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Dronedarone in High-Risk Permanent Atrial Fibrillation
Study Questions:
Does dronedarone improve outcomes in high-risk patients with permanent atrial fibrillation (PermAF)?
Methods:
In PALLAS (Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy), a multicenter double-blind study, patients with PermAF for ≥6 months, age ≥65 years, and ≥1 risk factor (coronary artery disease, class II-III heart failure, left ventricular ejection fraction ≤40%, peripheral artery disease, or the combination of age ≥75 years, hypertension, and diabetes) were randomly assigned to receive dronedarone, 400 mg twice daily, or a matching placebo. The primary outcome was a composite of stroke, myocardial infarction, systemic embolism, or cardiovascular death. The intended enrollment was 10,800 patients.
Results:
The study was terminated for safety reasons after enrollment of 3,236 patients (mean age 75 years). The median follow-up was 3.5 months. Compared to placebo, dronedarone significantly reduced the mean heart rate by 7 bpm and increased the corrected QT by a mean of 6 ms. Dronedarone was associated with significant increases in the incidence of the primary outcome (hazard ratio [HR] 2.29), death (HR 1.94), cardiovascular death (HR 2.11), arrhythmic death (HR 3.26), stroke (2.32), and hospitalization for heart failure (HR 1.81).
Conclusions:
The authors concluded that dronedarone increases the risk of death, stroke, and heart failure in high-risk patients with PermAF.
Perspective:
The results of the ATHENA trial suggested that dronedarone has benefits aside from restoration of sinus rhythm, for example heart rate slowing, blood pressure reduction, adrenergic blockade, or suppression of ventricular arrhythmias. This was the rationale for the present study, in which the patients were expected to remain in AF. The mechanisms by which dronedarone worsened outcomes are unclear, but could include a negative inotropic effect, ventricular proarrhythmia, and/or an increase in serum digoxin level.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure
Keywords: Stroke, Heart Failure, Atrial Fibrillation
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