7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical uses of dronedarone : Rod Passman, MD, MSCE, Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 10, 2023. INTRODUCTION Dronedarone, a noniodinated congener of amiodarone, was developed as an antiarrhythmic agent for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). Because of the molecular and structural differences between dronedarone and amiodarone, in particular the deletion of the iodine molecules which are present in amiodarone, researchers have hypothesized that dronedarone will have fewer thyroid and pulmonary effects than amiodarone. Clinical trials have shown the clinical use and short-term safety (up to 21 months) of dronedarone for the maintenance of sinus rhythm following cardioversion in patients with AF [1]. The efficacy and tolerability of dronedarone in children and adolescents aged <18 years have not been established. A review of the pharmacology of dronedarone, its clinical uses, adverse effects, and drug interactions will be presented here. The clinical uses and toxicities of amiodarone and the choice of antiarrhythmic agents in the management of AF are discussed separately. (See "Amiodarone: Clinical uses".) (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 1/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate ELECTROPHYSIOLOGY AND MECHANISMS OF ACTION Dronedarone is a class III antiarrhythmic agent ( table 1) and a potent blocker of multiple intracardiac ion channels with many electrophysiological properties in common with amiodarone [2]. Like amiodarone, dronedarone has antiadrenergic (ie, beta blocking) properties and inhibits multiple transmembrane potassium currents, including the delayed rectifier current, the ultra-rapid delayed rectifier current, the inward rectifier current, and the transient outward current. In addition, dronedarone blocks inward depolarizing sodium and L-type calcium currents. PHARMACOLOGIC DATA/PHARMACOKINETICS Limited pharmacokinetic data are available for dronedarone and are derived primarily from data in the US Food and Drug Administration (FDA) prescribing information and from data in the FDA briefing document [3]. Dronedarone is approximately 70 to 94 percent absorbed after oral administration, but its absolute bioavailability is only approximately 15 percent due to significant first pass metabolism. Peak plasma concentrations are achieved within three to six hours. However, there is a significant food effect which increases plasma dronedarone concentrations between two- and threefold when the drug is taken with food [3]. Following the initiation of dronedarone 400 mg twice daily, steady-state plasma concentrations are reached within four to eight days [4]. The clearance of dronedarone is principally nonrenal, with a terminal half-life of approximately 24 hours [3]. This is markedly shorter than the half-life of amiodarone, which has an effective half-life of up to 50 days. Dronedarone is highly bound to plasma proteins and is not associated with significant tissue accumulation. Therefore, it has been postulated that systemic side effects secondary to long-term usage of the drug, such as liver toxicity, pulmonary fibrosis, or thyroid dysfunction will be minimized in comparison to amiodarone. However, long-term toxicity data are not yet available. Dronedarone has been shown to increase serum creatinine by 10 to 15 percent, a change which appears to resolve once the drug is discontinued [5]. A phase I trial of dronedarone (400 mg twice daily for seven days) in 12 healthy males reported a decrease in creatinine clearance of 18 percent (compared with placebo) without adverse effects on glomerular filtration rate or renal plasma flow [5]. Partial inhibition of tubular organic cation transporters has been suggested as a mechanism to explain the decrease in creatinine clearance. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 2/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Dronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial, with some suggestion that this cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms [6]. In a report of patient samples from the ATHENA trial, dronedarone exerted direct inhibitory effects on parameters of hemostasis and platelet reactivity at plasma concentrations typically achieved after routine clinical dosing [7]. These actions appear to be independent of the drug's antiarrhythmic properties and suggest a previously unknown pleiotropic effect. The active metabolite of dronedarone, SR35021A, demonstrates direct anticoagulant and antiplatelet effects in vitro at plasma concentrations typically achieved during conventional therapeutic dosing. These antithrombotic effects are likely to have contributed to the reported beneficial effects of dronedarone on ischemic events in patients with paroxysmal AF [6]. Further studies are needed to better understand the mechanisms involved and to gauge the magnitude of these pleiotropic effects of dronedarone in patients. METABOLISM AND DRUG INTERACTIONS Oral dronedarone 400 mg twice daily (taken with morning and evening meals) is approved for the maintenance of normal sinus rhythm in patients with a history of atrial fibrillation or atrial flutter. Dronedarone is metabolized by the CYP3A4 system in the liver and has many potential drug interactions Additional information can also be found using the Lexicomp drug interactions tool. As dronedarone primarily undergoes hepatic metabolism, its clearance may also be altered in patients with hepatic impairment. No dose adjustment is required in patients with renal insufficiency. The pharmacokinetics of dronedarone in patients with severe hepatic