Dronedarone for Prevention of Atrial Fibrillation: An Unfulfilled Promise? A. CAPUCCI, G.Q.VILLANI,D.ASCHIERI,M.PIEPOLI The prophylactic treatment for many patients with atrial fibrillation (AF) remains unsatisfactory. The ideal anti-arrhythmic drug for the prevention of recurrences of both AF after cardioversion and paroxysmal AF is still a long way off. AF has an high propensity to recur, and only one-quarter of patients who undergo successful cardioversion remain in sinus rhythm at 1 year if no additional therapy is used [1]. Since the publication of studies documenting that certain class I drugs may increase mortality in high-risk post-infarction patients, basic science and clinical studies have focused on class III anti-arrhythmic drugs. Class III agents remain the focus of drug development efforts because they lack nega- tive haemodynamic effects, affect both atrial and ventricular tissue, and can be administered as either parenteral or oral preparations. Amiodarone is one of the most effective, and is associated with a comparatively low risk of drug-induced pro-arrhythmia, probably due to its multiple pharmacological actions on cardiac ion channels and receptors. However, amiodarone is asso- ciated with significant extra-cardiac side effects, and this has driven develop- ment of amiodarone analogues [2]. Developers of newer anti-arrhythmic agents have focused on identifying anti-arrhythmic medications with the following characteristics: appropriate modification of the arrhythmia substrate, suppression of arrhythmia trig- gers, efficacy in pathological tissues and states, positive rate dependency, appropriate pharmacokinetics, equally effective oral and parenteral formula- tions of similar efficacy in arrhythmias and their surrogates, few side effects, positive frequency blocking actions, and cardiac-selective ion channel block- Cardiology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy 110 A.Capucci et al. ade. New and investigational agents include azimilide, dofetilide, ersentilide, ibutilide, tedisamil, and trecetilide [3]. Dronedarone is one of a number of analogues that derive from the cur- rently most successful class III anti-arrhythmic drug, amiodarone [4]. This review describes some new studies providing insight into the mechanism of its action and the latest developments in the clinical usage of this drug. Electrophysiological Properties Dronedarone is a non-iodinated amiodarone derivative that inhibits Na+,K+, and Ca2+ currents. It is a potent inhibitor of the acetylcholine-activated K+ current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K+ currents and inhibits the L-type calcium current. It is also an antagonist at α- and β- adrenoceptors and, unlike amiodarone, has little effect at thyroid receptors. It is more potent than amiodarone in inhibiting arrhythmias and death in animal models of ischaemia- and reperfusion-induced arrhythmias [4]. Gautier et al. [5] studied the electrophysiological properties of dronedarone on the action potential (AP) and contraction of papillary mus- cle and on membrane ionic currents, Ca2+ transient, and shortening of ven- tricular cells of the guinea pig heart. The effects of dronedarone on AP dura- tions (APDs) at different percentages of repolarisation were not significantly changed, except for a slight decrease in APD30 and APD50 at the highest con- centration. In isolated ventricular myocytes, dronedarone inhibited rapidly + activating delayed rectifier K current (IKr), slowly activating delayed-rectifi- + er K current (IKs), and voltage-dependent and time-, frequency-, or use- independent and inward rectifier potassium current (IK1). Moreover, 2+ dronedarone blocked L-type Ca current (ICa(L)) in a use- and frequency- dependent manner. Simultaneously with these electrophysiological effects, dronedarone reduced contraction amplitudes of papillary muscle and decreased Ca2+ transient and shortening of ventricular myocytes. The results show that dronedarone is a multi-channel blocker because it decreases dV/dtmax (INa), ICa(L), IKr, IKs,and IK1 very similarly to amiodarone in cardiac ventricle, despite the absence of iodine in its molecular structure. Sun et al. [6] compared the acute and chronic electrophysiological effects of dronedarone and amiodarone in isolated rabbit atrial muscle by microelec- trode techniques. Four-week oral treatment with dronedarone or amiodarone increased the action potential duration (APD90) and effective refractory peri- od with an inverse rate dependency. In contrast to this, acute superfusion with 10 μM dronedarone or amiodarone decreased APD90, the effective refractory period, and the maximum upstroke slope of the action potential. Dronedarone for Prevention of Atrial Fibrillation: An Unfulfilled Promise? 