WO2012020377A1

WO2012020377A1 - Use of dronedarone for the preparation of a medicament for rhythm- and rate-controlling in patients with atrial fibrillation

Info

Publication number: WO2012020377A1
Application number: PCT/IB2011/053555
Authority: WO
Inventors: Christophe Gaudin; Martin Van Eickels
Original assignee: Sanofi
Priority date: 2010-08-11
Filing date: 2011-08-09
Publication date: 2012-02-16

Abstract

The present invention relates to the use of dronedarone or pharnnaceutically acceptable salts thereof, for the preparation of a medicament for rhythm- and rate-control in patients with atrial fibrillation.

Description

USE OF DRONEDARONE FOR THE PREPARATION OF A MEDICAMENT FOR RHYTHM- AND RATE-CONTROLLING IN PATIENTS WITH ATRIAL

FIBRILLATION

The present invention relates to the use of dronedarone or pharmaceutically acceptable salts thereof, for the preparation of a medicament for rhythm- and rate- control in patients with atrial fibrillation.

This invention also relates to methods for reducing the recurrence of AF/AFL in a patient comprising administering dronedarone.

This invention also relates to methods of preventing cardioversion in a patient comprising administrating to said patient a therapeutically effective amount of dronedarone, or a pharmaceutically acceptable salt thereof.

This invention also relates to methods of treating "permanent" AF/AFL in a patient comprising administrating to said patient a therapeutically effective amount of dronedarone, or a pharmaceutically acceptable salt thereof.

2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- methylsulphonamidobenzofuran, or dronedarone, and pharmaceutically acceptable salts thereof are described in European Patent EP 0 471 609 B1 .

Dronedarone blocks potassium, sodium and calcium channels and also has anti- adrenergic properties.

Dronedarone is an anti-arrhythmic that is effective in maintaining sinus rhythm in patients presenting atrial fibrillation or atrial flutter.

List of abbreviations

AF/AFL atrial fibrillation or atrial flutter ATHENA 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

CI confidence interval

ECG electrocardiogram

HR hazard ratio

The applicant has clinically proven that dronedarone significantly reduces cardiovascular hospitalizations and/or mortality in patients having a history of atrial fibrillation or of atrial flutter, in a safe and effective way.

In fact, the use of benzofuran derivatives to reduce post-infarction mortality in patients having a reduced left ventricular function after myocardial infarction, without any rhythm disorder requiring an anti-arrhythmic treatment, is known from Patent Applications WO 98/40067 and WO 97/34597.

In WO2009/144550, dronedarone has been shown to reduce relevant clinical endpoints such as cardiovascular hospitalizations or death in patients with atrial fibrillation (AF) and additional risk factors and notably in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter >50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted.

Atrial fibrillation is the most common arrhythmia that requires treatment, and is responsible for substantial morbidity and expenditure of health care dollars in the US and throughout the world. (Go AS, et al., JAMA 2001 ; 285: 2370- 2375). While rhythm control has not been demonstrated to provide a survival benefit, as compared with simply controlling the rate with AV nodal blocking, many patients desire maintenance of sinus rhythm to improve symptoms. (Roy D, et al., New Engl J Med 2008;358:2667-2677). Although ablation has been established to be a good option in many cases, drug therapy remains first-line therapy and is desired in many cases. Drug therapy for maintenance has been limited in terms of both efficacy and safety. (Roy D, et al., New Engl J Med 2008;358:2667-2677).

Dronedarone is a multichannel blocking antiarrhythmic drug for the treatment of patients with atrial fibrillation. In a dose-ranging study (Touboul P, et al., Eur Heart J2003 Aug;24(16):1481 -1487), and two large randomized placebo-controlled trials (EURIDIS and ADONIS), the rhythm-controlling efficacy of dronedarone has been demonstrated. (Singh BN, et al., N Engl J Med 2007;357:987-999). In addition, it was shown in the ERATO trial that dronedarone has rate-controlling properties in patients with permanent atrial fibrillation. (Davy JM, et al., Am Heart J 2008;156:52: e1 -9). However, the ANDROMEDA trial, comparing dronedarone with placebo in patients hospitalized with symptomatic unstable heart failure and severe left ventricular systolic function, was terminated early due to increased mortality among the patients receiving dronedarone. (Kober L, et al., N Engl J Med 2008; 358:2678- 2687). Of note, less than 40% of the patients in both arms of the study had atrial fibrillation at baseline.

