Dronedarone for Prevention of Atrial Fibrillation: an Unfulfilled Promise?

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 associated with significant extra-cardiac side effects, and this has driven development 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 muscle and on membrane ionic currents, Ca2+ transient, and shortening of ventricular 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 microelectrode techniques. Four-week oral treatment with dronedarone or amiodarone increased the action potential duration (APD90) and effective refractory period 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 amiodarone by applying conventional microelectrode and patch-clamp techniques. Chronic treatment with dronedarone, unlike chronic administration of amiodarone, did not significantly lengthen the QTc interval of the electrocardiogram 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-dependent 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 administration dronedarone exhibits effects on cardiac electrical activity similar to those of amiodarone, but it lacks the ‘amiodarone-like’ chronic electrophysiological characteristics. Pantos et al. [8] investigated the effects of dronedarone and amiodarone administered for 2 weeks in normal and thyroxine-treated animals on plasma 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 placebo. 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 randomised 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 by 2 consecutive 12-lead ECGs or trans-telephonic elec- trocardiographic monitoring (TTEM) tracings recorded approximately 10 min apart, with both showing AF/AFl. Both trials showed a significant decrease in the risk of recurrence of AF/AFl (Table 1). In EURIDIS, the median time to first recurrence of AF/AFl was 2.3 times longer in the dronedarone group than in the placebo group, with a 22% lower risk of a recurrence during the study. In ADONIS, there was an almost three-fold increase in the median time to recurrence with dronedarone and a 28% reduction in the risk of AF/AFl recurrence. However, the arrhythmic recurrence was quite high (around 75% for placebo and 65% for dronedarone in EURIDIS), but it must be remembered that the trials enrolled patients with different types of symptoms; there might be differences according to duration of symptoms and also between patients with AF and AFl. Dronedarone for Prevention of Atrial Fibrillation: An Unfulfilled Promise? 113

Table 1. Patients with adjudicated first recurrence of atrial fibrillation (AF)/flutter (AFl)

Placebo Dronedarone RR 95% CI P value*

EURIDIS Patients with AF/AFl 155 272 0.78 0.64–0.95 0.0318 Median time to relapse 41 96 (days)

ADONIS Patients with AF/AFl 146 246 0.72 0.59-0.89 0.0017 Median time to relapse 58 158 (days)

*Log-rank test

There were three subgroups of the primary endpoint prespecified for analysis, according to whether patients had cardioversion within 5 days of randomisation, prior amiodarone treatment, or structural heart disease. All three subanalyses showed the benefit of dronedarone over placebo in all groups. Furthermore, fewer patients had symptomatic recurrence of AF/AFl with dronedarone in EURIDIS (P = 0.055) and ADONIS (P = 0.021). The other secondary endpoint of both trials, mean ventricular rate during AF/AFl at first recorded recurrence (12-lead ECG or TTEM), was significantly reduced in both trials (Table 2).

Table 2. Ventricular rate (bpm) at first recurrence of atrial fibrillation

Ventricular rate (bpm) Placebo Dronedarone P value

EURIDIS Mean 117.5 102.3 0.0001 SD 29.1 24.7 Min–max 70–204 53–173

ADONIS Mean 116.6 104.6 0.001 SD 31.9 27.1 Min–max 56–226 57–173 bpm beats per minute, SD standard deviation 114 A.Capucci et al.

The incidence of adverse events was similar in the dronedarone and placebo groups (Table 3). In addition, there was no evidence of pro-arrhythmia in the patients receiving dronedarone; in particular, no case of torsades de pointes was reported during the 12-month follow-up period. There was also no evidence of amiodarone-related toxicities (thyroid or pulmonary). However, few data are available on the side effects with longer follow-up. Some studies have suggested that dronedarone is an antagonist of the thyroid hormone receptor-α1, and experimental data have indicated that it may be associated with more side effects on lung tissue than amiodarone. These may not be of clinical importance, but they should be investigated long term, along with any ophthalmological and liver-related side effects. Another ques- tion that remains unanswered is how safe dronedarone is in patients with depressed left ventricular ejection fraction. One trial in the phase III development program, the Anti-arrhythmic Trial with Dronedarone in Moderate- to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA), carried out in Europe and evaluating high-risk patients, was stopped in January 2003 after an interim safety analysis identified a potential increased risk of heart failure death in the dronedarone group.

Table 3. EURIDIS and ADONIS pooled tolerability and safety data

Incidence of treatment-emergent Placebo Dronedarone 800 mg adverse events (TEAEs) (n = 409) (n = 828)

Any adverse events (%) 65.8 69.8

Any serious adverse events (%) 24.4 19.8

Deaths (%) 0.7 1.0

Permanent drug discontinuations 7.1 9.7 following TEAE (%)

Future Perspectives

The results of another phase III trial with dronedarone, the Efficacy and Safety of Dronedarone for the Control of Ventricular Rate (ERATO), in patients with AF/AFl are expected to be reported in 2005. In addition, a phase II study in patients with AF is ongoing in Japan. Results of a pilot study of dronedarone in patients with an implantable cardioverter defibrillator (ICD) and an indication for adjunctive anti- arrhythmic therapy were reported at the 2004 annual meeting of the Heart Dronedarone for Prevention of Atrial Fibrillation: An Unfulfilled Promise? 115

Rhythm Society. Dronedarone at doses below 2000 mg/day was found to be safe, did not cause deterioration in ICD function, and reduced the need for ICD therapy. However, further clinical studies are required before we have a definitive answer to whether dronedarone has real advantages over amiodarone and other amiodarone analogues in this clinical setting.

References

1. Coplen SE, Antman EM, Berlin JA et al (1990) Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a meta-analysis of ran- domized control trials. Circulation 82:1106–1116 2. Khan MH (2004) Oral class III antiarrhythmics: what is new? Curr Opin Cardiol Jan 19:47–51 3. Camm AJ (2000) Clinical differences between the newer antiarrhythmic agents. Europace 1:C16–C22 4. Doggrell SA, Hancox JC (2004) Dronedarone: an amiodarone analogue. Expert Opin Investig Drugs 13:415–426 5. Gautier P, Guillemare E, Marion A (2003) Electrophysiologic characterization of dronedarone in guinea pig ventricular cells. J Cardiovasc Pharmacol 41:191–202 6. Sun W, Sarma JS, Singh BN (2002) Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone. J Cardiovasc Pharmacol 39:677–684 7. Varro A, Takacs J, Nemeth M et al (2001) Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. Br J Pharmacol 133:625–634 8. Pantos C, Mourouzis I, Delbruyere M et al (2002) Effects of dronedarone and amiodarone on plasma thyroid hormones and on the basal and postischemic perfor- mance of the isolated rat heart. Eur J Pharmacol 444:191–196 9. Touboul P, Brugada J, Capucci A et al (2003) Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 24:1481–1487 10. Hohnloser SH (2004) EURIDIS and ADONIS: maintenance of sinus rhythm with dronedarone in patients with atrial fibrillation or flutter. Hot Line II: Acute coro- nary syndromes /medical treatment II. Program and abstracts from the European Society of Cardiology Congress, 28 August–1 September, 2004, Munich, Germany