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. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NUMBER 3 MARCH 2011 179 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. DRONEDARONE ■ 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. 180 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NUMBER 3 MARCH 2011 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. PENUGONDA AND COLLEAGUES ■ 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