CURRENT DRUG THERAPY CME EDUCATIONAL OBJECTIVE: Readers will list indications for and contraindications to dronedarone CREDIT NEELIMA PENUGONDA, MD ADAM MOHMAND-BORKOWSKI, MD JAMES F. BURKE, MD Department of Internal Medicine, Lankenau Department of Internal Medicine, Division of Cardiology, Department of Internal Medicine, Division of Hospital, Wynnewood, PA Lankenau Hospital, Wynnewood, PA Cardiology, and Program Director, Fellowship in Cardiovascular Disease, Lankenau Hospital, Wynnewood, PA; Clinical Associate Professor, Thomas Jefferson University, Philadelphia

Dronedarone for atrial fibrillation: How does it compare with amiodarone?

■■ ABSTRACT ronedarone (Multaq), approved by the D US Food and Drug Administration in Dronedarone (Multaq), an analogue of amiodarone July 2009, is a congener of the antiarrhythmic (Cordarone), was designed to cause fewer adverse ef- drug amiodarone (Cordarone). Designed in fects than the parent compound. Studies have indeed the hope that it would be safer than amioda- shown dronedarone to be safer than amiodarone, but rone, its official indication is to lower the risk less effective. Its official indication is to reduce the risk of of hospitalization in patients with paroxysmal hospitalization in patients with paroxysmal or persistent or persistent atrial fibrillation or atrial flut- ter. However, its precise role in the manage- atrial fibrillation or atrial flutter and other cardiovascular ment of atrial fibrillation is yet to be defined. risk factors, reflecting the parameters of its effectiveness If dronedarone remains well tolerated, it may in clinical trials. permit clinicians to pursue a rhythm control ■■ KEY POINTS strategy more often. In this article, we present a progress report on this new agent. Patients with persistent or paroxysmal atrial fibrillation are candidates for dronedarone therapy if they are in ■■ Better antiarrhythmic drugs sinus rhythm or will be cardioverted soon after starting. are needed This drug is not indicated for the acute management of atrial fibrillation, for example, in the emergency depart- Atrial fibrillation increases the risk of stroke ment. fivefold and accounts for 15% to 20% of all strokes.1 It also increases the risk of heart fail- ure. Drugs are the mainstay of therapy, but Dronedarone is an option if a patient cannot tolerate many antiarrhythmic drugs are not very effec- amiodarone or has an underlying condition such as tive and cause cardiac and extracardiac toxic- pulmonary or thyroid disease that is a contraindication to ity. Thus, the need for safe and effective new amiodarone. drugs.2 Much effort is going into the development Dronedarone is contraindicated in patients with signifi- of drugs that target specific ion channels or cant left ventricular dysfunction or heart failure with proteins expressed predominantly in atrial recent decompensation. myocardium. The rationale is to avoid the un- wanted effects of ionic currents on the ven- tricle and thus avoid ventricular proarrhyth- The ultimate role for dronedarone is yet to be defined. mic effects. At the same time, alternatives Little evidence exists as to whether it will succeed when to the multiple channel blocker amiodarone, other drugs have failed. the mainstay of heart rhythm control therapy in atrial fibrillation, are being developed to retain the electrophysiologic efficacy of the mother compound but avoid its extracardiac doi:10.3949/ccjm.78a.10049 toxicity.

