Dronedarone increases risk for death in permanent AF
MedWire News: The Permanent Atrial Fibrillation Outcomes Study Using Dronedarone on Top of Standard Therapy (PALLAS) study shows that dronedarone increases rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation (AF).
In this randomized trial comparing dronedarone to placebo in patients aged 65 years and older with permanent AF, dronedarone more than doubled the risk for stroke and death from cardiovascular causes.
"In patients with permanent atrial fibrillation and major risk factors for vascular events, dronedarone increased both PALLAS primary outcomes," principal investigator Stuart Connolly (McMaster University, Hamilton, Ontario, Canada) told delegates at the American Heart Association scientific sessions in Orlando, Florida.
"This was due to increases in death, heart failure, and stroke. There was an increased rate of discontinuation of dronedarone due to adverse events. Dronedarone should not be used in this patient population."
Dronedarone was shown in the Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation (ATHENA) trial to reduce the incidence of the primary outcome of unplanned hospitalizations for cardiovascular causes or death in patients with intermittent AF. The anti-arrhythmic drug was also associated in that trial with significant reductions in rates of death from cardiovascular causes, stroke, and of hospitalizations for acute coronary syndrome.
The PALLAS trial was designed to see whether dronedarone would have benefits similar to those seen in ATHENA in patients with permanent AF at high risk for vascular events.
Patients age 65 and older with permanent AF and at least one major risk factor (history of coronary artery or peripheral artery disease, history of stroke or transient ischemic attack, heart failure hospitalization within the past year or a left ventricular ejection fraction <40%, or age 75 years and older with both hypertension and diabetes) were enrolled.
The participants were randomly assigned to receive either dronedarone 400 mg twice daily (5400 patients) or placebo (5400 patients). The trial was stopped for safety just shy of 1 year after the start of enrollment. By that time, 3326 patients had been enrolled, with a median follow-up of 3.5 months.
The co-primary outcomes were a composite of stroke, myocardial infarction, systemic embolism, or cardiovascular death; and unplanned cardiovascular hospitalization or death (the ATHENA primary endpoint). The first of these endpoints occurred in 2.7% of the dronedarone group versus 1.2% of the placebo group (hazard ratio [HR]=2.29, p=0.002) and the second occurred in a corresponding 7.8% versus 4.1% (hazard ratio=1.95, p<0.001).
The investigators also looked at the individual components of the primary outcome and found significantly greater incidences of death (25 on dronedarone vs 13 on placebo, HR=1.94, p=0.049), cardiovascular death (21 vs 10, HR=2.11, p=0.049), arrhythmia death (13 vs 4, HR=3.26, p=0.03), unplanned cardiovascular hospitalizations (113 vs 59, HR=1.97, p<0.001), and heart failure hospitalizations (43 vs 24, HR=1.81, p=0.02).
In a simultaneous publication of the data in the New England Journal of Medicine, the investigators note that unlike ATHENA, which enrolled patients with paroxysmal or persistent AF, PALLAS enrolled patients with permanent AF, which is very unlikely to convert to a sinus rhythm.
"We can hypothesize that for high-risk patients with permanent atrial fibrillation, direct and indirect toxic effects of dronedarone are not offset by the benefits of maintaining sinus rhythm, and any benefits that might occur from heart-rate slowing, blood-pressure reduction, anti-adrenergic action and suppression of ventricular arrhythmia were either small or non-existent," they conclude.
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By Neil Osterweil