A post hoc analysis of the EURIDIS and ADONIS trials suggested that dronedarone reduced the risk for cardiovascular hospitalization or death from any cause. The ATHENA (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) was undertaken to evaluate the effect of dronedarone on a combined endpoint of all- cause mortality and cardiovascular hospitalization, in a moderate- to high-risk population with atrial fibrillation who were believed to potentially benefit from antiarrhythmic drug therapy in a large outcomes trial. (Hohnloser SH et al., J Cardiovasc Electrophysiol 2008;19:69-73). Patients that met the enrollment criteria for the ANDROMEDA study were excluded from ATHENA. The ATHENA trial did not aim to reexamine the antiarrhythmic efficacy of the agent, but rather was designed to assess the safety of dronedarone in patients with AF and to evaluate for the clinical benefit of dronedarone that had been previously observed in the post hoc analysis of the EURIDIS and ADONIS trials. ATHENA demonstrated that dronedarone reduced major clinical outcomes in patients with atrial fibrillation including cardiovascular hospitalizations, cardiovascular mortality, and stroke. (Hohnloser SH, et al., N. Engl. J. Med. 2009;360:668-678) (Connolly SJ, et al., Circulation 2009;120:1 174-1 180).

The post hoc analysis of the present invention was undertaken to examine the rhythm and rate controlling effects of dronedarone in ATHENA

Thus a subject of the invention is the use of dronedarone for the preparation of a medicament for rhythm and rate-controlling in patients with atrial fibrillation.

Another subject of the invention is the use of dronedarone for the preparation of a medicament for use in the prevention of recurrence of AF/AFL or the lowering of ventricular rate notably in patients with atrial fibrillation notably patient as defined in the ATHENA study.

Among the patients of ATHENA, mention may be made of a first group of patients having a history of atrial fibrillation or atrial flutter.

Among the patients of ATHENA, notably patients having a history of atrial fibrillation or atrial flutter, mention may also be made of a second group of patients also exhibiting at least one of the following risk factors:

age notably equal to or above 70, or even above 75,

hypertension,

diabetes,

- history of cerebral stroke or of systemic embolism, i.e. prior cerebrovascular accident,

- left atrial diameter greater than or equal to 50 mm measured for example by echocardiography,

- left ventricular ejection fraction less than 40%, measured for example by two-dimensional echography. Among the patients of ATHENA, notably patients having a history of atrial fibrillation or atrial flutter, mention may also be made of a third group of patients also exhibiting additional risk factors, i.e. at least one of the following pathologies:

hypertension,

underlying structural heart disease,

tachycardia,

coronary disease,

non-rheumatic heart valve disease,

dilated cardiomyopathy of ischemic origin,

- ablation of atrial fibrillation or flutter, for example catheter ablation or endomyocardial ablation,

- supraventricular tachycardia other than atrial fibrillation or flutter,

- history of heart valve surgery,

- non-ischemic dilated cardiomyopathy,

- hypertrophic cardiomyopathy,

- rheumatic valve disease,

- sustained ventricular tachycardia,

- congenital cardiopathy,

- ablation, for example catheter ablation, for tachycardia other than for atrial fibrillation or flutter,

- ventricular fibrillation,

and/or at least one cardiac device chosen from:

a cardiac stimulator,

an implantable defibrillator ("ICD").

Among the patients of ATHENA, notably patients having a history of atrial fibrillation or atrial flutter, mention may also be made of a fourth group of patients not exhibiting at least one of the following criteria:

- Refusal or inability to give informed consent to participate in the study.