impairment have not been assessed; however, administration of dronedarone to patients with severe hepatic impairment is contraindicated [3]. Currently, there are no dose adjustment recommendations for patients with moderate hepatic impairment; however, data provided from the manufacturer indicate that patients with moderate hepatic impairment achieve higher dronedarone values with the potential to rise to supra-therapeutic concentrations [3]. (See "Drugs and the liver: Metabolism and mechanisms of injury".) Several drugs or classes of medications deserve special mention, as the risks associated with concomitant administration of dronedarone are potentially significant [3]: Ketoconazole and other potent CYP3A inhibitors Repeated doses of ketoconazole, a strong CYP3A4 inhibitor, result in a 17-fold increase in dronedarone exposure and a ninefold increase in the peak concentration (C ). Concomitant use of ketoconazole as max https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 3/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate well as other potent CYP3A inhibitors ( table 2) such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated. Dronedarone is also a CYP2D6 inhibitor and causes a modest increase in bioavailability of metoprolol in CYP2D6 extensive metabolizers [8]. (See "Drugs and the liver: Metabolism and mechanisms of injury".) QT prolonging medications Coadministration of drugs with the potential to prolong the QT interval (such as some phenothiazines, tricyclic antidepressants, some macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated due to the risk of inducing torsade de pointes-type ventricular tachycardia. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia'.) Digoxin Concomitant administration of dronedarone and digoxin results in higher serum digoxin levels, likely due to a P-glycoprotein-mediated interaction in the kidney, and may be associated with a greater risk of death [4,9]. Studies have shown that when compared with placebo, concurrent digoxin and dronedarone administration was associated with an approximately 40 percent increase in digoxin levels [9,10]. Additionally, among 1070 patients from the PALLAS trial who were taking digoxin and randomized to dronedarone (544 patients) or placebo (526 patients), there were 15 cardiovascular deaths in patients receiving dronedarone (compared with two deaths in patients receiving placebo; adjusted hazard ratio [HR] 7.3, 95% CI 1.7-32.2) [9]. (See "Digitalis (cardiac glycoside) poisoning".) When dronedarone and digoxin are co-administered, a 50 percent digoxin dose reduction is recommended because of increased digoxin exposure [11-13]. Digoxin levels should be monitored closely to maintain serum concentrations of 0.5 to 0.8 ng/mL, with additional digoxin dose reductions as needed. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification".) Oral anticoagulants Dronedarone increases serum warfarin exposure by 1.2-fold and does not cause clinically significant prolongation of INR values. Clinical trials have not identified a clinically significant interaction between dronedarone and warfarin [14,15]. A small, single-center crossover trial evaluating the competitive thrombin inhibitor dabigatran in 16 healthy volunteers demonstrated that dabigatran levels were increased when it was administered with dronedarone (1.7- to 2.0-fold greater than dabigatran alone) [16]. The increase was within the range seen with other dabigatran-drug combinations, and no dose adjustment has been recommended. Rivaroxaban levels can also increase when given concurrently with dronedarone, particularly in patients with decreased renal function [3]. The same is true for apixaban, and while no specific dose adjustments are required, patients should be routinely evaluated for signs and symptoms of blood loss. A study from a United States Claims Database showed a modest increased risk of gastrointestinal https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 4/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate bleeding when dronedarone was used with dabigatran (HR 1.40; 95% CI 1.01-1.93) or rivaroxaban (HR 1.31; 95% CI 1.01-1.69) [17]. There was no increased risk of intracranial hemorrhage associated with combined use of dronedarone and any nonvitamin K oral anticoagulant. Metoprolol Dronedarone increases the bioavailability of metoprolol in CYP2D6 extensive metabolizers and induces an additive dronedarone dose-dependent negative inotropic effect [8]. These effects are modest when taking dronedarone 400 mg twice daily, and no dose adjustment is necessary. Neither higher doses of dronedarone nor metoprolol combinations have been evaluated; however, the potential for more marked effects on left ventricular function could be expected with higher doses [8]. In addition, while other beta blockers have not been reported, it is likely that a similar negative inotropic effect could result. Statins Dronedarone increases simvastatin, rosuvastatin, and atorvastatin exposure by 1.4- to 4-fold, which increases the potential for statin-induced myopathy [3]. (See "Statin muscle-related adverse events".) Grapefruit juice Grapefruit juice is a moderate inhibitor of CYP3A and results in a threefold increase in dronedarone exposure and a 2.5 increase in C . Therefore, patients max should avoid beverages containing grapefruit juice when using dronedarone [3]. Calcium channel blockers Verapamil, diltiazem, and nifedipine are moderate CYP3A inhibitors and increase dronedarone exposure by approximately 1.4 to 1.7-fold [3]. DRUG APPROVAL AND RESTRICTIONS Dronedarone is approved for maintenance of sinus rhythm in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation. Dronedarone is contraindicated in patients with permanent atrial fibrillation who will not or cannot be cardioverted to normal sinus rhythm. The use of dronedarone in these patients has resulted in increases in death, stroke, and heart failure hospitalizations when compared with placebo [18]. Other contraindications to dronedarone include: Concomitant use of strong CYP3A inhibitors. NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization. Severe hepatic disease. