After a brief announcement earlier this year that the trial had been terminated early, the full results of PALLAS (Permanent Atrial Fibrillation Outcomes Study Using Dronedarone on Top of Standard Therapy) have now been presented at the AHA and published simultaneously in the New England Journal of Medicine. PALLAS shows that dronedarone (Multaq, Sanofi) should not be used in patients who have permanent atrial fibrillation (AF). The larger question, which the trial can’t answer, is whether anyone else should be taking the drug.
3236 elderly patients with permanent AF were randomized to dronedarone or placebo. The study was stopped for safety reasons by the data monitoring committee less than a year after enrollment began.
A first coprimary outcome (stroke, MI, systemic embolism, or cardiovascular death) event occurred in 43 dronedarone patients versus 19 placebo patients (HR 2.29, CI 1.34-3.94, p=0.002):
- CV deaths: 21 versus 10 (HR 2.11, CI 1.00-4.49, p=0.046
- death from arrhythmia: 13 vs 4 (HR 3.26, CI 1.06-10.00, p=0.03)
- stroke: 23 versus 10 (HR 2.32, CI 1.11-4.88, p=0.02)
In addition, there were 113 hospitalizations for CV causes in the dronedarone group versus 59 in the placebo group (HR 1.97, CI 1.44-2.70, p=0.001).
The investigators wrote that although the early termination of PALLAS diminished its statistical power, “the assessment of net harm from dronedarone in patients with permanent atrial fibrillation who are at high risk appears to be sound.”
Seeking to explain the difference in outcome between their study and the positive ATHENA study, the authors noted that patients in PALLAS were older and more likely to have heart failure, coronary artery disease, or stroke. A subgroup analysis, however, did not turn up a worse prognosis for the high risk patients in PALLAS.
Very few patients in PALLAS converted to sinus rhythm. The authors speculated that “for high-risk patients with permanent atrial fibrillation, direct and indirect toxic effects of dronedarone are not offset by the benefit of maintaining sinus rhythm, and any benefits that might occur from heart-rate slowing, blood-pressure reduction, antiadrenergic action, and suppression of ventricular arrhythmia were either small or nonexistent.”
In an accompanying editorial, Stanley Nattel writes that “it is possible” that the adverse effects of dronedarone in PALLAS “were due to the fact that all the participating patients had permanent atrial fibrillation,” but “in the final analysis, we can not really know for sure.” Dronedarone, he said, should not be used in patients with permanent AF and should be avoided in high-risk patients with nonpermanent AF, particularly those with heart failure. Use of dronedarone, he writes, should be reserved “for selected low-risk patients with persistent or paroxysmal atrial fibrillation, possibly those in whom other antiarrhythmic drugs have failed.”