Author + information
- David Singh, MD,
- Eugenio Cingolani, MD,
- George A. Diamond, MD and
- Sanjay Kaul, MD⁎ ()
- ↵⁎Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048
We appreciate the opportunity to clarify the issues raised by Drs. Connolly and Hohnloser regarding our study (1). We agree that dronedarone reduces first hospitalizations driven primarily by atrial fibrillation in 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) trial (2), but reject the assertion that this makes it a major advance for the treatment of atrial fibrillation. Although no other antiarrhythmic drug has been shown to do this, it is entirely plausible that class I or III antiarrhythmic drugs would have similar effects if systematically evaluated in this manner. This is precisely why comparative effectiveness research has become a cornerstone of evidence-based medicine and health care reform. In this regard, it is surprising that the ATHENA trial was not designed as an active control trial.
The validity of the observation that dronedarone reduces cardiovascular hospitalization would have been strengthened if the trial had documented systematically the underlying reasons for hospitalizations (typically hemodynamic instability, exacerbation of heart failure, anticoagulation, or cardioversion) and the expected attendant improvement in symptom status and quality of life. Coupled with the lack of external adjudication (that minimizes the vulnerability to cardiovascular versus noncardiovascular misclassification errors, particularly in trials that span geographic regions and clinical practice settings) (3,4) and the exploratory nature of the analysis (given the pre-specified hierarchical sequential plan), these limitations serve not only to undermine the clinical relevance of this finding, but also to raise questions about the overall quality of the data, and ultimately the reliability of the findings.
The original report mentions 1 amendment dated March 8, 2006, to alter the enrollment criterion to include older subjects (2). No further protocol changes are mentioned, including the amendment dated August 25, 2006, to increase the sample size from 3,700 to 4,300, nor is any reason given for the extension of the sample size from 4,300 to 4,628. We do not doubt these protocol changes were done blindly, without knowledge of any emerging treatment effects. However, we are intrigued that investigators stopped at 255 deaths, 5 short of achieving the protocol-specified goal of 260 deaths. Nonetheless, these protocol changes should have been reported in a transparent manner and appropriate caution should have been urged in interpreting cardiovascular death results as being exploratory, given the rules of engagement of a hierarchical sequential analysis plan. Instead, the published conclusion that the drug reduced cardiovascular deaths is highly misleading, when in reality that benefit was not significant under the original plan (1). Although no malfeasance is implied, we nonetheless feel strongly that changing rules in the middle of the trial is antithetical to the principles of good clinical trial practice. Moreover, the mechanisms that underlie dronedarone's reduction of cardiovascular death remain unclear. Death resulting from stroke, ventricular arrhythmia, or heart failure was not impacted favorably by dronedarone (2). Did the associated reductions in acute coronary syndromes—a post-hoc observation—account for this finding, or was this merely the play of chance? In the end, the ATHENA trial was not designed to answer these questions, and the observed reduction in cardiovascular death is at best exploratory and hypothesis generating, requiring confirmation in subsequent studies.
The authors have raised issues with our meta-analysis. The objective was not solely to estimate an overall measure of effect (a synthesis-centric goal), where it is appropriate to question whether certain studies should be combined, but rather to explore the reasons for differences between the studies (an analysis-centric goal) to place the evidence in its proper context. The results are insightful because they provide reassurance about dronedarone's safety in the target population (1). The weighting is described in the figure legend (1), and adjusting for patient-years of exposure did not materially change the summary relative risk estimate. Finally, we acknowledge the typographical error regarding the mean follow-up in the ANDROMEDA (ANti-arrhythmic trial with DROnedarone in Moderate to severe congestive heart failure Evaluating morbidity DecreAse) trial, which had no impact on our analysis.
Rather than missing the forest for the trees, we present the evidence in an objective and unembellished manner. Although the truth can be determined by each reader, the plain fact, in our opinion, is that dronedarone has very modest efficacy as an antiarrhythmic agent, and based on the current evidence, its use for the treatment of nonpermanent atrial fibrillation or atrial flutter can be supported only as a second- or third-line agent in individuals who are not able to tolerate amiodarone or other first-line agents recommended by the guidelines.
- American College of Cardiology Foundation
- Singh D.,
- Cingolani E.,
- Diamond G.A.,
- Kaul S.
- Mahaffey K.W.,
- Harrington R.A.,
- Akkerhuis M.,
- et al.,
- PURSUIT Investigators