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■■ Rate control vs rhythm control rhythm control strategy has not been shown to be superior to a rate control strategy is the In the acute care setting, heart rate control side effects of the presently available drugs for with atrioventricular nodal agents (beta- rhythm control. blockers, calcium channel blockers, and digi- In a subgroup analysis of the Atrial Fibrilla- talis) is the preferred initial strategy in most tion Follow-up Investigation of Rhythm Man- hemodynamically stable patients presenting agement (AFFIRM) trial,6 antiarrhythmic with new-onset atrial fibrillation.3 therapy was associated with a 49% increase Since we lack an effective method for in the mortality rate that offset the benefits of maintaining sinus rhythm without incurring conversion and maintenance of sinus rhythm, significant adverse effects, rate control is also which was associated with a 53% reduction in often chosen for chronic management of atri- mortality rates. al fibrillation. This is particularly true for pa- The hope is that newer drugs with less tox- tients who have no symptoms or only minimal icity may produce better outcomes for patients symptoms and in whom adequate rate control treated with rhythm control. is easily attained. Indeed, results of large clini- cal trials suggest that rate control is satisfac- ■■ AN ANALOGUE OF AMIODARONE, tory for many patients. WITHOUT THE IODINE The main purpose of rate control is to con- trol symptoms as opposed to merely lowering Dronedarone is a structurally modified version the ventricular rate. Effective rate control of- of amiodarone, the antiarrhythmic drug that ten prevents hemodynamic instability in pa- has shown the greatest efficacy at maintain- tients with underlying heart disease who pre- ing sinus rhythm in patients with paroxysmal sent acutely with atrial fibrillation. In patients atrial fibrillation. Although historically amio- with permanent atrial fibrillation, the RACE darone has been effective in maintaining sinus II study4 (Rate Control Efficacy in Permanent rhythm and has been used safely in patients Atrial Fibrillation: a Comparison between with advanced heart failure, its use has been The main Lenient Versus Strict Rate Control II), dur- limited by cumulative and often irreversible advantage of ing a 3-year follow-up, showed that lenient extracardiac organ toxicity. rate control (resting heart rate < 110 beats per Dronedarone was designed to match amio- dronedarone minute) is not inferior to strict rate control darone's efficacy but with a better safety pro- is its lower (resting heart rate < 80 beats per minute) in file. An iodine radical makes up more than adverse- preventing major cardiovascular events (heart one-third of amiodarone's molecular weight. failure, stroke) or arrhythmic events such as The omission of iodine in dronedarone was in- effect profile syncope and sustained ventricular tachycar- tended to reduce the likelihood of toxic side dia.4 effects. As a long-term strategy, rate control also Dronedarone is a benzofuran derivative prevents tachycardia-induced cardiomyopa- pharmacologically related to amiodarone, thy, reduces the risk of worsening of underly- with the addition of a methylsulfonamide ing heart failure, and can improve symptoms group. This reduces lipophilicity and the pro- and quality of life. pensity to cross the blood-brain barrier; over a Although maintenance of sinus rhythm 2-year period this drug has not been shown to is most likely associated with a survival ben- have neurotoxic effects.7 efit, heart rhythm control with antiarrhyth- Dronedarone has proved efficacious with- mic drugs has not shown an advantage over out toxic or proarrhythmic effects and has rate control in overall or cardiovascular death minimal side effects, but concerns remain re- rates, thromboembolic complications, or im- garding its use in advanced heart failure. To pact on heart failure. Indeed, a rhythm con- date, its adverse-event profile appears compa- trol strategy has been associated only with rable to that of placebo. However, whether its better exercise tolerance and, although less efficacy and incidence of adverse effects are clear, with better quality of life.5 comparable to what has been reported in the One possible explanation as to why a literature may take time to assess.

