Author + information
- Thorsten Lewalter, MD⁎ ()
- ↵⁎University of Bonn, Academic Hospital, Heart, Vascular, and Arrhythmia Center Rhineland-Bonn, Department of Internal Medicine, St. Marien-Hospital Bonn, Robert-Koch-Str. 1, Bonn 53115, Germany
In ATHENA (A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation), dronedarone was shown to reduce morbidity and cardiovascular mortality in patients with atrial fibrillation (AF) who had additional risk factors for death (1). Available antiarrhythmic drugs are limited by a lack of effect on reducing morbidity and their potential for serious proarrhythmia or extracardiac toxic effects. However, no morbidity and mortality end point trial is available for a direct comparison.
Every effort to quantify the relative efficacy and safety of dronedarone is welcome to define its role in improving the prognosis of patients with AF. In the September 15 issue of the Journal (2), a meta-analysis was published showing that dronedarone is less effective than amiodarone in maintaining sinus rhythm while showing a trend toward reduced mortality and fewer adverse events.
A careful exploration, however, reveals a number of inconsistencies:
1. Particularly evident is the reported lack of efficacy of dronedarone for the prevention of recurrent AF (odds ratio: 0.79; 95% confidence interval: 0.33 to 1.87). This result is largely based on EURIDIS (EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenance of Sinus rhythm)/ADONIS (American-Australasian trial with DronedarONe In atrial fibrillation or flutter patients for the maintenance of Sinus rhythm) trials (3) for which Piccini et al. (2) reported a trend for an increased recurrence with dronedarone (Fig. 2A of their paper ; odds ratio: >1). However, this is not consistent with the original publication (hazard ratio: 0.75; 95% confidence interval: 0.65 to 0.87). Piccini et al. (2), in recalculating the results, obviously falsely used the number of patients at 12 months, excluding those with a drug exposure of <5 days. This error has a direct impact on the overall reported relative efficacy of dronedarone and amiodarone, resulting in a more favorable odds ratio for amiodarone and a lower number of AF recurrences.
2. In DAFNE (Dronedarone Atrial FibrillatioN study after Electrical Cardioversion) (4), 90% of 48 patients receiving placebo and 65% of 54 patients receiving dronedarone (800 mg) had recurrence of AF at 6 months. Piccini et al. (2) extrapolated these numbers to the group size of the safety population (placebo n = 66, dronedarone 800 mg n = 76), which is not feasible.
3. In ATHENA, 290 of 2,291 patients taking dronedarone and 187 of 2,313 patients taking placebo discontinued treatment because of adverse events. Piccini et al. (2) related these discontinuations to the 2,301 and 2,327 patients of the intention-to-treat population. However, 10 patients randomized to dronedarone and 14 randomized to amiodarone never received the study drug.
4. Piccini et al. (2) restricted data of GEFACA (Grupo de Estudio de Fibrilación Auricular Con Amiodarona) (5) to patients with successful cardioversion only, whereas all patients including those with unsuccessful cardioversion were considered for DAFNE.
5. In SAFE-T (Sotalol Amiodarone Atrial Fibrillation Efficacy Trial) (6), patients were not considered in whom AF recurred within the first 28 days. Therefore, the data used for the meta-analysis are likely to overestimate the effect of amiodarone on reducing the recurrence of AF.
Further to these obvious discrepancies, the Methods section fails to report whether important variables like the mean duration of follow-up; differences in the proportion of paroxysmal, persistent, and permanent atrial fibrillation; and anticoagulation use have been accounted for in the analyses.
Taken together, false aggregation of available randomized clinical trials has led to an underestimation of the true antiarrhythmic effect of dronedarone and should be corrected. However, it cannot be overemphasized that sinus rhythm maintenance in patients with AF might not translate into better outcomes and survival as demonstrated in trials like the PIAF (Pharmacological Intervention in Atrial Fibrillation) trial (7), CTAF (Canadian Trial of Atrial Fibrillation) (8), and AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) (9). Therefore, it is time for a reappraisal of end points in the treatment of AF that should focus on true patient-related benefits like hospital stays and cardiovascular and cerebrovascular events (10).
- American College of Cardiology Foundation
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