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ALPHEE: Celivarone no better than placebo for preventing sudden cardiac death, ICD triggering
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AHA Scientific Sessions 2011
ORLANDO, Fla. — When it comes to stabilizing irregular heart rhythms, celivarone and placebo appear to have similar effects in the prevention of sudden cardiac death and unnecessary firings of implantable cardioverter defibrillators, according to results of the ALPHEE trial.
Peter R. Kowey, MD, and colleagues found no differences among high-risk patients randomly assigned to placebo or 50-mg, 100-mg or 300-mg daily doses of celivarone (Sanofi-Aventis). The primary endpoint of ICD intervention or sudden cardiac death was 61.5% in the placebo group vs. 67% in the 50-mg celivarone group, 58.8% in the 100-mg group and 54.9% in the 300-mg group. In a fifth group that received amiodarone, 45.3% experienced ICD intervention or sudden cardiac death.
“It’s somewhat disappointing because we thought we had something promising for a very serious problem,” Kowey, a Cardiology Today Editorial Board member and chief of cardiology at Main Line Health, Philadelphia, Pa., said in a press release.
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Celivarone is an investigational drug for stabilizing irregular heart rhythms. It is biochemically similar to amiodarone and dronedarone (Multaq, Sanofi-Aventis), according to the researchers.
The ALPHEE trial assessed the effects of three doses of celivarone in 486 patients with left ventricular ejection fraction <40% and at least one ICD therapy or implantation for ventricular tachycardia or ventricular fibrillation in the previous month as compared with placebo. Amiodarone was used in the calibrator arm to validate the study design, Kowey said. ALPHEE was started after ICARIOS, the smaller study of ICD patients, completed in 2008 and suggested beneficial effects of celivarone.
In other results, 44% of patients experienced the secondary primary endpoint of ICD shock or death in the placebo group vs. 45% in the 50-mg celivarone group, 37.3% in the 100-mg group, 41.6% in the 300-mg group and 26.4% in the amiodarone group. Examining ICD shocks alone, researchers found no significant differences between celivarone and death, but a significant decrease between amiodarone and placebo (HR=0.333; 95% CI, 0.157-0.706).
Six patients died of sudden cardiac death, but differences between the groups were not significant.
The tolerability of celivarone was satisfactory, Kowey said. The drug was well tolerated at all three doses. In addition, serious adverse events and deaths did not occur at a rate different from placebo.
“An unmet medical need remains for the prevention of shocks in patients with ICD. A search for alternative antiarrhythmatic drugs and procedures for this indication should continue, Kowey said at a press conference.
“We are very proud of the [ALPHEE] study because we think it is statistically valid and important to present negative trial results and to do it reasonably fast after the trial ends,” he said. “This study provides a template we can use in the future for the development of alternative antiarrhythmic drugs for this very important indication.” – by Casey Murphy and Katie Kalvaitis
For more information:
- Kowey PR. LBCR.03. Presented at: the American Heart Association Scientific Sessions 2011; Nov. 12-16, 2011; Orlando, Fla.
- Kowey PR. Circulation. 2011;doi:10.1161/CIRCULATIONAHA.111.072561.
Disclosure: Dr. Kowey reports receiving consulting and lecture fees and honoraria from Sanofi-Aventis.
The methodology of ALPHEE is excellent. It provides us a way of evaluating antiarrhythmic drugs, not just evaluating antiarrhythmic drugs in the setting of patients with ICDs, although this is where it belongs. We cannot, at this point, justify doing trials without an ICD in place, so testing an antiarrhythmic [drug] for efficacy becomes problematic. We need the ICD in place as a backup.
Cynthia Tracey, MD
Director of
electrophysiology
Associate director of cardiology
George Washington
University Hospital
Disclosure: Dr. Tracey reports no relevant financial disclosures.
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The ALPHEE study is very timely and appropriate at this stage of ICD maturation and development. ICD shocks are not only painful and associated with impaired quality of life, but the literature also suggests that their delivery negatively impacts survival. Thus, interventions that decrease therapy delivery have the potential to improve a variety of outcomes. The patients studied by Dr. Kowey and colleagues are exactly those about whom we are concerned and are also representative of those who have been in clinical trials of defibrillators. The patients were mostly men; their mean age was 64 years, which is exactly as in every other trial that has been published for the last 30 years; and their ejection fractions were importantly depressed at 29%.
Although the results are at one level disappointing because celivarone alone was not different from placebo in preventing ICD interventions and death, it does reemphasize the importance of continuing investigations to find methods for decreasing appropriate and inappropriate ICD shocks to improve outcomes. We know the ICD is an outstanding therapy to prevent death, but we can always find ways to enhance its efficacy with ancillary prescriptions whether they are for a drug or some other therapy.
There is much more that needs to be done; we shouldn’t rest on our laurels. Given the track record for drugs being either ineffective or associated with serious adverse effects in this arena, it again raises the question of whether ablation can be used prophylactically to decrease shocks in the future.
Andrew E. Epstein, MD
Cardiology
Today Editorial Board member
Disclosure: In the past, Dr. Epstein has been an advisor for and involved in clinical trials for Sanofi-Aventis.
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