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■■ DRONEDARONE’S PHARMACOLOGY 400 mg twice a day produced a significantly Dronedarone, like amiodarone, blocks mul- lower rate of recurrence of atrial fibrillation tiple sodium and potassium ion channels. It after electrical cardioversion compared with also exerts an antiadrenergic effect by non- placebo. competitive binding to beta-adrenergic re- Overall, treatment with dronedarone ceptors as well as by inhibiting an agonist-in- significantly reduced the risk of a first recur- duced increase in adenylate cyclase activity.8 rence of atrial fibrillation by 22% (ADON- Compared with amiodarone, dronedarone is a IS) and 27.5% (EURIDIS) (table 1). more potent blocker of peak sodium current. ERATO (Efficacy and Safety of Droneda- Dronedarone is largely metabolized by the rone for the Control of Ventricular Rate Dur- hepatic enzyme cytochrome P450 3A4 isoform ing Atrial Fibrillation),12 an additional phase (CYP3A4). Only 6% of dronedarone is excret- III study, showed that dronedarone controlled ed renally; however, no trial has yet assessed the heart rate in patients with persistently dronedarone’s safety in patients with marked accelerated ventricular rates despite con- kidney dysfunction.89 comitant standard therapy with a beta-block- Dronedarone’s steady-state terminal elimi- er, digitalis, or a calcium-channel blocker. nation half-life is approximately 30 hours. Dronedarone reduced the mean 24-hour heart When taken twice a day, it achieves steady- rate by 11.7 beats per minute and the maxi- state concentrations in 5 to 7 days. mal exercise ventricular rate by 24.5 beats per Dronedarone is available only for oral ad- minute at the 14th day. ministration at 400 mg twice daily. Dose ad- ANDROMEDA (Anti-arrhythmic Trial justment or titration is not recommended. With Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease)13 was ■■ CLINICAL TRIALS OF DRONEDARONE a study not of patients with atrial fibrillation but rather of patients with symptomatic con- Dronedarone vs placebo gestive heart failure, a left ventricular ejection ATHENA (A Placebo-Controlled, Dou- fraction of 35% or less, and recent hospitaliza- ble-Blind, Parallel Arm Trial to Assess the tion with new or worsening heart failure. The Dronedarone’s Efficacy of Dronedarone 400 mg bid for the study was terminated early because of a higher efficacy and 13 Prevention of Cardiovascular Hospitalization rate of death with dronedarone (table 1). or Death From any Cause in Patients With safety are yet Atrial Fibrillation/Atrial Flutter)10 was a pro- Dronedarone vs amiodarone to be defined spective, double-blind study to assess mor- DIONYSOS (Efficacy and Safety ofin those who bidity and death rates in 4,628 patients with Dronedarone Versus Amiodarone for the atrial fibrillation or atrial flutter and at least Maintenance of Sinus Rhythm in Patients have undergone one other cardiovascular risk factor. With Atrial Fibrillation)14 was a randomized coronary artery ATHENA showed that dronedarone, in double-blind trial. It evaluated the efficacy addition to standard therapy, significantly and safety of dronedarone (400 mg twice dai- bypass surgery reduced the risk of a first cardiovascular hos- ly) or amiodarone (600 mg daily for 28 days, or have marked pitalization or death by 24% in patients with then 200 mg daily thereafter) for at least 6 atrial fibrillation or atrial flutter.9 The study months for the maintenance of sinus rhythm LV hypertrophy excluded patients with decompensated heart in patients with atrial fibrillation. It enrolled failure (TABLE 1). 504 patients with persistent atrial fibrilla- EURIDIS and ADONIS. Two trials,11 tion; patients had not previously taken amio- EURIDIS (European Trial in Atrial Fibrilla- darone. Dronedarone was less effective than tion or Flutter Patients Receiving Droneda- amiodarone in maintaining sinus rhythm: the rone for the Maintenance of Sinus Rhythm) rate of recurrent atrial fibrillation was 63% and ADONIS (American-Australian Trial with dronedarone and 42% with amiodarone. With Dronedarone in Atrial Fibrillation or But dronedarone was associated with fewer Flutter Patients for the Maintenance of Si- adverse effects and less need for premature nus Rhythm), enrolled a total of more than discontinuation of drug treatment at a mean 1,200 patients and showed that dronedarone follow-up of 7 months (table 1).

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TABLE 1 Clinical trials of dronedarone

Study Inclusion criteria Exclusion criteria Treatment AND EFFECTS ON Primary EFFECTS ON Secondary follow-up end points end points ATHENA10 Paroxysmal or Permanent AF Dronedarone 400 Death from all causes or Death from any cause: persistent AF or atrial Unstable hemo- mg twice daily first hospitalization for a 16% fewer deaths with flutter, plus age > 75 dynamic status for 12 months vs cardiovascular event: dronedarone or age > 70 and more NYHA class IV placebo 24.2% RR Death from cardiovascular than one other risk heart failure reduction, HR 0.76 event: factor (hypertension, 29% RR reduction diabetes, stroke or Hospitalization for cardio- transient ischemic at- vascular event: tack, left atrium 26% RR reduction > 50 mm or left Incidence of stroke: ventricular ejection 34% RR reduction fraction < 40%) Length of hospitalization reduced by 1.26 days/pa- tient/year

EURIDIS Paroxysmal AF Permanent AF Dronedarone 400 Time to AF Ventricular rate during AF and CHF (NYHA class mg twice daily recurrence: recurrence: ADONIS11 III or IV) for 12 months vs Dronedarone 116 days Dronedarone 103.4 ± 25.9 Renal placebo Placebo 53 days Placebo 117.1 ± 30.4 insufficiency Symptomatic AF recurrence: Recurrence rate: Dronedarone 37.7% Dronedarone 64.1% Placebo 46% Placebo 75.2% Hospitalization or death: Dronedarone 22.8% Placebo 30.9%

ANDROMEDA13 NYHA class III or Recent acute MI Dronedarone 400 Death from any cause Death from all causes: IV heart failure, or Acute pulmonary mg twice daily or hospitalization from Dronedarone 8.1% paroxysmal noctur- edema for 12 months vs worsening heart failure: Placebo 3.8% (HR 2.13) nal dyspnea and left placebo Dronedarone 17.1% Hospitalization for cardio- ventricular ejection Placebo 12.6% vascular event: fraction < 35% Dronedarone 22.9% Placebo 15.7%

