Is dronedarone really safer than amiodarone?

Sir,

Atrial fibrillation (AF) is estimated to affect more than 10 million patients by 2050 in the United States.[1] Most patients develop recurrent AF within one year despite antiarrhythmic therapy.[2] Amiodarone has been the drug of choice for AF but has several side effects like tremors, peripheral neuropathy, pulmonary inflammation, hypo/hyperthyroidism, and photosensitivity. Dronedarone is a benzofuran analog of amiodarone, developed by modifying the structure of amiodarone. Dronedarone appears to share its pharmacological actions, but lacks the iodine component that is largely responsible for the multiple organ toxicities of the latter.

Several trials [A Placebo-Controlled, Double-Blind, 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 (ATHENA), the ANtiarrhythmic trial with DROnedarone in Moderate to severe CHF Evaluating morbidity DecreAse (ANDROMEDA), the EURopean trial In atrial fibrillation patients receiving Dronedarone for the maIntenance of Sinus rhythm (EURIDIS), the American-Australian-African trial with DronedarONe In atrial fibrillation patients for the maintenance of Sinus rhythm (ADONIS), and the Dronedarone Atrial FibrillatioN Study after Electrical Cardioversion (DAFNE)] have evaluated dronedarone in different populations. In ATHENA, cardiovascular death/hospitalization was significantly reduced in the dronedarone group compared to placebo in 4,628 patients with AF and additional risk factors. ANDROMEDA recruited patients with recent hospitalization for heart failure, and it was terminated early because dronedarone increased early mortality [hazard ratio (HR): 2.13]. ADONIS and EURIDIS showed significant prevention of AF recurrence HR compared with placebo.[3] The Randomized Double blind trIal to evaluate the efficacy and safety of drOnedarone (400 mg bid) versus amiodaroNe loading dose 600 mg dailY for 28 dayS then 200 mg daily thereafter for at least 6 mOnths for the maintenance of Sinus rhythm in patients with atrial fibrillation (AF) (DIONYSIS) was a comparative trial that demonstrated less efficacy for dronedarone, but improved tolerability compared to amiodarone. Dronedarone is not appropriate in patients with recently decompensated heart failure or those treated with strong CYP3A4 inhibitors or medications prolonging the QT interval.[4] The United States Food and Drug Administration (US FDA), after analyzing the results of clinical trials, approved dronedarone as an alternative to amiodarone, for the treatment of AF and flutter in patients who have either returned to a normal rhythm or who undergo drug therapy or electric shock treatment to maintain the normal rhythm. Since then, dronedarone has been used as an alternative to amiodarone with improved tolerability at the expense of decreased efficacy. However, another analysis for the efficacy and safety of amiodarone reported that the one-year net risk of events was 0.6% for hepatic toxicity, 0.3% for peripheral neuropathy, and 0.9% for hyperthyroidism. Hypothyroidism was quite common during the first year of treatment. These adverse drug reactions (ADRs) could be overcome by proper vigilance, periodic investigations, adjustment of dose, and proper treatment.[5] A study[6] comparing both drugs in AF and flutter reported that the tolerance of amiodarone is limited by noncardiac dose-related toxicity in spite of fewer cardiovascular adverse effects than many other antiarrhythmic drugs.

It has been concluded that for every 1,000 patients treated with dronedarone instead of amiodarone, there would be approximately 228 more recurrences of AF in exchange for 62 fewer adverse events requiring discontinuation of the drug.[7] There was no statistically significant difference between amiodarone and dronedarone for all-cause mortality. More patients discontinued treatment because of adverse effects with amiodarone than with dronedarone [odds ratio (OR): 1.81; 95% confidence interval (CI): 1.33 to 2.46; p <0.001). The incidence of thyroid toxicity (4 vs. 3%), symptomatic bradyarrhythmias (2.8 vs. 1.1%), and hepatotoxicity (3.5 vs. 2.5%) were comparable between dronedarone and placebo, whereas the incidence of thyroid toxicity (7.5 vs. 0%), symptomatic bradyarrhythmias (3.7 vs. 0%), and hepatotoxicity (0.1 vs. 0%) were more with amiodarone than placebo.

Recently, the FDA issued a warning that dronedarone should not be prescribed to patients with permanent AF as it significantly doubles the risk of cardiovascular death, stroke, systemic embolism, and heart failure rate in such patients. It has also advised to monitor the cardiac rhythm at least once every three months. Further, patients should stop taking dronedarone and, if clinically indicated, should undergo cardioversion. The warning was based on data from the PALLAS trial.[8] The FDA is still reviewing the Risk Evaluation and Mitigation Strategy (REMS) to determine whether the benefits of the drug outweigh the risks. It is suggested that the prescriber should remain vigilant while prescribing these drugs.