Back to the drawing board as ALPHEE study fails to show benefit of celivarone

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A study presented at the recent AHA sessions and published online in Circulation has found that the new antiarrhythmic drug celivarone does not prevent implantable cardioverter defibrillator (ICDs) interventions or sudden cardiac death, ending hopes that the drug would be a new weapon in the antiarrhythmic drugs armoury.

Lead investigator Peter Kowey, Lankenau Hosptial and Institute of Medical Research, Pennsylvania, USA, told delegates at the AHA that a previous study, ICARIOS (Gojkovic et al, Heart Rhythm 2011, Epub) indicated that the drug could be used to prevent shocks or sudden cardiac death in patients with ICDs. He explained that ICARIOS had demonstrated: “efficacy for 300mg/d for celivarone, compared with placebo, at a non-significant level-just a trend.” He added that he and his fellow investigators thought that the non-significance finding was probably due to an insufficient number of patients being enrolled in the study rather than a lack of efficacy of the drug itself. “Because of this very strong clue of there being a trend towards efficacy, we went ahead with a larger randomised clinical trial and this was ALPHEE (Efficacy and safety of celivarone with amiodarone as a calibrator in patients with an implantable cardioverter defibrillator for prevention of implantable defibrillator interventions or death).”

The ALPHEE study assessed three doses of celivarone (50, 100, and 300mg/d) compared with placebo and its primary endpoint was the prevention of sudden death or appropriate ICD interventions (triggered by ventricular tachycardia or ventricular fibrillation). In a fifth arm of the study, amiodarone (200mg/d) was used a calibrator. Kowey explained: “The intention of the calibrator arm was to establish the sensitivity and validity of this patient population.” After a median treatment duration of nine months, 61.5% of patients in the placebo arm had experienced an appropriate ICD intervention or sudden death compared with 67%, 58.8%, 54.9%, respectively, in the celivarone arms (50, 100, 300mg/d). This figure was 45.3% in the amiodarone group. Kowey said: “It was a negative trial on the primary endpoint. We did not see a difference among the groups compared with placebo with regard to the combined primary endpoint of ventricular tachycardia/ventricular fibrillation triggering an intervention or sudden cardiac death. The secondary endpoint was first shock or death from any cause. Again, there was not a statistically significant difference between the celivarone groups and the placebo group.” He added that amiodarone did reduce the secondary endpoint, compared with placebo, by a nearly significant level (p=0.503) and this proved the validity of using amiodarone as a calibrator.

Concluding his presentation of the results, Kowey said: “Celivarone was fairly definitively not found to be effective for the prevention of ICD interventions or sudden cardiac death. An unmet need remains for the prevention of shocks in patients with ICDs. A search for alternative antiarrhythmic drugs and procedures should continue.”

Cynthia Tracy, director of Electrophysiology, Associate Director of Cardiology at the George Washington University Hospital, presented a discussion of the ALPHEE results at the AHA sessions. She said that a possible reason for the failure of the trial was that celivarone was the “daughter” of the antiarrhythmic dronedarone (Multaq, Sanofi Aventis). She added that the trial, although negative, was well designed. “I think it is excellent to present data even if it is a negative trial because it does provide us with a good road map for going forward. It was a very carefully done and very elegant study.”

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