Dronedarone: an alternate choice to sotalol and amiodarone in the treatment of atrial fibrillation/flutter in patients who have coronary heart disease.

A large number of patients with atrial fibrillation (AF) have coronary heart disease (CHD) or concomitant risk factors. In ATHENA (A placebo controlled, double blind Trial to assess the efficacyof dronedarone for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation and flutter), 30% of the patients had CHD. The results of the CAST (Cardiac Arrhythmia Suppression Trial) led physicians to carefully select antiarrhythmic drugs that can be used safely in the CHD population. The clinical trials have demonstrated neutral mortality risk in CHD patients treated with sotalol, amiodarone, dofetilide, and most recently dronedarone. 6 Based on these data, these drugs have been recommended by the guidelines for use in the CHD population. –9 Dofetilide is only available in the USA and not included in the ESC guidelines. Thus, physicians in most countries only have sotalol, amiodarone, and dronedarone as therapeutic options for the treatment of AF in patients with CHD. Owing to the over prescribing of amiodarone and its potential adverse effects, the revised guidelines downgraded amiodarone as a second choice in many patient subgroups with AF. The results of the PALLAS (Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard therapy) raised concerns of adverse outcomes with dronedarone in patients with permanent AF and this concern diminished some of the enthusiasm for using dronedarone as a front-line alternative to amiodarone. The ATHENA trial demonstrated that dronedarone significantly reduced cardiovascular hospitalization and death. ATHENA was the largest antiarrhythmicdrug trial in AF/atrial flutter (4628 patients) ever performed. The explanation of this benefit has puzzled clinicians since other drugs, like amiodarone, have not been able to demonstrate this beneficial effect. An overlooked finding of the ATHENA was the 30% reduction of cardiovascular hospitalization secondary to acute coronary syndromes (ACS). This outcome suggested the possible benefit and safety of dronedarone use in a CHD population. In apost hoc analysis of theCHD patients in theATHENApublished in this issue of the Journal, Pisters et al. highlight some of dronedarone’s benefits in a substudy of 1405 patients followed for 2.5 years. The primary outcome (cardiovascular hospitalization or death) occurred in 47% of the placebo comparedwith 38% of the dronedarone population. This 27% relative risk reduction in the primary endpoint was statistically significant (P 1⁄4 0.0002) and consistent with the overall ATHENA findings (24% decrease). In addition, dronedarone reduced the number of first ACS events by 33% compared with the placebo (P 1⁄4 0.04). The mechanism of these beneficial findings has not been wellstudied. Dronedarone, similar to amiodarone, is a coronary artery dilator, slows the heart rate, and has a low risk of ventricular proarrhythmia. Dronedarone causes coronary vasodilatation that is refractory to the inhibition of the nitric oxide synthase pathway while amiodarone has coronary vasodilatation highly dependent on this pathway. In vitro studies demonstrate that dronedarone is a more potent inhibitor of the slow L-type calcium channels when compared with amiodarone. Dronedarone is an antagonist of the aand the b-adrenoreceptors and thus exhibits Class II activity, but has less b-1 adrenoreceptor antagonistic effect compared with amiodarone. Multiple basic science studies have demonstrated that dronedarone suppresses ischaemia-induced and reperfusion ventricular arrhythmias. 19 It is unclear if any of these mechanisms explain the safety of dronedarone in CHD. Pisters et al. stated that ‘whilst the underlying mechanism of action is unclear, dronedarone appears to prevent the occurrence of microcirculatoryabnormalities in the ventricles during AF. The alleviation of these abnormalities, which appear to represent early changes in the myocardial structure of AF patients, suggests that dronedarone might be particularly effective in the early stages of the disease’. Some of dronedarone’s benefits might partially be explained by its ability to decrease systolic and diastolic blood pressure by