In reviewing “all available evidence on the cardiovascular safety” of dronedarone, Dr. Saurav Chatterjee and colleagues found evidence of increased cardiovascular risk with the drug, regardless of duration of use and across a wide spectrum of clinical cardiovascular conditions.
Dronedarone is a novel antiarrhythmic, with an electropharmacologic profile closely resembling that of amiodarone, but with a shorter half-life and structural differences minimizing the adverse effects of amiodarone. The US Food and Drug Administration approved dronedarone in July 2009 to reduce rehospitalizations in atrial fibrillation (AF) patients in sinus rhythm with a history of paroxysmal or persistent AF.
In the ATHENA trial, dronedarone 400 mg bid decreased the incidence of the primary outcome of unplanned hospitalization for cardiovascular causes or death. Significant decreases in rates of death from cardiovascular causes and stroke were also seen.
However, in the subsequent PALLAS trial, dronedarone increased rates of stroke, heart failure, and death from cardiovascular causes in patients with permanent AF and cardiovascular risk factors, prompting the FDA to undertake a cardiovascular safety review of the drug.
In January 2011, the agency revised the label on dronedarone to reflect the risk of heart problems, including death, for patients with irregular heart rhythms. The agency said the drug should not be used by patients who have permanent AF. For these patients, the drug doubles the rate of cardiovascular death, stroke, and heart failure, the FDA said. (See Reuters Health story Dec. 19, 2011).
Dr. Chatterjee and colleagues conducted their own cardiovascular safety assessment of dronedarone across the spectrum of patient populations in which it has been tested by performing a systematic review and meta-analysis of seven randomized controlled trials.
These trials included a total of 10,676 patients and compared dronedarone to comparators in atrial fibrillation/heart failure. Comparators included standard medical therapy and/or placebo and amiodarone in one study. Outcomes assessed were all-cause mortality, cardiovascular mortality, ventricular arrhythmias, embolic events, acute coronary syndrome, heart failure exacerbations, and hospitalization rates in the intervention versus comparator group at the end of at least three months follow-up.
The researchers report that dronedarone was associated with a trend toward worse all-cause-mortality (p=0.28), with significant heterogeneity stemming from the ATHENA trial. When data from this trial were excluded, dronedarone treatment was associated with worse all-cause mortality (p=0.009) and cardiovascular mortality (p=0.0002), without any heterogeneity, the researchers say.
An exploratory analysis excluding patients with heart failure (by excluding the ANDROMEDA) trial “removed the statistical significance of all-cause mortality (with a nonsignificnat trend toward worse outcomes) but maintained the significance of cardiovascular mortality, without any heterogeneity (p=0.008).”
Similarly, on excluding patients with permanent AF by excluding the PALLAS data, the dronedarone group still had a trend toward worse outcomes for all-cause mortality and a statistically significant worse cardiovascular mortality (p=0.02).
When the researchers considered dronedarone use in trials that included paroxymal and persistent AF and excluded permanent AF, they still didn’t find an all-cause mortality benefit with dronedarone use (p=0.15). However, in this subgroup of patients, dronedarone did seem to confer a benefit in cardiovascular mortality (p=0.04), they report.
Treatment with dronedarone showed a trend toward an increased risk of heart failure (p=0.20), significant heterogeneity. However, the results became significantly worse on exclusion of ATHENA data (p=0.008) and the difference persisted even after exclusion of the ANDROMEDA data (p=0.004).
All other secondary outcomes of interest except acute coronary syndromes (encompassing unstable angina and myocardial infarction) such as ventricular tachyarrhythmias, stroke and systemic embolism, and rehospitalizations also showed trends toward worse outcomes but were not statistically significant, the researchers report. Dronedarone did, however, decrease rehospitalization rates when used only in patients with paroxysmal or persistent AF (p=10.001).