- Any non cardiovascular illness or disorder that could preclude participation or severely limit survival including cancer with metastasis and organ transplantation requiring immune suppression - Pregnant women (pregnancy test must be negative) or women or childbearing potential not on adequate birth control: only women with a highly effective method of contraception [oral] contraception or intra-uterine device (IUD) or sterile can be randomize.

- Breastfeeding women

- Previous (2 preceding months) or current participation in another trial with an investigational drug (under development) or with an investigational device.

- Previous participation in this trial.

- Patients in permanent atrial fibrillation

- Patients in unstable hemodynamic condition such as acute pulmonary edema within 12 hours prior to start of study medication; cardiogenic shock; treatment with IV pressor agents; patients on respirator; congestive heart failure of stage NYHA IV within the last 4 weeks; uncorrected, hemodynamically significant primary obstructive valvular disease; hemodynamically significant obstructive cardomyopathy; a cardiac operation or revascularization procedure within 4 weeks preceding randomization

- Planned major non-cardiac or cardiac surgery or procedures including surgery for valvular heart disease, coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), or on urgent cardiac transplantation list

- Acute myocarditis or constrictive pericarditis

- Bradycardia < 50 bpm and/or PR-interval > 0.28 sec on the last 12-lead ECG.

- Significant sinus node disease (documented pause of 3 seconds or more) or 2^nd or 3^rd degree atrioventricular block (AV-block) unless treated with a pacemaker.

- Need of a concomitant medication that is prohibited in this trial, including the requirement for Vaughan Williams Class I and III anti-arrhythmic drugs, that would preclude the use of study drug during the planned study period, i.e. patients have to stop others antiarrhythmics such as Vaughan Williams Class I and III anti-arrhythmic drugs, for example amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, solatol.

- Plasma potassium < 3.5 mmol/l (as anti-arrhythmic drugs can be arrhythmogenic in patients with hypokalemia, this must be corrected prior to randomization. - A calculated GFR at baseline < 10 ml/min using the Cockroft Gault formula (GFR [ml/min] = (140 - AGE [years] ^* WEIGHT [kilograms] ^* CONSTANT / CREATININE [μηηοΙ/L], where CONSTANT is 1 for men and 0.85 for women )¹

- concomitant use of grapefruit juice and all potent inhibitors of CYP3A4 such as ketoconazole were prohibited.

Of course, the group of patients may be defined as a combination of the four above mentioned groups.

Mention may be made that the expression " patients having a history of atrial fibrillation or atrial flutter"," or "patients with paroxysmal or persistent atrial fibrillation or flutter" or or "patients with a history of, or current non-permanent AF" or "patients with paroxysmal or intermittent atrial fibrillation or atrial flutter and a recent episode of atrial fibrillation or atrial flutter, who are in sinus rhythm or who will be cardioverted" or "patients with paroxysmal or persistent atrial fibrillation or atrial flutter and a recent episode of atrial fibrillation or atrial flutter, who are in sinus rhythm or who will be cardioverted" means a patient who, in the past, has presented one or more episodes of atrial fibrillation or flutter and/or who is suffering from atrial fibrillation or atrial flutter at the time the dronedarone or a pharmaceutically acceptable salt thereof is used. More particularly, this expression means patients with documentation of having been in both atrial fibrillation or flutter and sinus rhythm within the last 6 months preceding the start of treatment. Patients could be either in sinus rhythm, or in atrial fibrillation or flutter at the time the dronedarone or a pharmaceutically acceptable salt thereof is initiated.

For their therapeutic use, dronedarone and pharmaceutically acceptable salts thereof are generally introduced into pharmaceutical compositions.

These pharmaceutical compositions contain an effective dose of dronedarone or of a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient. Said pharmaceutical composition may be given once or twice a day with food.

The dose of dronedarone administered per day, orally, may reach 800 mg, taken in one or more intakes, for example one or two.

More specifically, the dose of dronedarone administered may be taken with food.

