Safety and Efficacy of Dronedarone From Clinical Trials to Real-world Evidence

Implications for Its Use in Atrial Fibrillation

Giuseppe Boriani; Carina Blomström-Lundqvist; Stefan H. Hohnloser; Lennart Bergfeldt; Giovanni L. Botto; Alessandro Capucci; Ignacio Fernández Lozano; Andreas Goette; Carsten W. Israel; José L. Merino; A. John Camm


Europace. 2019;21(12):1764-1775. 

In This Article

Abstract and Introduction


Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone–digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban–dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban–dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.


Dronedarone is a non-iodinated benzofuran developed specifically for the treatment of atrial fibrillation (AF), designed to retain the efficacy of amiodarone, but with an improved safety profile. Dronedarone was approved in the European Union (EU) for rate and rhythm control of AF in 2009, following placebo-controlled trials in patients with AF (EURIDIS, ADONIS, ERATO, and ATHENA), and in comparison to amiodarone (DIONYSOS). The ATHENA trial showed that dronedarone significantly reduced the composite endpoint of cardiovascular (CV) hospitalization or all-cause death in patients with paroxysmal or persistent AF [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.69–0.84; P < 0.001] vs. placebo (Table 1).[1]

The efficacy of dronedarone in maintaining sinus rhythm (SR) was shown in the ADONIS and EURIDIS trials, with dronedarone reducing the risk of adjudicated AF recurrence by 26% (P = 0.02) and 29% (P = 0.006) vs. placebo from day 5 to 12 months post-randomization, respectively.[3] Rhythm control is an important factor for the quality of life (QoL) of patients with AF, therefore, it may be preferable compared with rate control.[10] Along with this, the prospective, open-label IMPULS study showed that after 12 months of treatment with dronedarone in 342 patients with paroxysmal or persistent AF, QoL was improved vs. baseline by +16.0 ± 23.5 points (P < 0.0001), as measured by the psychological domain of the AF-QoL questionnaire. The percentage of patients in SR increased from 44.6% at baseline to 70.2% at 12 months following dronedarone treatment.[11] Similarly, in a recent observational study of 824 Taiwanese patients with paroxysmal or persistent AF, dronedarone improved QoL following 6 months of treatment, as demonstrated by an increase in total score from 67.5 ± 15.1 (baseline) to 74.6 ± 11.5 (6 months) in an AF Effect on Quality of Life questionnaire.[12] Notably, two recent randomized controlled trials (RCT), CABANA and CAPTAF, found that catheter ablation resulted in greater improvements in QoL of patients with symptomatic AF compared with antiarrhythmic drug (AAD) therapy at 12 months, with the limitation that no sham-ablation procedure was performed in the AAD treatment arm.[13,14] However, in the CAPTAF trial, it could be demonstrated that the greater improvement in QoL was directly related to a greater reduction in AF burden in the ablation vs. AAD arm.[14]

While dronedarone was designed to have a better safety profile than amiodarone, results from RCTs identified safety concerns in selected patient populations. The ANDROMEDA study indicated that dronedarone was not safe in patients with recently decompensated severe heart failure (HF), and the PALLAS trial raised safety concerns in patients with permanent AF. These studies led to the contraindication of dronedarone in patients with permanent AF and in patients with symptoms of HF in the EU. The potential effects of dronedarone on liver function resulted in the European Medicines Agency (EMA) issuing warnings and requiring monthly liver function tests (LFT) for the first 6 months of treatment, followed by a reduced frequency thereafter. In addition, concerns were raised about potential drug–drug interactions between dronedarone and direct oral anticoagulants (DOAC).

New post-approval studies on the safety and efficacy of dronedarone have been completed, and the results of these studies and their place in the context of past trials is the subject of this review.