New Replacement for Amiodarone?

Abstract & Commentary

By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville

Source: Kowey PR, 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-cefibrillator interventions or death: The ALPHEE Study. Circulation 2011;124:2649-2660.

Celivarone is a noniodinated analog of amiodarone that is currently in clinical trials. This report gives us data about the effect of celivarone on ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICDs).

The study was designed to enroll only very high-risk patients. Patients were eligible for inclusion if they had an ICD for primary prevention and had received at least one ICD intervention for ventricular tachycardia (VT) or ventricular fibrillation (VF) in the previous month; if they had an ICD placed for secondary prevention with either a clinical episode VT or VF; or if they had an ICD intervention in the previous month. Patients were also required to have a left ventricular ejection fraction of ≤ 40%. Patients who met entry criteria were randomized to receive, in double-blind fashion, once daily oral celivarone at a dose of 50 mg, 100 mg, or 300 mg daily, amiodarone (600 mg for 10 days followed by 200 mg thereafter), or placebo. Patients were then followed at monthly intervals for 6 months and then every 3 months until completion of the study. Stored electrograms were analyzed by a trained electrophysiologist to classify any ICD interventions as either appropriate or inappropriate. The primary efficacy endpoint for the trial was the occurrence of an appropriate ICD intervention (shock or antitachycardia pacing) or sudden death analyzed using a time to first event approach. A secondary efficacy endpoint was occurrence of all ICD shock, including both appropriate and inappropriate shocks, or death from any cause.

The study enrolled 486 patients and the median duration of treatment was 9 months. The clinical characteristics at baseline were similar in all groups. The mean age was 64 years and 89% were male. The mean left ventricular ejection fraction was 29%, and 86% of the patients had a history of congestive heart failure.

An appropriate ICD intervention or sudden death was experienced by 62% of the patients in the placebo group, by 67%, 59%, and 55% of the patients in the celivarone 50-mg, 100-mg, and 300-mg daily groups, respectively, and by 45% of the patients in the amiodarone group. There were six sudden deaths in the trial with one in the placebo group, one in the celivarone 300 mg group, and four in the amiodarone group. None of the hazard ratios (HRs) for the primary endpoint were significantly different for any of the celivarone group vs the placebo group. There was a trend toward a decrease in the primary endpoint in the amiodarone group (HR = 0.7, P = 0.13). Life table analysis of the time to the primary endpoint showed no statistically significant differences between the curves for any of celivarone groups and the placebo group. For the secondary endpoint, the proportion of patients experiencing any ICD shock or death was 44% in the placebo group, 45%, 37%, and 42% in the celivarone, 50-mg, 100-mg, and 300-mg groups, respectively, and 26% in the amiodarone group. Although shocks were less frequent in the amiodarone group, all-cause mortality was increased in this group. There were 14 deaths in the amiodarone group with a HR vs placebo of 3.327. In general, celivarone was reasonably well tolerated. The most common treatment emergent adverse events were recurrent ventricular arrhythmias and neurological events. Adverse events related to the gastrointestinal, pulmonary, endocrine, and musculoskeletal systems were not increased in the celivarone groups vs placebo.

The authors conclude that in this study celivarone at any of the three doses was not effective in preventing ventricular arrhythmia-triggered ICD interventions. Although amiodarone was effective in preventing ICD interventions, an increase in mortality rate greater than placebo was noted in the amiodarone group.

Commentary

The results in this study will probably end the celivarone development program as an antiarrhythmic drug. Two earlier Phase II trials using celivarone in patients with atrial fibrillation had also shown no significant benefit. This large and extremely well-done trial using ICD interventions in a very high-risk population as the most important endpoint also clearly shows no benefit. This is an extremely disappointing result since there is an important unmet clinical need for well-tolerated agents that can decrease ICD shock frequency and thereby improve the tolerability of ICD therapy. Celivarone, which was designed to avoid the risks of thyroid dysfunction and organ toxicity associated with tissue accumulation seen with amiodarone, had been regarded as a potentially useful new agent.

The other important observation in this trial is that there were trends for increase in both sudden death and total mortality seen in the amiodarone group. This was seen despite the observation that amiodarone decreased the frequency of both appropriate and inappropriate shocks. A similar signal was also seen in patients with Class III heart failure in the Sudden Cardiac Death — Heart Failure Trial but has not been seen in other studies using amiodarone. However, the observation here should make clinicians think twice before they start amiodarone in patients with advanced heart failure. It also raises questions about the use of a reduction in ICD therapies as an endpoint in a study of an antiarrhythmic drug. To my knowledge, this is the first time that a decrease in ICD shocks has been associated with an increase in mortality.