Efficacy and safety of dronedarone by atrial fibrillation history duration: Insights from the ATHENA study

Abstract Background Atrial fibrillation/atrial flutter (AF/AFL) burden increases with increasing duration of AF/AFL history. Hypothesis Outcomes with dronedarone may also be impacted by duration of AF/AFL history. Methods In this post hoc analysis of ATHENA, efficacy and safety of dronedarone vs placebo were assessed in groups categorized by time from first known AF/AFL episode to randomization (ie, duration of AF/AFL history): <3 months (short), 3 to <24 months (intermediate), and ≥ 24 months (long). Results Of 2859 patients with data on duration of AF/AFL history, 45.3%, 29.6%, and 25.1% had short, intermediate, and long histories, respectively. Patients in the long history group had the highest prevalence of structural heart disease and were more likely to be in AF/AFL at baseline. Placebo‐treated patients in the long history group also had the highest incidence of AF/AFL recurrence and cardiovascular (CV) hospitalization during the study. The risk of first CV hospitalization/death from any cause was lower with dronedarone vs placebo in patients with short (hazard ratio, 0.79 [95% confidence interval: 0.65‐0.96]) and intermediate (0.72 [0.56‐0.92]) histories; a trend favoring dronedarone was also observed in patients with long history (0.84 [0.66‐1.07]). A similar pattern was observed for first AF/AFL recurrence. No new drug‐related safety issues were identified. Conclusions Patients with long AF/AFL history had the highest burden of AF/AFL at baseline and during the study. Dronedarone significantly improved efficacy vs placebo in patients with short and intermediate AF/AFL histories. While exploratory, these results support the potential value in initiating rhythm control treatment early in patients with AF/AFL.


| INTRODUCTION
Atrial fibrillation (AF) is a self-promoting progressive disease, driven by electrical and structural remodeling processes. [1][2][3] In comparison to patients with recent-onset disease, patients who have had AF for an extended period of time will likely have a greater burden of AF. Patients with longer durations of AF history have been shown to have worse outcomes with regard to cardioversion and ablation. 4,5 The impact of the duration of AF history on the efficacy and safety of commonly used antiarrhythmic drugs (AADs), however, has not been reported.
Dronedarone is an AAD indicated to reduce the risk of hospitalization for AF in patients in sinus rhythm with a history of paroxysmal or persistent AF. 6 In the ATHENA study ("A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular (CV) Hospitalization or Death from any Cause in Patients with AF/AFL (Atrial Flutter)"; NCT00174785), which is one of the largest placebo-controlled trials of an AAD to date, dronedarone decreased the composite rate of CV hospitalization or death vs placebo in patients with nonpermanent AF or AFL. A total of 4628 patients were randomized in the ATHENA study, with data on duration of AF/AFL history available in over 60% of patients. In this post hoc analysis, we assessed the impact of the duration of AF/AFL history prior to study enrollment on the efficacy and safety of dronedarone.
2 | METHODS 2.1 | Overview of the ATHENA study ATHENA was a double-blind, placebo-controlled phase 3 study of 4628 patients with paroxysmal or persistent AF/AFL randomized to dronedarone 400 mg twice daily or placebo in addition to rate-control therapy; the study design has been described in previous publications. 7,8 Patients were required to have a 12-lead electrocardiogram (ECG) within 6 months before randomization indicating AF/AFL and another 12-lead ECG indicating sinus rhythm during the same period.
Initially, patients were included if they were at least 70 years of age or had one of the following CV risk factors: hypertension, diabetes, prior stroke/transient ischemic attack/systemic embolism, left atrial diameter ≥50 mm, or left ventricular ejection fraction <40%. A subsequent amendment to the protocol allowed inclusion of patients ≥75 years old alone or ≥70 years old with at least one of the additional CV risk factors listed above. Patients in AF/AFL at enrollment were expected to undergo cardioversion after appropriate anticoagulation treatment before starting treatment with the study drug.
The primary endpoint was the composite of first CV hospitalization or death from any cause. Secondary endpoints included death from any cause, CV death, and first CV hospitalization. Patients were evaluated on days 7 and 14, and months 1, 3, 6, 9, and 12 after randomization, and every 3 months thereafter. First recurrence of AF/AFL was assessed in patients who were in sinus rhythm at baseline. 9 Assessment of AF/AFL recurrence was based on scheduled 12-lead ECGs (recorded at 7 and 14 days, 1, 3, and 6 months after randomization, then every 6 months thereafter) and ECGs recorded during unscheduled visits. Each ECG was classified by the investigator as demonstrating AF/AFL or sinus rhythm.
Recurrence of AF/AFL was said to occur at the first instance of AF/AFL based on electrocardiography, cardioversion, or hospitalization for AF/AFL.

| Statistical analysis
Baseline characteristics were summarized using descriptive statistics.
For time-to-event outcomes, cumulative incidence functions in each treatment group were calculated using the Kaplan-Meier method.
Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using an unstratified Cox regression model with treatment group as the only factor. Inter-treatment group comparisons were performed using the log-rank test. For safety analyses, the frequency of patients with TEAEs, serious TEAEs, and TEAEs leading to discontinuation of study drug were summarized using descriptive statistics. Data were analyzed using SAS version 9.4 (Cary, North Carolina).

| Outcomes associated with dronedarone vs placebo
Across all AF/AFL history groups, dronedarone was generally associated with improved clinical outcomes and efficacy compared with

| Safety
In both the dronedarone and placebo treatment arms, rates of TEAEs and serious TEAEs were similar across the short, intermediate, and long AF/AFL history groups ( The key results of this study are summarized in the Central Illustration.
Understanding the importance of the timing of initiating AAD therapy is becoming increasingly relevant, especially with the development of new technologies that have the potential to detect AF at an early stage. [10][11][12] Early treatment of AF has been shown to benefit patients by reducing the risk of AF progression. [13][14][15][16][17] Earlier electrical cardioversion, for example, has been shown to reduce time spent in AF, improve symptoms, and delay onset of a subsequent AF episode. 16 On the other hand, effective treatment may be more difficult in patients with a long AF history, which is associated with a greater disease burden. 4,5,18 Here, we report for the first time, the efficacy and An association between extended AF/AFL history and AF progression has been reported. 19 In this analysis, although CHA 2 DS 2 -VASc scores were similarly distributed across AF/AFL history groups, patients with long AF/AFL history had a greater burden of AF/AFL and other CV comorbidities including left atrial enlargement at baseline, compared with patients with short AF/AFL history.
Greater disease burden among placebo-treated patients in the long AF/AFL history group was also reflected in a higher incidence of AF/AFL recurrence, a shorter time to AF/AFL recurrence, and a higher rate of cardioversions in the long history group compared with the short history group. 9   Prospective trials are warranted to further investigate the impact of timing of AAD initiation on efficacy and safety among patients with AF/AFL.

ACKNOWLEDGMENTS
The authors thank all of the patients and their caregivers who took part in the ATHENA study. All authors contributed to the study concept and design, interpretation of the data, and the drafting and/or reviewing of the paper. All authors approved the final manuscript before submission. Under the direction of the authors and in accordance with GPP3 guidelines, medical writing and editorial support was provided by Ian Marshall PhD, for Evidence Medical Affairs (Horsham, United Kingdom) and Meenakshi Subramanian PhD, Evidence Medical Affairs (Philadelphia, United States) and was funded by Sanofi US Inc.

DATA ACCESSIBILITY
The data that support the findings of this study are available from the corresponding author upon reasonable request.