DIONYSOS14 Persistent AF Not yet reported Dronedarone 400 AF recurrence or prema- Main safety end point: mg twice daily vs ture drug discontinuation 20% decrease favoring amiodarone 600 for intolerance or lack of dronedarone mg/day for efficacy: Main safety end point 28 days, followed Dronedarone 73.9% excluding gastrointestinal by 200 mg daily Amiodarone 55.3% effects: for 6 months 39% decrease favoring dronedarone

AF = atrial fibrillation; CHF = congestive heart failure; NYHA = New York Heart Association; MI = myocardial infarction; HR = hazard ratio; RR = relative risk

■■ WHERE DOES DRONEDARONE FIT tion. It is indicated for the maintenance of si- IN ATRIAL FIBRILLATION management? nus rhythm and may be used in patients with persistent or paroxysmal atrial fibrillation and Dronedarone is indicated in persistent or flutter who are in sinus rhythm or will be un- paroxysmal atrial fibrillation, based on the dergoing cardioversion soon after starting the observed reduction of the rate of hospitaliza- drug. Dronedarone has no role in the acute

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management of atrial fibrillation, such as in coronary artery disease. Its use in patients who cardioversion to sinus rhythm in the emer- have undergone coronary artery bypass surgery gency department. remains to be defined. We do not have substantial evidence of the efficacy of dronedarone in patients with ■■ WHEN SHOULD WE SWITCH PATIENTS resistant atrial fibrillation, in whom multiple TO DRONEDARONE? antiarrhythmics have failed to maintain sinus rhythm, and no published trial has used the Preliminary experience suggests that droneda- inclusion criterion of treatment failure with rone, unlike most antiarrhythmic drugs, can other antiarrhythmic drugs. be safely started about 48 hours after amioda- The role of dronedarone in heart failure rone is discontinued. Cumulative toxicity has with preserved systolic function is unclear. Pa- not been noted with dronedarone. Caution tients taking dronedarone are twice as likely should be exercised when switching if the pa- as those taking amiodarone to have a recur- tient has baseline bradycardia or QT interval rence of atrial fibrillation. prolongation. No algorithm has been devel- The main advantage of dronedarone is oped for switching from other antiarrhythmic its lower adverse effect profile. However, this drugs to dronedarone. statement is based on only a few years of ob- servation. If the patient has developed adverse ■■ CONTRAINDICATIONS TO DRONEDARONE effects with amiodarone, or if the clinician is concerned about the risk of serious adverse Dronedarone is contraindicated in: effects, dronedarone presents an alternative • Patients with New York Heart Association for those patients without heart failure or (NYHA) class IV heart failure or NYHA significant left ventricular dysfunction. One class II or III heart failure with recent de- such group may be younger patients, because compensation requiring hospitalization or of concerns about the cumulative effects of referral to a specialized heart failure clinic amiodarone taken over a lifetime. • Patients with second- or third-degree atrio- Dronedarone may represent an accept- ventricular block or sick sinus syndrome Dronedarone able alternative to many of the current anti- (except when used in conjunction with a is designed arrhythmic drugs. Based on the results of functioning pacemaker) or bradycardia (a the Cardiac Arrhythmia Suppression Trial heart rate < 50 beats per minute) for initiation (CAST),15 class IC antiarrhythmics such as • Patients with a QTc interval of 500 ms or in an outpatient flecainide (Tambocor) are generally avoided longer setting in patients with prior myocardial infarction • Patients with severe hepatic impairment or with known or even suspected coronary • Women who are pregnant, are attempting artery disease. Similarly, sotalol (Betapace) to become pregnant, or are breast-feeding is generally avoided in patients with marked • Patients taking potent CYP3A inhibi- left ventricular hypertrophy because of ad- tors—antifungals like ketoconazole (Ni- verse effects.16 Dofetilide (Tikosyn) and often zoral), itraconazole (Sporanox), or vori- sotalol require hospitalization with telemetric conazole (VFEND); macrolide antibiotics monitoring for QTc prolongation and the risk like telithromycin (Ketek) or clarithromy- of proarrhythmia with torsades de pointes. cin (Biaxin); protease inhibitors; or other Dronedarone, however, generally can be safely drugs that prolong the QT interval. started in the outpatient setting. In patients with new or worsening heart As when considering prescribing any an- failure, one should consider suspending or tiarrhythmic, the clinician must assess the stopping dronedarone therapy. patient’s thromboembolic risk, since this risk persists with a rhythm control strategy. ■■ DRONEDARONE’S ADVERSE EFFECTS There is substantial evidence from the ATHENA trial,10 in which 30% of the pa- In trials to date, dronedarone has not shown tients had coronary artery disease, that drone- evidence of proarrhythmia (tachyarrhyth- darone is safe and effective in patients with mia or bradyarrythmia), torsades de pointes,