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 5/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate History of amiodarone-induced lung toxicity. Bradycardia <50 beats per minute, advanced AV block (second or third degree), or sick sinus syndrome, except when used in conjunction with a pacemaker. Use caution when administering dronedarone to Asian patients. Pharmacokinetic studies show Asian males (Japanese) have an approximate twofold higher dronedarone exposure than White males. DOSING AND MONITORING The adult and geriatric dose of dronedarone is 400 mg PO twice daily. Safety and efficacy in adolescents, children, and infants have not been established. Dose adjustments are not needed in mild to moderate liver impairment. Dronedarone use is contraindicated in severe liver impairment. Discontinue Class I or III antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong CYP3A4 inhibitors (eg, ketoconazole) prior to initiating dronedarone therapy. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' below.) INDICATIONS/CLINICAL USES Overview Dronedarone is primarily used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter ( algorithm 1) and no evidence of moderate to severe heart failure due to left ventricular systolic function [19]. Although spontaneous cardioversion occasionally occurs following the initiation of dronedarone, its efficacy is low for chemical cardioversion, and other drugs should be used. Dronedarone should not be used exclusively as a rate control medication given the greater likelihood of adverse cardiovascular events (based on the PALLAS trial preliminary results) and the availability of other agents for this purpose [19]. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 6/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Dronedarone has been reported to significantly increase mortality in patients with recently decompensated NYHA class III and IV heart failure and, as such, is contraindicated in this population. Little evidence has been published indicating that dronedarone has any efficacy in the treatment of ventricular arrhythmias. Because of this, there is no role for dronedarone in the treatment of ventricular tachyarrhythmias. Maintenance of sinus rhythm For the maintenance of sinus rhythm in patients with AF, dronedarone has been consistently shown to be more effective than placebo. In the ADONIS, EURIDIS, and DAFNE trials, patients treated with dronedarone compared with placebo had significantly longer times to first recurrence of AF and significantly greater chances of remaining in sinus rhythm at 6 and 12 months [1,20]. As an example, the following significant benefits from dronedarone therapy were noted in the ADONIS and EURIDIS trials [1,21]: A longer time to first recurrence of AF compared with placebo (96 versus 41 days in EURIDIS, 158 versus 59 days in ADONIS, and 116 versus 53 days on pooled analysis). A significantly higher percentage of patients remaining in sinus rhythm at 12 months (36 versus 25 percent receiving placebo). A significantly reduced risk of recurrent AF in patients who had previously failed another antiarrhythmic drug, with the greatest reduction among patients who failed therapy with a class Ic agent ( table 1) [21]. Compared with placebo, post-ablation patients treated with dronedarone in the ATHENA study had a reduced risk of recurrent AF (57 versus 71 percent) and a prolonged median time to first AF/AFL recurrence (561 days versus 180 days). There was no difference in the risk of first CV hospitalization/all-cause mortality [22]. At 12 months post-ablation, patients treated with dronedarone compared with sotalol had lower risks of hospitalization (HR 0.70; 95% CI 0.66-0.93) and proarrhythmia (HR 0.83; 95% CI 0.73-0.94) [23]. These findings were predominantly attributable to lower rates of atrial- tachyarrhythmia-related hospitalizations and lower rates of bradycardic proarrhythmia and need for pacemaker implantation. One trial directly compared dronedarone with amiodarone, which has long been considered to be the most effective antiarrhythmic drug for the maintenance of sinus rhythm following cardioversion for AF or atrial flutter. The DIONYSOS trial was a double-blind trial of 504 patients with AF that randomly assigned patients to dronedarone or amiodarone [24]. Patients were followed for at least six months, with a primary composite endpoint of recurrence of AF https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 7/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate (including unsuccessful electrical cardioversion, no spontaneous conversion, and no electrical cardioversion) or premature study drug discontinuation for intolerance or lack of efficacy. After 12 months of treatment, the primary composite endpoint was significantly more likely to have occurred in patients receiving dronedarone (75 versus and 59 percent in the amiodarone group, respectively; hazard ratio [HR] 1.59; 95% CI 1.28-1.98). This result was mainly driven by a more frequent recurrence of AF in the dronedarone group (64 versus 42 percent with amiodarone). However, there was a trend toward less frequent study drug discontinuation for intolerance in the