Abstract & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco does research for Medtronic, is a consultant for Medtronic, Novartis, and St. Jude, and is a speaker for Boston Scientific.
Source: Connolly SJ, et al, for the PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;15;365: 2268-2276.
Dronedarone was approved by the FDA in the United States for the treatment of patients with atrial fibrillation (AF) several years ago. FDA approval was largely based on the results of the ATHENA trial, which reported that dronedarone reduced the primary outcome of unplanned hospitalization for cardiovascular causes or death with significant reductions in cardiovascular deaths, stroke, and hospitalization for acute coronary syndromes. In ATHENA, post-study subgroup analysis indicated that even patients who were in AF at all visits showed benefit. This observation led to the design and conduct of the current study. Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top of Standard Therapy (PALLAS) was designed to test whether dronedarone would reduce major cardiovascular events in patients with permanent AF. Patients were eligible for enrollment if they had permanent AF that had been present for at least 6 months. Eligible patients also had to be at least 65 years of age with one or more of the following risk factors: coronary artery disease, prior stroke of TIA, congestive heart failure (class II or class III or recent admission), a depressed left ventricular ejection fraction, and peripheral arterial disease. Patients older than 75 years of age with hypertension and diabetes were also eligible. Patients were randomly assigned to receive either dronedarone (400 mg twice daily) or matching placebo. Patients were then followed clinically. The first co-primary outcome was a composite of stroke, myocardial infarction, systemic embolism, and death from cardiovascular causes. The second co-primary outcome was unplanned cardiovascular hospitalization or death.
Study enrollment began on July 19, 2010. On July 5, 2011, the study was terminated for safety reasons by the Data Monitoring Committee. At that time, a total of 3236 patients had undergone randomization with a median follow-up of 3.5 months. The patients had a mean age of 75 years and almost 70% had been in permanent AF for more than 2 years. Resting ventricular rates at baseline were well controlled in both groups. The mean CHADS2 score was elevated at 2.9. A slightly higher proportion of patients converted to sinus rhythm during dronedarone therapy, 23 of 621 patients (3.7%), compared to 9 of 638 patients (1.4%) in the placebo group. Mean heart rate was reduced by 7.6 ± 14.5 bpm in the dronedarone group and remained stable in the placebo group. The systolic blood pressure was slightly decreased and the mean corrected QT interval was slightly increased by dronedarone. Serum digoxin concentrations also increased on dronedarone. Before termination of the study, study medication had been permanently discontinued in 21% of 348 dronedarone patients compared to 11% of 178 patients in the placebo group. The first co-primary outcome occurred in 43 patients receiving dronedarone and in 19 patients receiving placebo for a hazard ratio (HR) of 2.29, P = 0.002. The second co-primary outcome occurred in 127 patients receiving dronedarone compared to 67% receiving placebo (HR 1.95, P < 0.001). Overall, there were 25 deaths in the dronedarone group and 13 in the placebo group. Cardiovascular deaths were noted in 21 dronedarone patients compared to only 10 placebo patients. Stroke occurred in 23 patients in the dronedarone group compared to 10 in the placebo group (HR 2.32, P = 0.02). Unplanned cardiovascular hospitalizations were also more common in patients receiving dronedarone (HR 1.97, P < 0.001). Other drug-related adverse events included diarrhea, nausea and vomiting, dyspnea, and bradycardia. An elevation of alanine aminotransferase occurred in 21 patients receiving dronedarone (1.5%) compared to 7 (0.5%) receiving placebo. The increased risk for dronedarone on the two co-primary composite outcomes was consistent across all subgroups analyzed.
The authors conclude that among high-risk patients with permanent AF, direct and indirect toxic effects of dronedarone lead to adverse clinical events. There is no apparent benefit of dronedarone in patients who remain in permanent AF.
The market release of dronedarone in 2009 was welcomed by most physicians who treat patients with AF. Although data suggested that dronedarone might not be as potent as amiodarone in suppressing recurrent AF, the drug appeared to be very well tolerated. The ATHENA trial, the largest antiarrhythmic drug trial ever performed, was also the first trial in which an antiarrhythmic drug was associated with decreased hospitalizations and mortality. Over the last 2 years, however, most of the new data about dronedarone has been negative. There have been at least two cases of fulminant hepatic failure in patients on dronedarone, and liver function test monitoring is now recommended. Interactions with other compounds, including dabigatran, via P-glycoprotein inhibition, were reported. Now the PALLAS study raises questions about cardiac and vascular safety and seems to contradict the favorable results seen in ATHENA.
The mechanisms responsible for the adverse events seen in PALLAS are not known. The authors speculate about the role of increased digoxin levels but only about one-third of the patients in PALLAS were taking digoxin. Dronedarone does lower heart rate during AF and it's possible that lower heart rates may not always be beneficial. Dronedarone might also convert some patients from continuous to intermittent AF and the resulting instability may have adverse consequences.
For now, both the European and U.S. regulators have left dronedarone on the market. However, in my personal practice, I will now restrict it to patients with either no structural heart disease or only uncomplicated, mild hypertension.Dronedarone was approved by the FDA in the United States for the treatment of patients with atrial fibrillation (AF) several years ago.
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