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or amiodarone-like organ toxicity affect- digoxin concentration about 2.5 times, and ing the thyroid or the lungs. Recently, rare this necessitates monitoring the digoxin level cases of severe hepatic injury were associated and possibly reducing the digoxin dose.13 with dronedarone; therefore, periodic liver Diuretics. Hypokalemia and hypomagne- function testing is advised for patients tak- semia may occur with concomitant adminis- ing dronedarone, especially during the first 6 tration of potassium-depleting diuretics. Po- months of therapy. tassium levels should be maintained in the Dronedarone has been associated with normal range before and during administra- higher rates of diarrhea, nausea, bradycardia, tion of dronedarone. QT interval prolongation, and cutaneous rash Tacrolimus, sirolimus. Dronedarone may compared with placebo. In DAFNE (Drone- increase levels of tacrolimus (Prograf) or siro- darone Atrial Fibrillation Study After Electri- limus (Rapamune) in posttransplantation pa- cal Cardioversion),17 10.8% of patients taking tients. This requires dose monitoring and ad- dronedarone had to stop taking it because of justment in concomitant therapy with these adverse events. With 800 mg daily, the dis- agents. continuation rate was only 3.9%. The most common cause of drug discontinuation was ■■ COST VARIES gastrointestinal effects. Anecdotal reports sug- gest that the gastrointestinal side effects may The cost of dronedarone varies based on fac- be self-limited and may not always require dis- tors that include location. Dronedarone’s re- continuation of the drug. tail cost ranges from $3.20 to $4.00 per pill Serum creatinine levels increase by about (approximately $7.20 per day). It is not avail- 0.1 mg/dL after the start of treatment. This able in generic form. It is presently covered by elevation occurs after 1 to 2 days, reaches a many health plans as a tier 2 drug, represent- plateau after 7 days, and is reversible. The ing a $15 to $40 monthly copay. mechanism is thought to be that dronedarone partially inhibits tubular organic cation trans- ■■ MORE DATA NEEDED Recently, porters, which in turn reduces renal creatinine rare cases of clearance by about 18%, but with no evidence Dronedarone represents the first in what may of an effect on glomerular filtration, renal well be a number of new antiarrhythmic drugs severe hepatic plasma flow, or electrolyte exchanges.18 A lim- for the treatment of patients with paroxysmal injury were ited increase in serum creatinine is, therefore, atrial fibrillation. Although less efficacious associated with expected with dronedarone treatment, but then amiodarone, dronedarone appears to be this does not mean there is a decline in renal better tolerated and have less serious side ef- dronedarone function. fects. It is contraindicated in patients with se- vere systolic dysfunction and in those with re- ■■ dronedarone and potential cent heart failure decompensation. It appears DRUG INTERACTIONS safe in coronary artery disease and marked left ventricular hypertrophy, unlike flecainide, Warfarin. Dronedarone does not increase propafenone (Rythmol), and sotalol. the international normalized ratio when used To further understand how dronedarone with warfarin (Coumadin). will fare against other antiarrhythmic drugs, Verapamil, diltiazem. Dose reduction is more studies with longer follow-up are need- required to avoid bradyarrhythmias with co- ed. These studies need to demonstrate supe- administration of moderate CYP3A4 inhibi- rior tolerability of dronedarone, acceptable tors such as verapamil (Calan, Verelan) and quality of life without unacceptable loss of ef- diltiazem (Cardizem). ficacy, or a decrease in morbidity or mortality Simvastatin. Dronedarone increases levels rates compared with amiodarone. of simvastatin (Zocor), a CYP3A4 substrate, Dronedarone can be safely started in most two to four times, thus increasing the risk of patients on an outpatient basis. The risk of statin-induced myopathy. proarrhythmia with dronedarone appears to be Digoxin. Dronedarone increases the serum very low. ■

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