Dronedarone: Boon or bust?

A

trial fibrillation (AF) affects over 2.2 million Americans and is estimated to affect up to 10 million by 2050.¹ This disorder and its associated complications are becoming more prevalent as the US population ages. Because AF remains an increasing cause of morbidity and mortality, and its incidence is expected to rise dramatically, cardiologists are continuously searching for new treatments. In spite of advances in catheter-based ablation techniques and implantable devices, suppression of atrial and ventricular arrhythmias is often accomplished with the use of antiarrhythmic medications. Unfortunately, currently available medications are limited by lack of effectiveness, intolerable adverse effects, and risk of potentially fatal proarrhythmia. In fact, worse mortality outcomes in clinical trials have led to restrictions on drug use in many patients at highest risk for developing arrhythmias.^2-4

When treating AF in patients with coronary artery disease or left ventricular systolic dysfunction, clinicians’ options are limited to Vaughan Williams Class III medications (dofetilide [Tikosyn], sotalol [Betapace, Sotalex], and amiodarone [Cordarone]) for rhythm control.⁵ Of these, dofetilide and sotalol require close monitoring to minimize the risk of proarrhythmia, specifically torsade de pointes. Both medications must be adjusted for renal insufficiency and require hospitalization with electrocardiographic monitoring during initiation or dose titration. Although amiodarone carries less risk for proarrhythmia,⁶ many noncardiac adverse effects limit its usefulness; thus, the search continues for an antiarrhythmia medication that is safe and effective in patients with various comorbidities and that has a low risk of proarrhythmia or other serious adverse effects. Dronedarone is a novel class III antiarrhythmic medication that is being developed in an attempt to fill this void.

Mechanism of action

Dronedarone’s chemical structure is similar to amiodarone, but it does not contain iodine, the element that infers much of amiodarone’s toxicity. Animal studies reveal that dronedarone inhibits calcium, sodium, and several types of potassium channels as well as alpha- and beta-adrenergic receptors.⁷ This multichannel antagonism results in decreased heart rate and blood pressure and lengthening of the PR- and QTc-intervals.⁸ Its pharmacokinetic parameters are distinct from amiodarone, most notably a shorter half-life and a much smaller volume of distribution (

).^9-11

Table

Safety

The most common adverse effects observed with dronedarone have been gastrointestinal ailments. Thus far, clinical trials have demonstrated no pulmonary toxicity with dronedarone, and, unlike amiodarone, no adverse effects on the thyroid have been encountered.¹² Dronedarone is not renally eliminated, yet clinical trials have shown significantly increased serum creatinine levels in subjects receiving this therapy.¹³ It appears this results from inhibition of the renal cation transport system, but the glomerular filtration rate does not seem to be affected. Of note, dofetilide toxicity has been documented when it is used concomitantly with other medications that

are eliminated via the renal cation transport system. Although this has not been documented for dronedarone, there is a possibility for drug interactions similar to those with dofetilide (ie, metformin [Glucophage, Glumetza, Fortamet, Riomet], hydrochlorothiazide [eg, Aldoril, Lopressor, Moduretic]).

Clinical trials

DAFNE trial

The DAFNE (Dronedarone Atrial Fibrillation Study after Electrical Cardioversion) trial was a dose-ranging study to elucidate the most appropriate dose of dronedarone to maintain sinus rhythm after cardioversion in patients with persistent AF.⁸ The primary efficacy outcome was time to first AF recurrence. The trial included 199 patients who were randomized to dronedarone, 800, 1200, or 1600 mg daily, or to placebo. Patients were followed for up to 6 months. Only the 800-mg dose of dronedarone showed significant improvement over placebo for the primary outcome (60 vs 5 days to AF recurrence,

P

= .001). Maintenance of sinus rhythm at 6 months was 35% with 800 mg of dronedarone compared with 10% for placebo. There did not appear to be a dose-response relationship with dronedarone; thus, the dose for subsequent trials would be 400 mg twice daily.

