
      New York Heart Association (NYHA) class: I (15.6%), II (60.4%), III (24.0%)

    Exclusions:

    • Patients age >21 years (or the age of legal consent of the country)
    • Women of childbearing potential without adequate birth control or pregnant or breastfeeding women
    • Patients with known ICD lead problem (lead dislodgement)
    • ICD without the following characteristics:
      • Data logging function with cumulative counting of device Intervention (shocks and ATP)
      • Electrogram storage capabilities
      • Ventricular demand pacing
    • Recent unstable angina pectoris or myocardial infarction (<4 weeks)
    • History of torsades de pointes
    • Genetic channelopathies including congenital long QT syndrome
    • Wolff-Parkinson-White syndrome
    • Patients in unstable hemodynamic condition such as acute pulmonary edema within 12 hours prior to start of study medication; cardiogenic shock; treatment with intravenous pressor agents; patients on respirator; congestive heart failure of stage NYHA IV within the last 4 weeks; uncorrected, hemodynamically significant primary obstructive valvular disease; hemodynamically significant obstructive cardiomyopathy; a cardiac operation or revascularization procedure within 4 weeks preceding randomization
    • Incessant sustained VT/VF (VT/VF that recurs promptly despite termination attempts) during the 3 days preceding randomization
    • Patients with inappropriate (not triggered by VT or VF) shocks during the month preceding randomization
    • Clinically relevant hematologic, hepatobiliary (ALT, AST >3 times the upper limit of normal at randomization), gastrointestinal, renal (serum creatinine >221 µmol/l [2.5 mg/dl] at randomization), pulmonary, endocrinologic or psychiatric disease
    • Patients treated with oral amiodarone (>20 tablets during the 2 months preceding randomization)

    Primary Endpoints:

    • VT/VF triggered ICD interventions or sudden death
      • VT/VF leading to any ICD interventions (antitachycardia pacing or ICD shock) adjudicated by a Central Adjudication Committee (up to 10 episodes/patient)

    Secondary Endpoints:

    • ICD shocks or death

    Drug/Procedures Used:

    Patients were randomized in a 1:1:1:1:1 fashion to either placebo, amiodarone 600 mg for 10 days followed by 200 mg daily, or celivarone 50 mg, 100 mg, or 300 mg daily.

    Concomitant Medications:

    Beta-blockers (89.1%), angiotensin-converting enzyme inhibitors (85.2%), statins (73.3%)

    Principal Findings:

    A total of 486 patients were enrolled at 151 centers in 26 countries, 109 to placebo, 53 to amiodarone, and 324 to celivarone. Baseline characteristics were similar between the different arms. About 24% of the patients were age ≥75 years, 92% were White, and 64% had a body mass index <30. The mean left ventricular ejection fraction (LVEF) was 29.1%, with an EF < 35% in 65% of the patients. About 85% of the patients had a creatinine clearance of ≥50, 71% had coronary artery disease, 51% had dilated ischemic cardiomyopathy, and 6% had prior stroke.

    The primary endpoint of VT/VF triggering ICD intervention or sudden cardiac death (SCD) was similar between the placebo, amiodarone, and celivarone 50 mg, 100 mg, and 300 mg arms (61.5% vs. 45.3% vs. 67.0% vs. 58.8% vs. 54.9%, p > 0.05 for all vs. placebo). The vast majority of events were VT/VF. The secondary endpoint of first shock or death was also similar between the different arms, as were ICD shocks (p > 0.05) and all-cause mortality (5.5% vs. 17.0% vs. 7.3% vs. 5.9% vs. 9.7%, p > 0.05 vs. placebo). The incidence of treatment-related adverse events resulting in permanent discontinuation of study drug was lowest with placebo (16.5%), intermediate with celivarone (about 24%), and highest with amiodarone (31.4%).

    Interpretation:

    The results of this trial indicate that celivarone, a novel AAD with a profile similar to amiodarone and dronedarone, is not effective in reducing VT/VF shocks or SCD as compared with amiodarone or placebo in the doses studied. However, the burden of this problem in the population studied in this trial (low EF with history of VT/VF) was high (about 50-60% of all patients). Further, ICD shocks are associated with increased morbidity (e.g., post-traumatic stress disorder, depression). This highlights the importance of conducting further studies to identify agents or strategies that may help ameliorate this problem.

    References:

    Kowey PR, Crijns HJ, Aliot EM, et al., on behalf of the ALPHEE Study Investigators. Efficacy and Safety of Celivarone, With Amiodarone as Calibrator, in Patients With an Implantable Cardioverter-Defibrillator for Prevention of Implantable Cardioverter-Defibrillator Interventions or Death: The ALPHEE Study. Circulation 2011;Nov 14:[Epub ahead of print]

    Presented by Dr. Peter Kowey at the American Heart Association Scientific Sessions, Orlando, FL, November 14, 2011.

    Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias

    Keywords: Depression, Stroke, Coronary Artery Disease, Ventricular Fibrillation, Creatinine, Stress Disorders, Post-Traumatic, Tachycardia, Ventricular, Body Mass Index, Cardiomyopathies, Stroke Volume, Benzofurans, Defibrillators, Implantable, Death, Sudden, Cardiac


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