Dronedarone for atrial fibrillation: How does it compare with amiodarone?
ABSTRACTDronedarone (Multaq), an analogue of amiodarone (Cordarone), was designed to cause fewer adverse effects than the parent compound. Studies have indeed shown dronedarone to be safer than amiodarone, but less effective. Its official indication is to reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter and other cardiovascular risk factors, reflecting the parameters of its effectiveness in clinical trials.
KEY POINTS
- Patients with persistent or paroxysmal atrial fibrillation are candidates for dronedarone therapy if they are in sinus rhythm or will be cardioverted soon after starting. This drug is not indicated for the acute management of atrial fibrillation, for example, in the emergency department.
- Dronedarone is an option if a patient cannot tolerate amiodarone or has an underlying condition such as pulmonary or thyroid disease that is a contraindication to amiodarone.
- Dronedarone is contraindicated in patients with significant left ventricular dysfunction or heart failure with recent decompensation.
- The ultimate role for dronedarone is yet to be defined. Little evidence exists as to whether it will succeed when other drugs have failed.
Dronedarone (Multaq), approved by the US Food and Drug Administration in July 2009, is a congener of the antiarrhythmic drug amiodarone (Cordarone). Designed in the hope that it would be safer than amiodarone, its official indication is to lower the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. However, its precise role in the management of atrial fibrillation is yet to be defined. If dronedarone remains well tolerated, it may permit clinicians to pursue a rhythm control strategy more often. In this article, we present a progress report on this new agent.
BETTER ANTIARRHYTHMIC DRUGS ARE NEEDED
Atrial fibrillation increases the risk of stroke fivefold and accounts for 15% to 20% of all strokes.1 It also increases the risk of heart failure. Drugs are the mainstay of therapy, but many antiarrhythmic drugs are not very effective and cause cardiac and extracardiac toxicity. Thus, the need for safe and effective new drugs.2
Much effort is going into the development of drugs that target specific ion channels or proteins expressed predominantly in atrial myocardium. The rationale is to avoid the unwanted effects of ionic currents on the ventricle and thus avoid ventricular proarrhythmic effects. At the same time, alternatives to the multiple channel blocker amiodarone, 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 toxicity.
RATE CONTROL VS RHYTHM CONTROL
In the acute care setting, heart rate control with atrioventricular nodal agents (beta-blockers, calcium channel blockers, and digitalis) is the preferred initial strategy in most hemodynamically stable patients presenting with new-onset atrial fibrillation.3
Since we lack an effective method for maintaining sinus rhythm without incurring significant adverse effects, rate control is also often chosen for chronic management of atrial fibrillation. This is particularly true for patients who have no symptoms or only minimal symptoms and in whom adequate rate control is easily attained. Indeed, results of large clinical trials suggest that rate control is satisfactory for many patients.
The main purpose of rate control is to control symptoms as opposed to merely lowering the ventricular rate. Effective rate control often prevents hemodynamic instability in patients with underlying heart disease who present acutely with atrial fibrillation. In patients with permanent atrial fibrillation, the RACE II study4 (Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient Versus Strict Rate Control II), during a 3-year follow-up, showed that lenient rate control (resting heart rate < 110 beats per minute) is not inferior to strict rate control (resting heart rate < 80 beats per minute) in preventing major cardiovascular events (heart failure, stroke) or arrhythmic events such as syncope and sustained ventricular tachycardia.4
As a long-term strategy, rate control also prevents tachycardia-induced cardiomyopathy, reduces the risk of worsening of underlying heart failure, and can improve symptoms and quality of life.
Although maintenance of sinus rhythm is most likely associated with a survival benefit, heart rhythm control with antiarrhythmic drugs has not shown an advantage over rate control in overall or cardiovascular death rates, thromboembolic complications, or impact on heart failure. Indeed, a rhythm control strategy has been associated only with better exercise tolerance and, although less clear, with better quality of life.5
One possible explanation as to why a rhythm control strategy has not been shown to be superior to a rate control strategy is the side effects of the presently available drugs for rhythm control.
In a subgroup analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial,6 antiarrhythmic therapy was associated with a 49% increase in the mortality rate that offset the benefits of conversion and maintenance of sinus rhythm, which was associated with a 53% reduction in mortality rates.
The hope is that newer drugs with less toxicity may produce better outcomes for patients treated with rhythm control.
AN ANALOGUE OF AMIODARONE, WITHOUT THE IODINE
Dronedarone is a structurally modified version of amiodarone, the antiarrhythmic drug that has shown the greatest efficacy at maintaining sinus rhythm in patients with paroxysmal atrial fibrillation. Although historically amiodarone has been effective in maintaining sinus rhythm and has been used safely in patients with advanced heart failure, its use has been limited by cumulative and often irreversible extracardiac organ toxicity.
Dronedarone was designed to match amiodarone’s efficacy but with a better safety profile. An iodine radical makes up more than one-third of amiodarone’s molecular weight. The omission of iodine in dronedarone was intended to reduce the likelihood of toxic side effects.
Dronedarone is a benzofuran derivative pharmacologically related to amiodarone, with the addition of a methylsulfonamide group. This reduces lipophilicity and the propensity to cross the blood-brain barrier; over a 2-year period this drug has not been shown to have neurotoxic effects.7
Dronedarone has proved efficacious without toxic or proarrhythmic effects and has minimal side effects, but concerns remain regarding its use in advanced heart failure. To date, its adverse-event profile appears comparable to that of placebo. However, whether its efficacy and incidence of adverse effects are comparable to what has been reported in the literature may take time to assess.
