AHA: PALLAS shows dronedarone is harmful in permanent AF patients
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PALLAS, which was terminated for safety reasons on July 5 at the recommendation of the study’s data monitoring committee, was a randomized, double-blind, controlled clinical trial designed to test whether dronedarone (Multaq, Sanofi-Aventis) reduced major vascular events in patients with permanent AF. PALLAS trial researchers hypothesized that dronedarone would prove beneficial to permanent AF patients after the drug was found in ATHENA and other trials to prevent recurrences of AF and reduce cardiac death, arrhythmic death and stroke in patients with paroxysmal and persistent AF.
“This [permanent AF] is a patient population with high-burden vascular events and for whom there previously have been very few clinical trials and no very promising therapies,” said Stuart J. Connolly, MD, study chair and director of the division of cardiology at McMaster University and a cardiologist with the Population Health Research Institute, both in Hamilton, Ontario. He presented results from the study at a late-breaking clinical trials session; the study was simultaneously published online in the New England Journal of Medicine.
The study enrolled 3,236 patients who were 65 years and older who had a history of permanent AF for at least six months and risk factors for major vascular events. Patients with severe heart failure symptoms, recent unstable NYHA Class III, bradycardia or an implantable cardioverter-defibrillator were excluded. The two co-primary outcomes were a composite of vascular events (stroke, MI, systemic embolism, cardiac death) or unplanned cardiovascular hospitalization or death.
Patients were randomized to either a dronedarone group with a dose of 400 mg twice daily (1,619 patients) or a placebo group (1,617 patients). Median follow-up was 3.5 months.
“We originally planned to enroll almost 11,000 patients and follow them up for two years,” Connolly said. The final cohort was high-risk with many comorbidities, he added.
Some 43 patients in the dronedarone group and 19 in the control group experienced a first co-primary outcome, including 25 deaths and 23 strokes vs. 13 deaths and 10 strokes in the control group. “There was about a doubling in the rate of events and that was highly statistically significant,” he said.
The second co-primary outcome also favored the control group, with 127 events in the dronedarone group compared with 67 in the control group. “We see an almost doubling in the rate of an unplanned cardiovascular hospitalization or death,” Connolly said. “Again, this is highly statistically significant. In the ATHENA trial this was reduced by about 25 percent, a rather shocking difference between the results of this trial and the previous ATHENA trial.”
An analysis of adverse events found a higher percentage in any adverse event (49.4 percent for the dronedarone group vs. 37.3 percent for the control group) and higher percentages in the dronedarone group for each individual adverse event. These side effects led to an increased rate of discontinuation of the drug, he noted.
“It is clear from our data that dronedarone should not be used in patients with permanent atrial fibrillation who have a high burden of vascular disease,” he said.
N.A. Mark Estes III, MD, director of the New England Cardiac Arrhythmia Center at Tufts Medical Center in Boston reviewed results from previous trials that included dronedarone and noted the favorable findings in ATHENA for patients with paroxysmal or persistent AF led to the drug’s FDA approval to reduce rehospitalization in that patient population.
“The critical question that comes up based on the PALLAS study is, do the unfavorable results of the PALLAS study obtained in patients with permanent AF also apply to patients who are using dronedarone for the approved indication?” Guidelines published this year included dronedarone as indicated, he said.
“These guidelines apply, with caveats,” Estes said. He pointed to differences in ATHENA and PALLAS, including the AF type, age, comorbidities and disease burden. “Clearly, dronedarone should not be used with patients with heart failure or permanent AF,” he said. “Currently I think patients who fit the ATHENA trial should be monitored regularly, at least every six months, to ensure they remain within the approved indication and do not progress to permanent afib or a new or worsening heart failure.”
He recommended physicians who begin a regime using dronedarone also monitor their patients for the same reason, an approach that several panelists agreed was appropriate.
Sanofi-Aventis sponsored the PALLAS study.