Author + information
- Stuart J. Connolly, MD and
- Stefan H. Hohnloser, MD⁎ ()
- ↵⁎Division of Clinical Electrophysiology, J. W. Goethe University Hospital, Theodor-Stern-Kai 7, D 60590 Frankfurt, Germany
Recently in the Journal, Singh et al. (1) emphasized the modest efficacy of dronedarone as a rate and rhythm control agent for atrial fibrillation (AF), questioned its safety, and concluded that it is not an important clinical advance. The rate and rhythm control effects of dronedarone have been extensively studied and consistently demonstrated across studies and populations (2–4). Although dronedarone is less effective against AF recurrence than amiodarone in persistent AF (5), this was not the point of the ATHENA (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) (6). For the first time, a large, randomized, controlled trial has shown that an antiarrhythmic therapy can go beyond symptom control by reducing important cardiovascular outcomes. The ATHENA trial clearly demonstrated that dronedarone decreases its primary outcome of cardiovascular hospitalization or death, with consistent findings across all important subgroups (6). Although the primary outcome was driven mostly by a reduction in cardiovascular hospitalization, nonetheless, the mortality reduction was consistent with the overall benefit. Arrhythmic deaths were reduced without evidence that other causes of death were increased, and the study also observed statistically significant reductions in cardiovascular death and stroke (7). Although these findings need to be confirmed in future clinical studies, these observed reductions in the ATHENA trial nonetheless support the general conclusion that dronedarone provides an important clinical benefit in patients with AF (6,7). Reducing unplanned hospitalizations for AF and other cardiovascular causes is not a small matter. Not only has cardiovascular hospitalization been shown to be a strong predictor of subsequent mortality (8), but also unplanned hospitalizations, usually through emergency rooms, are widely acknowledged to be serious adverse events.
Can we rely on the results of the ATHENA trial, a global, multicenter, double-blind, placebo-controlled, randomized clinical trial? Total mortality was not significantly reduced; however, the study was not powered to demonstrate such a benefit. The ATHENA trial was designed to have only enough deaths to exclude an important increase in mortality, which it did, with consistent findings across all important subgroups (6). In fact, the ATHENA trial has more clearly demonstrated the safety of dronedarone than has ever been previously achieved for any other antiarrhythmic drug. Cardiovascular death reduction is a very important finding that not only is consistent with the other benefits of dronedarone, but also was 1 of 3 secondary outcomes pre-specified. Should we discount this finding because Singh et al. (1) are concerned that increased enrollment from 4,300 to 4,600 patients might have been influenced by knowledge of emerging trends in treatment effects, even though this was a double-blind study? The protocol changes made during the ATHENA trial were carried out without knowledge of any emerging treatment effects and were performed to achieve the protocol-specified goal of having 260 deaths, the required number pre-specified to exclude an important increase in total mortality. The reduction in cardiovascular hospitalization is clearly one of the pivotal findings of the ATHENA trial. Should we, as Singh et al. (1) suggest, discount this because events were not adjudicated by an external committee? Although adjudication would have increased the precision of the outcome, it would not have affected the validity of the observation that dronedarone reduces cardiovascular hospitalization. This is because investigators and patients were blinded to treatment, so there was virtually no chance for bias. Although we have observed some variation in rates of cardiovascular hospitalization between regions, the treatment effect of dronedarone was highly consistent in all regions studied (9).
Should we be concerned that we still do not fully understand the mechanisms whereby dronedarone reduces cardiovascular hospitalization and other vascular events? Some mechanisms are obvious—rate and rhythm effects slow heart rate and improve a variety of cardiovascular conditions, which are adversely affected by high rates. Blood pressure-lowering and vasodilating and possible ventricular antiarrhythmic effects may turn out to be important. Future studies will help us to understand these effects.
The meta-analysis presented by Singh et al. (1) of 6 dronedarone trials suffers from errors in methodology and accuracy, a few of which are listed here:
1. Inclusion of 1 trial of patients with heart failure (10) together with 5 trials of patients with AF introduces needless heterogeneity, especially because dronedarone is indicated only for AF.
2. The binomial approach does not take into account the censoring process, whereas the most widely recommended approach to summarize time-to-event data in clinical trials is the use of a hazard ratio.
3. The weighting of studies is not explained, nor does it even reasonably reflect the patient-years of exposure of the studies, vastly underweighting the ATHENA trial.
4. Mean duration of follow-up in the ANDROMEDA (ANti-arrhythmic trial with DROnedarone in Moderate to severe congestive heart failure Evaluating morbidity DecreAse) trial is incorrectly stated. It is 2 months, rather than 13 months (10).
In conclusion, the findings of the ATHENA trial are unique in antiarrhythmic drug therapy (6). For the first time, an antiarrhythmic drug has been shown to have an important impact on cardiovascular outcomes. Physicians no longer need to be satisfied with merely suppressing AF symptoms. Let us not miss the forest for the trees, as Singh et al. (1) seems to have done. The ATHENA results really do indicate a promising way forward to improving patient outcomes through antiarrhythmic therapy.
- American College of Cardiology Foundation
- Singh D.,
- Cingolani E.,
- Diamond G.A.,
- Kaul S.
- Touboul P.,
- Brugada J.,
- Capucci A.,
- Crijns H.J.,
- Edvardsson N.,
- Hohnloser S.H.
- Le Heuzey J.Y.,
- De Ferrari G.,
- Radzik D.,
- Santini M.,
- Zhu J.,
- Davy J.M.
- Connolly S.J.,
- Crijns H.J.,
- Torp-Pedersen C.,
- et al.
- ↵Multaq European Public Assessment Report. http://www.emea.europa.eu/humandocs/Humans/EPAR/multaq/multaq.htm. Accessed April 2010.