More specifically, the dose of dronedarone administered per day, orally, may reach 800 mg, taken in two intakes with a meal.

The dose of dronedarone administered per day, orally may be taken at a rate of twice a day with a meal for example with the morning and the evening meal.

More specifically, the two intakes may comprise same quantity of dronedarone.

There may be specific cases where higher or lower dosages are appropriate; such dosages do not depart from the context of the invention. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the method of administration, the weight, the pathology, the body surface, the cardiac output and the response of said patient.

Said excipients are chosen according to the pharmaceutical form and the method of administration desired, from the usual excipients which are known to those skilled in the art.

In said pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, dronedarone, or the salt thereof, can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals and to humans in the cases mentioned above.

The suitable unit administration forms comprise forms for oral administration, such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, dronedarone and pharmaceutically acceptable salts thereof can be used in creams, gels, ointments or lotions.

By way of example, a unit administration form of dronedarone or a pharmaceutically acceptable salt thereof, in tablet form, may correspond to one of the following examples:

According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of dronedarone or a pharmaceutically acceptable salt thereof.

The present invention is illustrated by the data hereinafter with reference to the attached drawings in which:

Figure 1 represents a Kaplan Meier curve of time to first AF/AFL recurrence;

Figure 2 represents a Kaplan-Meier cumulative incidence curve of time to first electrical cardioversion. ATHENA was a randomized, double-blind, placebo-controlled trial conducted in 4628 patients recruited by 551 centers in 37 countries. (Hohnloser SH, et al., J Cardiovasc Electrophysiol 2008;19:69-73) (Hohnloser SH, et al., N. Engl. J. Med. 2009;360:668-678).

Patients with paroxysmal or persistent atrial fibrillation or flutter and additional cardiovascular risk factors were eligible. For each patient, a 12-lead electrocardiogram (ECG) within 6 months prior to randomization had to be available showing atrial fibrillation or flutter and a second 12-lead ECG within the same period had to show sinus rhythm. Patients could be included either in sinus rhythm or in atrial fibrillation or flutter. Randomization was stratified according to rhythm status at baseline.

Patients were randomized to dronedarone 400 mg bid (D, n=2301 ) or placebo (P, n=2327). All ECG tracings available were classified for AF/AFL or sinus rhythm; ventricular rate was determined in AF/AFL recordings. Patients with AF/AFL in every post-baseline ECG were classified as having permanent AF/AFL. All electrical cardioversions were prospectively documented.

Baseline characteristics and baseline drug therapy were well balanced between the treatment groups. All medications were managed by the enrolling physician. Use of class I or III agents was not allowed during the study, and decisions about cardioversion or dosing of rate-controlling agents, such as beta-adrenergic blockers, non-dihydropyridine calcium-channel blocking agents and digoxin, were at the discretion of the treating physician. Details of the dosing of rate-controlling agents were not recorded in the case report forms.

The follow-up visit schedule included clinical evaluations at days 7 and 14 and at months 1 , 3, 6, 9, 12 and every three months thereafter. In case of clinical deterioration, patients were seen as clinically appropriate.

Recording of ECGs: During the course of the study, 12-lead ECGs were recorded at each visit up to 6 months and every 6 months thereafter. The investigator classified each ECG as AF/AFL or sinus rhythm and the ventricular rate was recorded. In addition, ECGs were recorded on other occasions such as recurrence of symptoms. These scheduled and unscheduled ECGs provided the timing of recurrence of AF/AFL for those patients who were in sinus rhythm at the onset of the trial.

Cardioversion: Decisions of whether or when to perform electrical cardioversion were at the discretion of the treating physician. All electrical cardioversions were prospectively documented.

Hospitalization for AF/AFL: All hospitalizations during the study were reported in specific case record forms. The main reason for each cardiovascular hospitalization was classified by the investigator according to a pre-specified list of reasons including AF/AFL.