111 However, dronedarone can not be considered a simple copy of amiodarone. Varro et al. [7] studied the electrophysiological effects of dronedarone after chronic and acute administration in dog Purkinje fibres, papillary muscle, and isolated ventricular myocytes, and compared them with those of amio- darone by applying conventional microelectrode and patch-clamp tech- niques. Chronic treatment with dronedarone, unlike chronic administration of amiodarone, did not significantly lengthen the QTc interval of the electro- cardiogram or the APD in papillary muscle. After chronic oral treatment with dronedarone, a small but significant use-dependent Vmax block was noticed, while after chronic amiodarone administration a strong use-depen- dent Vmax depression was observed. Acute superfusion of dronedarone, like that of amiodarone, moderately lengthened APD in papillary muscle but shortened it in Purkinje fibres. Both dronedarone and amiodarone superfusion reduced the incidence of early and delayed in Purkinje fibres. The authors showed that after acute adminis- tration dronedarone exhibits effects on cardiac electrical activity similar to those of amiodarone, but it lacks the ‘amiodarone-like’ chronic electrophysi- ological characteristics. Pantos et al. [8] investigated the effects of dronedarone and amiodarone administered for 2 weeks in normal and thyroxine-treated animals on plas- ma thyroid hormones and the possible consequences on the response of the heart to ischaemia. Amiodarone resulted in increased T4,T4/T3,and rT3, whereas dronedarone did not alter the thyroid hormone profile in normal animals. In thyroxine-treated animals, amiodarone increased the T4/T3 ratio but T4,T3,and rT3 levels were not altered. Baseline functional parameters and ischaemic contracture were not changed by amiodarone and/or dronedarone in either normal or thyroxine-treated hearts. Clinical Studies At present three clinical studies have demonstrated that the drug is safe and effective for the maintenance of normal sinus rhythm in patients with atrial fibrillation (AF) or atrial flutter (AFl). In the Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE), a phase IIb clinical trial, a dose of 800 mg dronedarone per day was established as effective and safe for the prevention of AF relapses after cardioversion [9]. Patients with persistent AF were randomly allocated to receive a daily dose of 800 mg, 1200 mg, or 1600 mg dronedarone or place- bo. The main analysis was conducted on 199 of 270 patients who entered the maintenance phase following pharmacological cardioversion or, if that was unsuccessful, DC cardioversion. Within a 6-month follow-up period, the time 112 A.Capucci et al. to AF relapse increased in the group receiving dronedarone 800 mg, with a median of 60 days compared to 5.3 days in the placebo group [relative risk reduction 55% (95% CI, 28 to 72%) P = 0.001]. No significant effect was seen at higher doses. Spontaneous conversion to sinus rhythm on dronedarone occurred in 6–15% of patients (P = 0.026). There were no pro- arrhythmic reactions. Drug-induced QT prolongation was only noticed in the 1600 mg group. Premature drug discontinuation affected 23% of subjects given 1600 mg dronedarone versus 4% on 800 mg and was mainly due to gastrointestinal side effects. No evidence of thyroid, ocular, or pulmonary toxicity was found. Recently the results of two phase III trials were reported at the 2004 European Society of Cardiology Congress [10]. In the European Trial In Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and the American–Australian Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS), dronedarone administered at a dose of 400 mg twice daily was effective in preventing both symptomatic and asymptomatic recurrences of AF or AFl and had a safety profile similar to that of placebo. Patients enrolled in EURIDIS and ADONIS were men and women aged > 21 years who had been in sinus rhythm for ≥ 1 h at the time of randomisation and had experienced at least one electrocardiogram (ECG)-documented episode of AF/AFl during the previous 3 months. After a screening period (pre-trial day 6 to day 1), patients in both trials were ran- domised 2:1 (dronedarone:placebo) to receive either 400 mg twice daily of dronedarone or matching placebo twice daily for 12 months. A total of 1237 patients were enrolled in both trials, 828 randomised to dronedarone and 409 to placebo. The primary endpoint of both trials – time from randomisation to first documented AF/AFl occurrence – was defined as an episode lasting ≥ / = 10 minutes as indicated