Editor’s Note:  This article is based on Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268-76

Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, and whose overall disease burden is expected to escalate in concert with an aging patient population.^(1,2) There had been growing enthusiasm for dronedarone after recent large-scale randomized trials demonstrated reduced cardiovascular death and hospitalization in patients with predominantly paroxysmal or persistent AF on therapy.^(3,4) PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy, NCT01151137) was explicitly formulated to test the hypothesis that dronedarone would reduce cardiovascular hospitalization, embolic sequelae, and death in a patient population with permanent AF at risk for significant vascular comorbidity.⁽⁵⁾

Methods

PALLAS was a large-scale randomized, double-blind trial conducted at 489 sites in 37 countries. The target population consisted of patients with documented permanent atrial fibrillation (lasting 6 or more months) in whom restoration of sinus rhythm was not planned. Eligible patients were over the age of 65 years with at least one additional risk factor for major vascular events, including: coronary artery disease; prior stroke or transient ischemic attack; symptomatic New York Heart Association (NYHA) Class II or III heart failure (but with no hospitalization in the most recent month); a left ventricular ejection fraction (LVEF) ≤ 40%, or peripheral arterial disease. A combination of age ≥ 75, hypertension, and diabetes was also included as a risk factor. Patients were considered ineligible if they had a history paroxysmal or persistent atrial fibrillation, demonstrated significant bradycardia, required use of an implantable-cardioverter defibrillator, or had a prolonged QT interval (> 500 ms or >530 ms paced).

The trial was designed with coprimary outcomes. The first coprimary consisted of a composite of stroke, myocardial infarction, systemic embolism, or cardiovascular death. Unplanned cardiovascular hospitalization or death was the second coprimary. A relative reduction of 20% of the first coprimary outcome was intended, and an event rate of 4.5% was expected in the control arm. This necessitated a sample size of 10,800 subjects over 2 years for suitable power.

Results

Approximately one year after initiation, the data monitoring committee recommended early termination of the trial due to excess mortality and morbidity observed in the treatment arm. At that point, 3236 patients had undergone randomization, with a median follow-up period of 3.5 months. Patients were slightly older than in prior dronedarone trials, at a mean of 75 years (versus 72 years in ATHENA(4) and ANDROMEDA(6)); 35% were women. A majority (69%) had a history of permanent atrial fibrillation or flutter lasting greater than 2 years. With respect to cardiovascular risk factors, patients enrolled in PALLAS were sicker than in ATHENA, but not as ill as those in ANDROMEDA: close to 90% of patients demonstrated a CHADS2 score of  ≥ 2, just over half (54%) demonstrated NYHA Class II-III heart failure, and 41% had a history of coronary artery disease.

Dronedarone was observed to double the combined coprimary endpoint as compared with placebo (Hazard Ratio [HR] 2.29, 95% CI, 1.34-3.94, p = 0.002). This was driven by an increased risk of death from any cause or cardiovascular causes. Notably, death from arrhythmic causes was three-fold higher in the dronedarone arm (HR 3.26. 95% CI, 1.06-10.0, p = 0.03). In addition, the rate of unplanned cardiovascular hospitalization or death in patients assigned to dronedarone was also almost twice that of the placebo group (HR 1.97, 95% CI, 1.44-2.70, p < 0.001). Hospitalization for heart failure was also markedly increased in the dronedarone group in comparison to the placebo (HR 1.81, 95% CI, 1.10-2.99, p = 0.02). Surprisingly, an increased rate of stroke (HR 2.32 95% CI 1.11-4.88, p=0.02) was also found among patients receiving dronedarone, which had not been found in prior subset analysis of similar patients enrolled in ATHENA.(7)

Conclusion

Dronedarone increases the risk of heart failure, stroke and death in patients with permanent atrial fibrillation who are at risk for major vascular events, and should be avoided in this group.