EURIDIS trial

EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm) were jointly published phase 3 trials.¹⁴ More than 1200 patients with paroxysmal AF or atrial flutter were randomized to dronedarone, 400 mg twice daily, or to placebo and followed for 1 year. Notably, few patients with heart failure were enrolled (17%), and patients with New York Heart Association (NYHA) class III and IV heart failure were excluded. All patients were in normal sinus rhythm at study initiation, and the primary outcome was time to arrhythmia recurrence. Dronedarone significantly delayed arrhythmia recurrence (116 vs 53 days) compared with placebo. Recurrence at 1 year was lower in the dronedarone group than in the placebo group (64.1% vs 75.2%,

P

<.001). No incidence of torsade de pointes was reported in either trial. These trials show that dronedarone is safe and effective for maintenance of sinus rhythm in patients who have AF but no heart failure.

ERATO trial

The ERATO (Efficacy and Safety of Dronedarone for Control of Ventricular Rate) trial was undertaken to evaluate the effect of dronedarone on control of ventricular rate.¹⁵ All patients had symptomatic permanent AF and had failed traditional methods of rate control, including other antiarrhythmic medications. Patients included were randomized to receive dronedarone or matching placebo and were followed for 14 days. The investigators found a statistically significant decrease in both resting and exercise heart rate in the dronedarone treatment group, but no improvement in exercise tolerance or symptoms was observed.

ANDROMEDA trial

To address dronedarone use in heart failure patients, the ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease) study was conducted.¹⁶ Patients hospitalized for new or worsening heart failure and with at least 1 episode of shortness of breath or paroxysmal nocturnal dyspnea within 1 month of admission were randomized to dronedarone, 400 mg twice daily, or to matching placebo. The 626 patients enrolled in this trial had an estimated average ejection fraction of 35% or less. The primary end point was the composite of death from any cause or hospitalization for heart failure. The study was stopped because of excessive mortality in the dronedarone group (25 vs 12 patients in the placebo group,

P

= .03). The ANDROMEDA results show that dronedarone should be avoided in patients with NYHA class III or IV heart failure.

ATHENA trial

The ATHENA (A Placebo-controlled, Doubleblind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter) trial evaluated the effect of dronedarone on mortality or cardiovascular hospitalization in patients with AF.¹⁷ Patients were included if they were older than 75 years or at least 70 years of age with 1 or more cardiovascular risk factors. Patients with NYHA class IV heart failure were excluded from this trial, but those with class II or class III were allowed in the study. In this trial of over 4600 moderate- to high-risk elderly AF patients, those who received dronedarone showed a 24% relative drop in risk of cardiovascular hospitalizations or death over almost 2 years compared with those receiving placebo.¹⁸ Analysis revealed that a statistically significant drop in risk of cardiovascular death with dronedarone was driven by fewer arrhythmic deaths. There was also a significant decline in cardiovascular hospitalizations, which was primarily attributed to reductions in admissions for AF and acute coronary syndromes.

Potential place in therapy

Because so many people suffer from cardiac dysrhythmias, research to identify medications relatively free of major adverse drug events and with established safety and efficacy in a variety of patient subpopulations is ongoing. Dronedarone, a new noniodinated amiodarone analogue, has been studied for the maintenance of normal sinus rhythm in patients with AF and atrial flutter, as well as morbidity and mortality outcomes. Dronedarone has been shown to increase the time to recurrence of AF and to provide rate control of AF as compared with placebo. In ATHENA, for the first time, an antiarrhythmic drug for AF seemed to reduce cardiovascular mortality. This is in contrast to the majority of antiarrhythmic drugs, which actually increase mortality; however, safety of dronedarone in patients with class IV heart failure remains a concern.

Dronedarone has demonstrated several advantages over other class III antiarrhythmic medications, many of which are pharmacokinetic, but the most important appears to be a low incidence of torsade de pointes and other proarrhythmic effects. A major advantage of dronedarone over amiodarone is lack of long-term pulmonary toxicity. Having established safety compared with placebo, we now need head-to-head trials against amiodarone with longer follow-up to confirm their relative safety profiles.

The DIONYSUS (Dronedarone versus Amiodarone for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation) study will compare dronedarone directly with amiodarone for maintenance of sinus rhythm in a randomized AF trial.

Based upon the ATHENA data, Sanofi-Aventis plans to submit a registration dossier to the European Medicines Agency and a new drug application to the US Food and Drug Administration during the third quarter of 2008. If approved, dronedarone will likely be used for the maintenance of normal sinus rhythm in patients with atrial arrhythmias without concomitant

class IV heart failure.