For the analysis of maintenance of sinus rhythm only the subpopulation of patients who were in sinus rhythm at study initiation was analyzed. One of the following events was regarded as evidence for recurrence of AF/AFL: ECG in AF/AFL, cardioversion, or hospitalization for AF/AFL, whichever came first.

"Permanent AF/AFL": For the purpose of this study, "permanent AF" was defined if every ECG from beginning to end of the study showed AF/AFL.

Analyses were performed on the intention-to-treat population. The time to event was estimated according to the Kaplan-Meier method and compared by the log-rank test. All P values were two tailed. Mean heart rates were compared using Student's T- test.

Results

The baseline characteristics were reported in Hohnloser SH, et al., N. Engl. J. Med. 2009;360:668-678. Of note class I and III (including sotalol) antiarrhythmic drugs were contraindicated during the treatment with study drug. Heart rate control was provided according to the investigator's judgment; 81 .8% (90.3%) of the placebo patients and 82.6% (87.9%) of the dronedarone patients received at least one rate- controlling agent (beta blocker, calcium antagonist with heart rate lowering effects or digitalis) at baseline and during the study. Antiarrhythmic effect: The antiarrhythmic effect was evaluated in several ways, including time to recurrence of AF/AFL (for the patients in sinus rhythm at baseline) and the time to first cardioversion.

As shown in figure 1 , over a mean follow up of 21 months there was a reduction in the likelihood of developing AF/AFL in the dronedarone group (HR = 0.749, 95% CI 0.681-0.824; P<0.001 ). The median time to first recurrence was prolonged from 498 days with placebo to 737 days with dronedarone. The majority of the events were documented as an outpatient on ECG that was either symptom-related or part of routine follow-up (Table 1 ).

Table 1 : First AF/AFL recurrence composition

Placebo Dronedarone

N=1741* N=1732*

Number of patients with event 950 54.6% 779 45.0%

Endpoint composition

- 12-lead ECG in AF/AFL 586 33.7% 525 30.3%

- hospitalization for AF/AFL 265 15.2% 178 10.3%

- electrical cardioversion 99 5.7% 76 4.4%

^* All randomized patients without AF/AFL at baseline as per stratification factor

Patients receiving dronedarone were less likely to undergo electrical cardioversion (n=481 ) compared with patients receiving placebo (n=339; HR = 0.684, 95% CI 0.596-0.786, P<0.001 . See figure 2.)

Further evidence of antiarrhythmic effect of dronedarone was suggested by a lower frequency of patients considered to be in permanent AF/AFL in the patients receiving dronedarone (n=178; 7.7%) as compared with those receiving placebo (n=295; 12.7%, P<0.001 ).

Rate-controlling effect: At the time of first recurrence of AF/AFL, mean heart rate (SD) was lower in the dronedarone group 85.3 (22.3) beats per minute (bpm) compared with the placebo group 95.5 (25.6) bpm (P<0.001 ; Table 2). The effect of dronedarone on the ventricular rate control was also evaluated by determining the ventricular rate recorded on all 12-lead ECG for patients in AF and AFL and SR. Heart rate was lower in all three rhythms (AF, AFL and sinus) in dronedarone- treated patients compared to placebo-treated patients. The median heart rate was 8, 9 and 4 beats lower in AF, AFL and sinus rhythm respectively. Of note, the administration of other AV nodal blocking agents was left to the judgment of the treating physician and dose adjustments were not recorded.

Table 2: Heart rate in bpm during first AF/AFL recurrence and according to rhythm status during study

Placebo Dronedarone P

Number of Number of

Median Mean (SD) N ₊ Median Mean (SD)

ECGs^† ECGs^†

585 90 95.5 (25.6) 1732 524 80 85.3(22.3)

AF 2327 4645 83 86.5(20.1) 2301 3470 75 78.5(18.2) <0.001

AFL 2327 393 86 90.6(24.2) 2301 320 77 84.0(23.8) <0.001

Sinus Rhythm 2327 10956 64 65.0(11.1) 2301 11892 60 61.5(10.1) <0.001

ECG = electrocardiogram

^*AII randomized patients without AF/AFL at baseline as per stratification factor

