Role of Dronedarone in Atrial Fibrillation: More Questions Than Answers

Role of Dronedarone in Atrial Fibrillation: More Questions Than Answers Daniel E. Hilleman, Pharm.D., FCCP, and Aryan N. Mooss, M.D. Key Words: dronedarone, atrial fibrillation, sinus rhythm, hypertension, antiarrhythmic drugs. (Pharmacotherapy 2010;30(9):867 871) In this issue of Pharmacotherapy, Dr. Ola Oyetayo and his colleagues review the available evidence concerning the role of dronedarone in patients with atrial fibrillation. 1 Dronedarone is used to maintain sinus rhythm in patients with a history of atrial fibrillation or atrial flutter. Dr. Oyetayo and his colleagues suggest that dronedarone s ultimate place in therapy will be determined by clinicians willingness to accept a less effective antiarrhythmic agent for one that offers a more favorable safety profile compared with amiodarone. According to their proposed algorithm, dronedarone is a first-line treatment for patients with lone atrial fibrillation, for those with atrial fibrillation and hypertension without left ventricular hypertrophy, and for those with atrial fibrillation and coronary artery disease. We offer a different perspective concerning the role of dronedarone in patients with atrial fibrillation. Treatment Strategies for Atrial Fibrillation The two most common treatment strategies in patients with atrial fibrillation, rate control and rhythm control, have been compared in six randomized trials. 2 7 None of these studies demonstrated an advantage of one treatment strategy over the other in terms of clinical end points. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) was adequately powered to assess differences in From Creighton University Cardiac Center, Creighton University, Omaha, Nebraska (both authors). The opinions expressed in this editorial are those of the author and do not necessarily represent the position of Pharmacotherapy or the American College of Clinical Pharmacy. Invited editorials are not peer reviewed. For reprints, visit http://www.atypon-link.com/ppi/loi/phco. For questions or comments, contact Daniel E. Hilleman, Pharm.D., Creighton University Cardiac Center, 3006 Webster Street, Omaha, NE 68131; e-mail: hilleman@creighton.edu. all-cause mortality between the rate control (2027 patients) and rhythm control (2033 patients) strategies. 2 After 5 years of follow-up, no significant difference in the rate of mortality was noted between the treatment groups. Multivariate analysis of the AFFIRM trial found that patients who remained in sinus rhythm had a reduced risk of mortality, but this reduction was offset by an increased rate of mortality from the toxicity of the antiarrhythmic drugs used in the rhythm control group. 8 The AFFIRM trial used a variety of antiarrhythmic agents other than amiodarone, including class IA drugs in about 20% of patients and class IC drugs in about 25% of patients. 2 The Atrial Fibrillation Congestive Heart Failure (AF-CHF) trial randomized 1376 patients with heart failure symptoms, a left ventricular ejection fraction (LVEF) less than 35%, and a history of atrial fibrillation. 7 Although amiodarone, dofetilide, and sotalol were permitted in the rhythm control group, more than 96% of patients receiving antiarrhythmic therapy received amiodarone. After 37 months of follow-up, there was no significant difference in the primary end point of cardiovascular mortality or the secondary outcomes of all-cause mortality or worsening heart failure. Unlike the AFFIRM trial, however, antiarrhythmic therapy in the AF-CHF trial was not associated with an increased risk of mortality. 9 In addition, sinus rhythm in the AF-CHF trial was not associated with a reduced rate of cardio-vascular mortality, total mortality, or worsening heart failure. 9 Although it may be easy to ascribe the differences in the adverse impact of antiarrhythmic therapy in the AFFIRM and AF-CHF studies to the exclusion of class IA and IC drugs in the AFFIRM study, there is no plausible explanation why maintenance of sinus rhythm did not

868 PHARMACOTHERAPY Volume 30, Number 9, 2010 improve outcomes in the AF-CHF study. Given the apparent lack of benefit associated with rhythm control, rate control is the treatment strategy recommended initially for the vast majority of patients presenting with atrial fibrillation. 10 Patients remaining symptomatic despite adequate rate control could then be considered for a rhythm control strategy with the primary goal of reducing symptoms and improving quality of life. The available rhythm control agents are amiodarone, dofetilide, dronedarone, flecainide, propafenone, and sotalol; catheter ablation is also used. What are the relative advantages and disadvantages of dronedarone compared with these other therapies? Unfortunately, there are little comparative data that can used to base strong recommendations concerning the role of dronedarone in patients with atrial fibrillation. Dronedarone Clinical Trial Data The most intriguing data about dronedarone come from the Assess the Efficacy of Dronedarone for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter (ATHENA) trial. 