dronedarone group (10 versus 12 percent in the amiodarone group). (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Based upon the DIONYSOS study, dronedarone is less effective than amiodarone for the maintenance of sinus rhythm in patients with AF. While short-term toxicities appear to be less common among patients taking dronedarone, there are limited data regarding long-term toxicities. Our recommendations regarding the role of dronedarone in the maintenance of sinus rhythm are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) Chemical cardioversion of AF Dronedarone is only rarely effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients) [20]. As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Ventricular rate control in AF Dronedarone slows the resting ventricular heart rate by approximately 10 to 15 beats per minute in patients who develop recurrent AF and has been shown to reduce the maximum heart rate with exercise by up to 25 beats per minute [1,10,25]. However, dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. (See 'Effect on cardiovascular mortality' below and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Changing to another antiarrhythmic drug In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 8/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, clinical trial data describe three approaches: In the ADONIS and EURIDIS trials, dronedarone was initiated immediately upon discontinuation of amiodarone [1]. In the ERATO trial, patients underwent a two-month washout from amiodarone prior to initiation of dronedarone [10]. In the ATHENA trial, patients discontinued amiodarone one month prior to initiating dronedarone [6]. In general, dronedarone can be started promptly after amiodarone discontinuation, except in cases of clinically significant bradycardia or QT prolongation. SAFETY CONCERNS Effect on cardiovascular mortality There has never been any clear evidence of an overall mortality benefit with class I or class III antiarrhythmic medications ( table 1), including dronedarone, when used for the maintenance of sinus rhythm. Early post-hoc analyses of dronedarone trials suggested that patients receiving dronedarone may have reduced cardiovascular mortality and stroke risk. However, a preliminary analysis of the PALLAS trial showed increased mortality when dronedarone was used solely as a rate controlling agent in patients with chronic AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) A post-hoc analysis of the EURIDIS and ADONIS trials described above reported reduced rates of hospitalization or death in patients taking dronedarone [1]. In the ATHENA trial, the largest trial of dronedarone to evaluate cardiovascular hospitalization and mortality, 4628 patients with AF who were thought to be at high risk of cardiovascular events were randomly assigned to receive dronedarone or placebo; patients with NYHA class IV heart failure were excluded [6]. When compared with placebo, dronedarone was associated with a significant reduction in cardiovascular mortality (2.7 versus 3.9 percent, HR 0.71, 95% CI 0.51-0.98) that was mostly due to a reduction in arrhythmic mortality. Additionally, a post-hoc analysis of 1405 patients (followed for 2.5 years) from the ATHENA trial with paroxysmal or persistent AF and established coronary heart disease (CHD) demonstrated significantly lower rates of death or cardiovascular https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 9/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate hospitalization in those taking dronedarone (38 percent versus 47 percent with placebo; HR 0.73; 95% CI 0.62-0.86) [26]. Based upon the results of the ATHENA trial, the PALLAS trial was designed to test the hypothesis that dronedarone would improve major cardiovascular outcomes in patients with permanent rather than paroxysmal AF. Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled) after a significantly increased risk (HR 2.29, 95% CI 1.34-3.94) of cardiovascular events (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [27]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. While patients enrolled in the PALLAS trial were older, had a higher prevalence of baseline comorbidities including heart failure compared with those enrolled in ATHENA, and were in chronic AF with no plans for rhythm control, we are concerned about these findings which further underscore the potential toxicities of AADs. When used in routine clinical practice according to the appropriate guidelines and restrictions, dronedarone appears to be as safe as, or safer than, other antiarrhythmic drugs. In an analysis of nearly 175,000 Swedish patients with a diagnosis of AF between 2010 and 2012 (4856 received dronedarone, while 170,139 who did not served as the control population, mean follow-up 1.6 years) that used multivariable adjustment and propensity score matching to address baseline differences in the populations, patients who received dronedarone had significantly lower mortality compared with controls who did not receive dronedarone (1.31 versus 2.73 percent following adjustment and propensity score matching; HR 0.41; 95% CI 0.33-0.51) [28]. Patients receiving dronedarone also had lower mortality when compared with the general population. Our recommendations regarding the use of dronedarone for the maintenance of the sinus rhythm are discussed in detail separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone' and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Long-term follow-up'.) Patients with moderate to severe heart failure Because of the increase in mortality in patients with moderate to severe heart failure, dronedarone should NOT be used for the treatment of AF in such patients. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 10/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate The ANDROMEDA trial was a randomized, double-blind trial comparing dronedarone with placebo in 627 patients with a history of AF or atrial flutter hospitalized with symptomatic heart failure (NYHA III and IV) and a left ventricular ejection fraction 35 percent [29]. The primary endpoint was death from any cause or hospitalization for worsening heart failure. The trial was stopped prematurely because of significantly increased mortality in the dronedarone arm (8 versus 4 percent in the placebo arm, HR 2.13, 95% CI 1.07-4.25). The excess mortality in the dronedarone arm was primarily due to heart failure, with the risk being highest in those with the most severely reduced left ventricular systolic function. There were no significant differences with respect to arrhythmic or sudden death and other nonfatal adverse events (except for higher serum creatinine levels in the dronedarone arm). In a 2012 meta-analysis of seven randomized controlled trials (10,676 patients) involving dronedarone (six trials used placebo, and one trial used amiodarone as the comparator), dronedarone use was associated with a non-significant trend toward higher cardiovascular and 2 all-cause mortality but with significant heterogeneity in the outcomes (I of 75 and 53 percent respectively), with ATHENA identified as the source of the heterogeneity [30]. When the data 2 were reanalyzed following exclusion of the ATHENA data, the outcomes were homogeneous (I of 0), with the risk of both cardiovascular (relative risk [RR] 2.33, 95% CI 1.49-3.64) and all-cause (RR 1.75, 95% CI 1.15-2.66) mortality significantly increased in users of dronedarone. In the above-mentioned analysis of nearly 175,000 Swedish patients, dronedarone patients with a diagnosis of heart failure were reported to have lower mortality compared with other heart failure patients (HR 0.40; 95% CI 0.30-0.53) and compared with the general population [28]. While these data do not supplant the results of the prior randomized trials and meta-analysis, they are reassuring that dronedarone, when used according to prescribing guidelines and restrictions, appears to be as safe as, or safer than, other antiarrhythmic drugs. In contrast to those with moderate to severe congestive heart failure due to left ventricular dysfunction, a post-hoc analysis of 221 patients in the ATHENA trial found that dronedarone was associated with a reduction in the risk of death or cardiovascular hospitalization (HR 0.76; 95% CI, 0.69-0.84); results were similar in subgroups of patients with persistent atrial fibrillation or atrial flutter, heart failure with preserved ejection fraction, and heart failure with mildly reduced ejection fraction [31]. Ventricular arrhythmia/ICDs Other than a case report describing complete suppression of ventricular tachycardia that was resistant to multiple antiarrhythmic drugs and endocardial ablation, there are no clinical data evaluating the use of dronedarone for the treatment of ventricular tachyarrhythmias or for the prevention of appropriate ICD shocks for ventricular tachycardia or ventricular fibrillation [32]. Pending further evidence of benefit, dronedarone https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 11/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate should not be prescribed for the treatment of ventricular arrhythmias. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Antiarrhythmic drugs'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Background Dronedarone is a class III antiarrhythmic agent that may be considered for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). Dronedarone has many electrophysiological properties in common with amiodarone, including its antiadrenergic (ie, beta blocking) properties and the ability to inhibit multiple transmembrane potassium, sodium, and calcium currents. (See 'Electrophysiology and mechanisms of action' above and "Amiodarone: Clinical uses".) Metabolism and drug interactions Because of its hepatic metabolism, there are numerous potential drug interactions with dronedarone. Concomitant use of dronedarone with some medications (eg, ketoconazole, class I antiarrhythmic drugs) is contraindicated, while its use with other medications (eg, digoxin, warfarin, statins) may require dose adjustment. (See 'Metabolism and drug interactions' above.) Maintenance of sinus rhythm Dronedarone (400 mg twice daily) is used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter and no evidence of heart failure or left ventricular systolic dysfunction who have spontaneously reverted to sinus rhythm or in whom cardioversion is planned. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' above.) Not as a rate control medication Dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. Dronedarone is only rarely https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 12/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients). As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See 'Ventricular rate control in AF' above and 'Effect on cardiovascular mortality' above and 'Chemical cardioversion of AF' above.) Changing to another medication In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, dronedarone can usually be started immediately after amiodarone discontinuation unless there is clinically significant bradycardia or QT prolongation. (See 'Changing to another antiarrhythmic drug' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 2. Varr A, Tak cs J, N meth M, et al. 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