^†AII post baseline ECGs available during the selected rhythm for all randomized patients

This substudy of ATHENA confirms the antiarrhythmic efficacy of dronedarone, based on several secondary analyses. First, among the patients in sinus rhythm at the onset of the study, there was a 26% reduction in the recurrence of AF/AFL with dronedarone, with a 1 .5-fold prolongation of the median time to recurrence of 17 to 25 months compared to placebo. Second, although cardioversion was not controlled by the trial, it was less likely that patients receiving dronedarone would undergo conversion. Third, patients receiving dronedarone were less likely to remain in "permanent" AF/AFL throughout the course of the study.

These results are consistent with the multiple ion-channel (l_ks, Ikr, Iki, lca-L, Ικ-Ach, INA) blocking properties of dronedarone 'Wegener FT, et al., J Cardiovasc Electrophysiol 2006;17:S17-S20) and findings from previous clinical studies. Touboul P, et al., Eur Heart J2003 Aug;24(16):1481 -1487) (Singh BN, N Engl J Med 2007;357:987-999). The dose-ranging study DAFNE (Touboul P, et al., Eur Heart J2003 Aug;24(16):1481 -1487) demonstrated that dronedarone 400 mg twice daily showed a better benefit/risk ratio than higher doses, leading to the investigation of this regimen and demonstrated efficacy in EUR S and ADONIS. (Singh BN, et al., Engl J Med 2007;357:987-999).

The "real world" benefit of less frequent cardioversion and less frequent "permanent" AF/AFL in patients receiving dronedarone is novel and consistent with the previous studies measuring time to recurrence of AF/AFL using dronedarone.

A subject of the present invention is therefore the use of dronedarone or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for reducing the frequency of cardioversion and "permanent" AF/AFL in patients.

Rate controlling effect:

In addition to its multiple ion channel-blocking effects, dronedarone is known to have antiadrenergic properties (a- and 3-adrenoceptor antagonist) (Wegener FT, et al., J Cardiovasc Electrophysiol 2006;17:S17-S20) and has been shown to slow the ventricular rate response in patients with permanent AF/AFL. (Davy JM, et al., Am Heart J 2008;156:52: e1 -9).

The ERATO trial demonstrated a mean 1 1 .7 bpm reduction in rate among patients in AF/AFL receiving dronedarone compared with those receiving placebo on top of standard rate control therapy during this short-term study. Interestingly the effect of dronedarone was additive to those of other rate-control agents, including beta- blockers, calcium antagonists, and digoxin in the ERATO trial. (Davy JM, et al., Am Heart J 2008;156:52: e1 -9). The median reduction of heart rate in AF/AFL in ATHENA, in contrast, was observed in the setting where treating physicians could adjust other AV nodal blocking agents according to their clinical judgment. It is possible that the rate slowing effect of dronedarone seen in ATHENA was mitigated by additional AV nodal blocking agents being administered to the placebo patients since they had higher heart rates; as such, the 9 bpm reduction could underestimate the true effect of the drug. Interestingly the dronedarone-mediated heart rate reduction was observed during AF/AFL and in sinus rhythm, where heart rate was 4 bpm lower in the dronedarone group compared to the placebo group.

A limitation of this study is that ATHENA was not designed to test the antiarrhythmic efficacy of dronedarone; as such, clinical care was not controlled by the study, and estimates of antiarrhythmic efficacy are indirect. As noted above, the effect on heart rate in AF/AFL likely is underestimated, since physicians used their discretion with regard to AV nodal blocking drugs. The doses of the AV nodal drugs administered were not available.

Exploratory efficacy analyses have inherent limitations. We employed a multifaceted analysis with complementary approaches devised to minimize systematic bias. The consistency of our analyses and concordance with previous studies suggest that our findings are valid.