11 Compared with placebo, dronedarone reduced the primary composite outcome of a first hospitalization for a cardiovascular event or death from any cause by 24% in patients with a history of paroxysmal or persistent atrial fibrillation. These patients were considered to be relatively low risk for cardiovascular mortality but did have at least one risk factor for stroke. Comorbidities in the study population included structural heart disease in 60% of patients, hypertension in 86%, coronary heart disease in 30%, New York Heart Association (NYHA) class II heart failure in 17%, NYHA class III heart failure in 4%, and LVEF less than 35% in 4%. It is not known what percentage of patients enrolled in the ATHENA study had symptomatic atrial fibrillation. Dronedarone is the only antiarrhythmic agent shown to reduce a major adverse clinical outcome other than atrial fibrillation recurrence in this patient population. Whether other antiarrhythmic agents would produce similar reductions in clinical end points in this population is not known primarily because studies with other antiarrhythmic agents have only evaluated atrial fibrillation recurrence as the primary study end point. Amiodarone is the only antiarrhythmic agent that dronedarone has been compared with in clinical trials of relatively low-risk populations. Dronedarone has not been compared with dofetilide, flecainide, propafenone, or sotalol. The Efficacy and Safety of Dronedarone versus Amiodarone for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation (DIONYSOS) study enrolled 504 patients with atrial fibrillation of 72 hours duration or longer for whom cardioversion and antiarrhythmic therapy were indicated in the opinion of the investigator. 12 All patients had to be receiving oral anticoagulant therapy. Patients previously receiving amiodarone were excluded as were patients with a QTc interval longer than 500 msec, NYHA class III or IV heart failure, thyroid disease, paroxysmal atrial fibrillation, atrial flutter, or bradycardia or high-degree atrioventricular block. During the screening phase, eligible patients were randomized in double-blind fashion to amiodarone 600 mg/day for 28 days, then 200 mg/day (255 patients) or to dronedarone 400 mg twice/day (249 patients) for a minimum of 6 months. Electrical cardioversion was performed 10 28 days after randomization if spontaneous conversion to sinus rhythm did not occur. Failure to convert to sinus rhythm either spontaneously or after electrical cardioversion was considered a treatment failure in that treatment group. The composite outcome was recurrence of atrial fibrillation or study drug premature discontinuation due to lack of efficacy or intolerance. The primary composite outcome occurred significantly more often with dronedarone (75%) than with amiodarone (59%) (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.28 1.98, p<0.0001). This difference was due in large part to a higher rate of atrial fibrillation recurrence with dronedarone (64%) than with amiodarone (42%). Premature drug discontinuation occurred less frequently with dronedarone (10.4%) compared with amiodarone (13.3%). A substantially greater percentage of patients receiving dronedarone (33%) failed to convert to sinus rhythm before undergoing electrical cardioversion 10 28 days after randomization, compared with those receiving amiodarone (11%). This resulted in a greater number of electrical cardioversion attempts with dronedarone (200 procedures) compared with amiodarone (153). The percentages of patients experiencing adverse events after a median treatment duration of 7 months (maximum 13.8 mo) were 61% with dronedarone and 68% with amiodarone. The primary safety outcome (rate of thyroid, hepatic, pulmonary, neurologic, skin, eye, or gastrointestinal events) occurred in 39.3% and 44.5% of the

ROLE OF DRONEDARONE IN ATRIAL FIBRILLATION Hilleman and Mooss 869 dronedarone and amiodarone groups, respectively (HR 0.80, 95% CI 0.60 1.07, p=0.13). The primary toxicities associated with amiodarone were thyroid (6%) and neurologic (7%) events. Of these neurologic events, 5% of patients experienced sleep disturbances and 2% had tremor. Gastrointestinal events were reported in 13% of patients receiving dronedarone, of whom 8% had diarrhea. Pulmonary toxicity did not occur with either drug. Abnormal liver enzyme levels greater than 2 times the upper limit of normal occurred in 11% and 12% of patients treated with amiodarone and dronedarone, respectively. The incidence of serious treatmentrelated adverse events was similar between the two drugs (13.7% for dronedarone and 14.5% for amiodarone). In addition, the risk of premature drug discontinuation due to adverse events was higher with amiodarone but not significantly different between the drugs (HR 0.76, 95% CI 0.48 1.19, p=0.23). Many of the events leading to discontinuation of amiodarone were QTinterval prolongation, bradycardia or conduction disturbances, and thyroid toxicity. The short duration of therapy in the DIONYSOS study may have led to an underestimation of the true adverse-event rate with amiodarone. Many of amiodarone s toxicities have the potential to occur 13, 14 after many months or even years of therapy. Despite this limitation, the DIONYSOS study provides the only comparative data currently available to gauge the value of dronedarone against another viable treatment option. Dronedarone was clearly less efficacious than amiodarone at converting patients to sinus rhythm, leading to a higher rate of electrical cardioversion procedures and a higher rate of recurrences of atrial fibrillation during follow-up. In addition, dronedarone was not associated with a significant reduction in the risk of serious treatment-related adverse events or premature drug discontinuations due to adverse events compared with amiodarone. In the DIONYSOS study, the rate of abnormal liver enzyme level elevations experienced by patients receiving dronedarone raises the question as to whether monitoring for hepatic toxicity should be considered. The current labeling for dronedarone does not recommend monitoring alanine and aspartate aminotransferase levels. 