SAN FRANCISCO — An investigational agent, dronedarone, reduced by 24% the risk of hospitalization for cardiovascular problems or death from any cause in moderate- to high-risk patients with atrial fibrillation or flutter in the largest study of any antiarrhythmic medication for atrial fibrillation.
A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation (ATHENA trial) randomized 4,628 patients at 551 sites in 37 countries to treatment with dronedarone 400 mg b.i.d. or placebo, with a follow-up of at least 1 year. The overall rate of treatment-related adverse events did not differ between groups, and 30% in each group discontinued treatment prematurely, Dr. Stefan H. Hohnloser reported at the annual meeting of the Heart Rhythm Society.
The results have raised hopes that physicians may soon have a safer alternative to amiodarone for treating atrial fibrillation. Dronedarone's mechanism of action is similar but without the iodine moiety of amiodarone, which can cause hyperthyroidism, among the drug's other side effects.
The study was funded by Sanofi Aventis, which makes dronedarone.
The drug also showed significant benefits compared with placebo in several predefined secondary outcomes, including a 29% reduction in deaths from cardiovascular causes, a difference that mainly was due to a significant 45% decrease in the risk of cardiac arrhythmic deaths, said Dr. Hohnloser, lead investigator in the study and professor of medicine at J.W. Goethe University, Frankfurt, Germany. He has no association with Sanofi Aventis other than receiving research funding.
There was no significant difference between groups in cardiac nonarrhythmic deaths.
Cardiovascular-related hospitalizations were reduced 29% in the dronedarone group compared with placebo, mainly because of a 37% decrease in admissions to treat atrial fibrillation and a 30% reduction in admissions to treat acute coronary syndromes.
The study enrolled patients with paroxysmal or persistent atrial fibrillation who were at least 75 years of age or were at least 70 years of age with one or more additional risk factors, such as drug treatment for hypertension, diabetes, prior stroke or transient ischemic attack, enlarged left atrium, or depressed left ventricular function.
The cohort represents “the typical elderly atrial fibrillation population at risk for hospitalization,” Dr. Hohnloser noted. The mean age was 72 years, and 47% were female. At randomization, 25% were in atrial fibrillation, 60% had structural heart disease, 86% were being treated for hypertension, 30% had coronary artery disease, 16% had valvular heart disease, and 6% had nonischemic cardiomyopathy. A history of New York Heart Association (NYHA) functional class II or III was found in 21%, and 12% had ejection fractions below 45%. Only 6% were so-called lone atrial fibrillators.
The study excluded patients with recently decompensated heart failure or NYHA class IV heart failure, among others, because a previous study of dronedarone in heart failure was cancelled prematurely when it became clear that more patients on dronedarone were dying.
In the ATHENA trial, the beneficial effects of dronedarone for the treatment of atrial fibrillation or flutter held steady across clinically important subgroups, with no difference on the basis of the presence or absence of class II or III heart failure, age, gender, or ejection fractions if divided into quartiles. Results also did not vary by the presence or absence of structural heart disease or of atrial fibrillation at baseline, or by the use of some antihypertensive agents.
At baseline, medication use was similar between groups, with 71% on β-blockers, 70% on ACE inhibitors, 39% on statins, 60% on vitamin K antagonists for anticoagulation therapy, and 44% on antithrombotic therapy with aspirin.
Side effects were seen in 69% of patients on placebo and 72% on dronedarone. Only GI side effects were significantly more common with dronedarone (26%), compared with placebo (22%).
No differences were seen in skin-related side effects, thyroid-related events, or serious adverse events. Dronedarone interferes with the tubular secretion of creatinine, which produced a 5% increase in blood levels of creatinine, compared with a 1% increase on placebo.
Sanofi Aventis plans to resubmit a new drug application to the Food and Drug Administration and a dossier to the European Medicines Agency in late 2008 based on the ATHENA data. The FDA in August 2007 turned down a request for approval that had relied on two previous trials using a combined end point of all-cause hospitalizations or deaths.
The ATHENA trial's primary combined end point of cardiovascular-related hospitalizations or all-cause mortality has never been used in studies of antiarrhythmic agents, which is why the company chose to compare dronedarone with placebo. A separate comparison with amiodarone is ongoing—the Efficacy and Safety of Dronedarone Versus Amiodarone for Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation (DIONYSOS) trial.