Introduction: The efficacy and safety profiles of the dronedarone were rather praised when the molecule was placed on the market (2009). However, there are today some safety concerns (in particular, risk of liver toxicity) that have led to limit the use of this drug to paroxysmal or persistent atrial fibrillation, and to exclude it from therapy protocols for ventricular tachyarrhythmias. The aim of the present study was to explore some efficacy and safety endpoints concerning dronedarone, by analyzing the evidence derived from quantitative evaluation (meta-analysis) of literature data.
Evidence acquisition: We comprised in the meta-analysis exclusively randomized controlled trials (RCTs) that reported relevant clinical outcomes with dronedarone. In addition, eligible RCTs had to have randomized 100 patients at least in order to have adequate statistical power, and they had to have clearly reported the outcomes of interest. Primary efficacy outcomes were a) all-cause mortality,b) major acute cardiovascular events and c) worsening heart failure. Secondary outcomes of interest were ventricular tachyarrhythmias, stroke and systemic embolism. We performed a number of sensitivity analyses to better ascertain the sources of heterogeneity. We also performed a number of subgroup analyses.
Evidence synthesis: At the end of the selection process, the studies regarded suitable for meta-analysis were seven. Dronedarone use was not associated with any significant advantage as regards all-cause mortality(pooled odds ratio =1.31; 95% CI: 0.78 to 2.18; P= 0.31) and major cardiovascular events (pooled odds ratio=1.45; 95% CI: 0.7 to 3.01; P=0.28), as well as regarding the endpoint" worsening heart failure" (pooled odds ratio =1.32; 95% CI: 0.87 to 2.01; P= 0.20). Moreover, using subgroup analyses, in patients with permanent AF, dronedarone use was associated with increased all-cause mortality compared to placebo(P=0.03),as well as with higher risk of major acute cardiovascular events (P=0.04) and episodes of worsening heart failure(P=0.02). In addition, when data from ATHENA study were excluded, dronedarone use was associated with increased all-cause mortality (post exclusion pooled odds ratio=1.77; 95% CI: 1.15 to 2.72; P=0.0089), increased risk of major cardiovascular events (post exclusion pooled odds ratio=2.16; 95% CI: 1.34 to 3.47; P= 0.0014) and increased risk of worsening heart failure(post exclusion pooled odds ratio= 1.618; 95% CI: 1.14 to 2.3; P=0.006).
Conclusions: In our meta-analysis, dronedarone did not provide any significant benefit with regard to all-cause mortality and major cardiovascular events, as well as regarding the risk of worsening heart failure. Sensitivity analyses then showed that the exclusion of a study, namely ATHENA study, caused a shift in the overall odds ratio, so as to convert the dronedarone use to the ominous role of predictor of higher mortality, worse cardiovascular morbidity and increased risk of worsening heart failure. Thus, dronedarone should be used with caution as second-line medication and exclusively for the secondary prevention of paroxysmal or persistent atrial fibrillation, in patients without signs or symptoms of cardiac decompensation, preferably for limited periods of time and under assiduous clinical and laboratory surveillance.