15 The most disturbing data with dronedarone come from the Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease (ANDROMEDA) in which use of the drug significantly increased the mortality rate, compared with placebo, in patients hospitalized with new or worsening heart failure (NYHA class III or IV) and an LVEF of 35% or less. 16 In ANDROMEDA, only about one fourth of the patients were in atrial fibrillation at study entry. The apparent mode of death associated with dronedarone was worsened heart failure, with a higher risk of death in patients with poorer left ventricular function. There was also a small increase in the risk of hospitalizations for heart failure. Because the study was discontinued after only a median treatment duration of 2 months, it has been suggested that the increase in mortality may have been a chance finding, which would have become nonsignificant with a longer duration of follow-up. 17 Despite a variety of potential explanations including the unnecessary and premature discontinuation of angiotensin-converting enzyme inhibitors secondary to increased serum creatinine concentrations in patients receiving dronedarone, the true cause of the increased mortality during ANDROMEDA remains unknown. 17 The subsequent restrictions placed on dronedarone treatment in patients with substantial left ventricular dysfunction or severe heart failure also means that only amiodarone and dofetilide remain available to manage atrial fibrillation in 18, 19 these patients. This is especially important as the prevalence of atrial fibrillation increases with the severity of heart failure. Approximately 30% and 50% of patients with NYHA classes III and IV heart failure, respectively, have atrial fibrillation. 10 Comparison of Dronedarone with Amiodarone Being a benzfuran derivative designed to retain the electrophysiologic properties of amiodarone while avoiding its organ toxicity, dronedarone is most often considered a potential replacement for amiodarone. The two drugs do share some important similarities such as an ability to control the ventricular rate during atrial fibrillation, a low risk of torsade de pointes, substantial hepatic metabolism with no renal clearance, a substantial interaction with digoxin, interactions with potent cytochrome P450 3A4 inhibitors, and an inclination to increase serum creatinine 12, 20, 21 concentration. Dronedarone does have some important advantages compared with amiodarone including a lack of interaction with warfarin and a resultant lower risk of bleeding, a lower potential for certain noncardiac adverse effects (e.g., neurologic, thyroid, and dermatologic effects), and a lower risk of QT-interval prolongation, bradycardia, and conduction disturbances. 12 Despite amiodarone s reputation as a drug with

870 PHARMACOTHERAPY Volume 30, Number 9, 2010 substantial toxicity, with appropriate follow-up and monitoring, the drug can be used safely for relatively long periods of time. In the Antiarrhythmics versus Implantable Defibrillators (AVID) trial, 85% of patients continued to take amiodarone at the end of 2 years of treatment. 22 In the AF-CHF trial, 73% of patients continued with amiodarone after 3 years of treatment. 7 The rate of dronedarone discontinuation at the end of 21 months in the ATHENA trial was 30%. 11 Place in Therapy Ultimately, the greatest concern with dronedarone is its relative lack of efficacy. A recent metaanalysis evaluating the relative efficacy of the currently published dronedarone trials estimated the relative risk of atrial fibrillation recurrence to be 43% with dronedarone and 54% with placebo. 23 This translates into a modest 18% reduction in atrial fibrillation recurrence in patients receiving dronedarone compared with placebo. In addition, the authors estimated that dronedarone is only half as effective as amiodarone. Assuming that a rhythm control strategy be used only for patients with symptomatic recurrences of atrial fibrillation, a therapy that reduces those recurrences to the greatest extent would also be expected to have the greatest potential to reduce emergency department visits or hospitalizations. The authors of this meta-analysis argue that given its limited efficacy and a failure to demonstrate significant reductions in severe adverse reactions and premature drug discontinuation compared with amiodarone, dronedarone should be relegated to a second- or third-line agent for the majority of patients and should not be used for patients with severe heart failure or those with substantial left ventricular dysfunction (LVEF 35%). Dronedarone has been marketed in five countries: United States, Germany, Canada, Switzerland, and most recently, the United Kingdom. The National Institute for Health and Clinical Excellence (NICE) initially did not recommend the use of dronedarone, which prevented the National Health Service from allowing dronedarone to be prescribed in the United Kingdom. 24 However, the latest guidance from the NICE recommends dronedarone as a secondline agent in select patients with cardiac risk factors who have failed other therapies. 24 Unfortunately, there is no evidence that dronedarone is effective in patients failing other antiarrhythmic agents. Intuitively, it would be more likely that dronedarone would be less effective in treating atrial fibrillation that is refractory to other drugs. Recently, the manufacturer of dronedarone announced the start of a 10,000-patient trial, testing the efficacy of dronedarone in patients with permanent atrial fibrillation, with the end points of mortality and hospitalizations for cardiovascular events. 25 Conclusion Given the evidence with dronedarone, we believe that its use should be limited to those patients with symptomatic atrial fibrillation requiring rhythm control strategies who have failed other antiarrhythmic therapy primarily due to intolerable adverse effects or adverse electrocardiographic effects (bradycardia, atrioventricular block, or QT-interval prolongation). Until results from additional studies demonstrating a favorable risk:benefit ratio with dronedarone compared with other antiarrhythmic agents become available, dronedarone s place in the management of symptomatic atrial fibrillation will remain largely undefined. References 1. Oyetayo OO, Rogers CE, Hofmann PO. Dronedarone: a new antiarrhythmic agent. 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