The antiarrhythmic and rate-controlling effects of dronedarone were confirmed in the ATHENA trial. This efficacy, in combination with the safety data and other outcome benefits previously published, confirms the unique antiarrhythmic drug profile of dronedarone.

Claims

1 . Use of dronedarone for the preparation of a medicament for rhythm and rate- controlling in patients with atrial fibrillation.

2. Use of dronedarone according to claim 1 for the preparation of a medicament for use in the prevention of recurrence of AF/AFL or the lowering of ventricular rate in patients having a history of atrial fibrillation or atrial flutter.

3. Use according to claim 1 or 2 wherein said patients also exhibit at least one of the following risk factors:

age equal to or above 70,

hypertension,

diabetes,

- history of cerebral stroke or of systemic embolism, i.e. prior

cerebrovascular accident,

- left ventricular ejection fraction less than 40%, measured for example by two-dimensional echography.

4. Use according to claims 1 , 2 or 3 wherein said patients also exhibit additional risk factors, i.e. at least one of the following pathologies:

hypertension,

underlying structural heart disease,

tachycardia,

coronary disease,

non-rheumatic heart valve disease,

dilated cardiomyopathy of ischemic origin,

- supraventricular tachycardia other than atrial fibrillation or flutter,

- history of heart valve surgery,

- non-ischemic dilated cardiomyopathy, - hypertrophic cardiomyopathy,

- rheumatic valve disease,

- sustained ventricular tachycardia,

- congenital cardiopathy,

- ventricular fibrillation,

and/or at least one cardiac device chosen from:

a cardiac stimulator,

an implantable defibrillator ("ICD").

5. Use according to claims 1 , 2, 3 or 4 wherein said patients do not exhibit at least one of the following criteria:

- Refusal or inability to give informed consent to participate in the study;

- Any non cardiovascular illness or disorder that could preclude participation or severely limit survival including cancer with metastasis and organ transplantation requiring immune suppression;

- Pregnant women (pregnancy test must be negative) or women or childbearing potential not on adequate birth control: only women with a highly effective method of contraception [oral] contraception or intra-uterine device (IUD) or sterile can be randomize;

- Breastfeeding women;

- Previous (2 preceding months) or current participation in another trial with an investigational drug (under development) or with an investigational device;

- Previous participation in this trial;

- Patients in permanent atrial fibrillation;

- Patients in unstable hemodynamic condition such as acute pulmonary edema within 12 hours prior to start of study medication; cardiogenic shock; treatment with IV pressor agents; patients on respirator; congestive heart failure of stage NYHA IV within the last 4 weeks; uncorrected, hemodynamically significant primary obstructive valvular disease; hemodynamically significant obstructive cardomyopathy; a cardiac operation or revascularization procedure within 4 weeks preceding randomization; - Planned major non-cardiac or cardiac surgery or procedures including surgery for valvular heart disease, coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), or on urgent cardiac transplantation list;

- Acute myocarditis or constrictive pericarditis;

- Bradycardia < 50 bpm and/or PR-interval > 0.28 sec on the last 12-lead ECG;

- Significant sinus node disease (documented pause of 3 seconds or more) or 2^nd or 3^rd degree atrioventricular block (AV-block) unless treated with a pacemaker;

- Need of a concomitant medication that is prohibited in this trial, including the requirement for Vaughan Williams Class I and III anti-arrhythmic drugs, that would preclude the use of study drug during the planned study period, i.e. patients have to stop others antiarrhythmics such as Vaughan Williams Class I and III antiarrhythmic drugs, for example amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, solatol;

- Plasma potassium < 3.5 mmol/l (as anti-arrhythmic drugs can be arrhythmogenic in patients with hypokalemia, this must be corrected prior to randomization;

- A calculated GFR at baseline < 10 ml/min using the Cockroft Gault formula (GFR [ml/min] = (140 - AGE [years] ^* WEIGHT [kilograms] ^* CONSTANT / CREATININE [μηηοΙ/L], where CONSTANT is 1 for men and 0.85 for women ); and