Perspective

AF impacts the daily practice of the general cardiologist and electrophysiologist, and with a prevalence expected to double by 2050, it will continue to impose a significant financial burden to the health care system.⁽⁸⁾ The armamentarium of antiarrhythmic treatment options for AF remains limited, and dronedarone (Multaq®, Sanofi-Aventis) is a relative newcomer. Dronedarone is a benzofuran derivative and congener of amiodarone with the omission of iodine moieties (to reduce thyroid and lung toxicity), and the addition of a methylsulfonamide group (to reduce lipophilicity and shorten accumulation in tissue).⁽⁹⁾ Earlier studies (EURIDIS, ADONIS) showed that dronedarone effectively suppressed AF and controlled ventricular rate response in patients with AF.⁽³⁾ Although the ANDROMEDA study showed that there was an important association with death in patients with heart failure,(6) the landmark ATHENA study showed that dronedarone was associated with a marked decrease in unplanned hospitalization for cardiovascular causes and mortality when given to less sick patients with paroxysmal or persistent AF.⁽⁴⁾ Interestingly, it was also associated with a reduction in vascular events and stroke, although a clear mechanism was not elucidated.⁽⁷⁾

Given the salutatory effects in patients with intermittent atrial fibrillation, the Advisory Committee to the United States Food and Drug Administration (FDA) voted 10 to 3 to approve dronedarone in March 2009 to “prolong time to recurrence or time to hospitalization.”⁽¹⁰⁾ It is noteworthy that this approval was achieved despite dronedarone’s well-known reduced efficacy in maintaining sinus rhythm compared to amiodarone.^(11,12) The decision to approve dronedarone was largely driven by its favorable safety profile in non-heart failure patients, and there was a suggestion that expanded indication might be possible if mortality benefit could be shown more conclusively.⁽¹⁰⁾ PALLAS was designed in the hopes of capitalizing on the cardiovascular mortality and stroke reduction found in ATHENA in a broader group of patients.

The results of PALLAS, however, revealed significantly increased risk in patients with permanent atrial fibrillation. Although reduction in the heart rate and systolic blood pressure were observed in the dronedarone arm, these physiological effects did not translate into any clinical benefits. It is unclear if this was because the magnitude of change was small and inconsequential or there were other clinical covariates which interacted with dronedarone to worsen its clinical risk profile. In addition, although previous studies have not shown dronedarone to be proarrhythmic, greater arrhythmic death was observed. It is quite likely that the multi-ion channel blocking effect may have had “off-target,” deleterious impact in patients with this sicker clinical substrate, similar to what has been seen with other antiarrhythmics.⁽¹³⁾

Theses results clearly have had a serious impact on the credibility of dronedarone, and its usage in clinical practice needs to be reevaluated. The FDA has been quick to respond and has changed labeling, suggesting that healthcare professionals should not prescribe dronedarone to patients with AF who cannot or will not be converted in normal sinus rhythm.⁽¹⁴⁾ Along with this are recommendations that ECG guided monitoring of the heart rhythm should be performed every 3 months. If the patient is found to be in AF, either the drug should be stopped or the patient should be cardioverted.

Taken together, the results of PALLAS study have clearly tempered the enthusiasm of electrophysiologists and cardiologists for prescribing dronedarone. The hope that dronedarone would be safe and easy enough to use that it could be prescribed by the internist is now a thing of the past. This drug will need to be carefully chosen in the right population and closely monitored. Particularly salient to patient selection is that those over the age of 75 with hypertension and diabetes themselves constituted an independent risk factor for a worse outcome. Its use has and will diminish, and yet, the dronedarone story may be far from over. The recently announced HARMONY trial will explore the efficacy and safety of dronedarone in combination with ranolazine (Ranexa®, Gilead Sciences) on AF burden in approximately 150 pacemaker patients.⁽¹⁵⁾ Preclinical studies show significant ability of combination therapy to suppress AF, and there is muted enthusiasm that safe and effective treatment options for selected AF patients may still be within reach.

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References

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5. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268-76.
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7. Connolly SJ, Crijns HJ, Torp-Pedersen C, et al. Analysis of stroke in 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. Circulation 2009; 120:1174-80.
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11. Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597-605.
12. Piccini JP, Hasselblad V, Peterson ED, Washam JB, Califf RM, Kong DF. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089-95.
13. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med 1989; 321:406-12.
14. FDA Drug Safety Communication: Review update of Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events. In http://www.fda.gov/Drugs/DrugSafety/ucm283933.htm; December 19, 2011.
15. Miller R. Dronedarone gets another chance to prove itself in ranolazine combo trial. In http://www.theheart.org/article/1340897.do; 2012.

Keywords: Blood Pressure, Bradycardia, Comorbidity, Coronary Artery Disease, Double-Blind Method, Hypertension, Iodine, Ion Channels, Ischemic Attack, Transient, Myocardial Infarction, Peripheral Arterial Disease, Stroke, United States Food and Drug Administration

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