USE OF DRONEDARONE FOR THE PREPARATION OF A MEDICAMENT FOR USE IN THE PREVENTION OF CARDIOVASCULAR HOSPITALIZATION OR OF MORTALITY

Abstract

Methods of using dronedarone or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality, articles of manufacture and packages related thereto.

Claims

1. A method of decreasing the risk of cardiac hospitalizations in a patient, said method comprising administering to said patient an effective amount of dronedarone or a pharmaceutically acceptable salt thereof, with food.

2. The method according to claim 1 wherein said patient has a history of or current atrial fibrillation or flutter.

3. The method according to claim 1 wherein the administration of dronedarone or pharmaceutically acceptable salt thereof prevents cardiovascular hospitalizations.

4. The method according to claim 1 wherein said patient further receives a diuretic-based treatment.

5. The method according to claim 4 wherein said diuretic is a non-potassium-sparing diuretic.

6. The method according to claim 1 wherein the patient also exhibits at least one risk factor selected from the group consisting of: an age greater than or equal to 75, hypertension, diabetes, a history of cerebral stroke or of systemic embolism, left atrial diameter greater than or equal to 50, and left ventricular ejection fraction less than 40%.

7. The method according to claim 1 wherein the dose of dronedarone administered per day, orally, is less than or equal 800 mg, measured in base form, and taken in one or more intakes.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0259] The present invention is illustrated by the data hereinafter with reference to the attached drawings in which:

[0260] FIG. 1 represents a Kaplan Meier curve with the cumulative rate of hospitalization or of death from any cause over a period of 30 months;

[0261] FIG. 2 represents a Kaplan Meier curve with the cumulative rate of hospitalization or of cardiovascular death over a period of 30 months;

[0262] FIG. 3 represents a Kaplan Meier curve with the cumulative rate of hospitalization or of sudden death over a period of 30 months;

[0263] FIG. 4 represents a Kaplan Meier curve with the cumulative rate of hospitalization over a period of 30 months;

[0264] FIG. 5 represents a Kaplan Meier curve with the cumulative rate of death from any cause over a period of 30 months;

[0265] FIG. 6 represents a Kaplan Meier curve with the cumulative rate of cardiovascular death over a period of 30 months;

[0266] FIG. 7 represents a Kaplan Meier curve with the cumulative rate of sudden death over a period of 30 months;

[0267] FIG. 8 represents the mean variations in potassium between the first and the last administration over a period of 30 months.

[0268] FIG. 9 represents a Kaplan Meier curve with the cumulative rate of hospitalization or of death from any cause over a period of 30 months.

[0269] FIG. 10 represents a Kaplan Meier curve with the cumulative rate of is hospitalization or of death from any cause in Patients with NYHA class III congestive heart failure over a period of 30 months.

[0270] The efficacy, relative to a placebo, of dronedarone and of pharmaceutically acceptable salts thereof, in the prevention of cardiovascular hospitalizations or of mortality was demonstrated, by means of dronedarone hydrochloride, in a prospective, multinational, multicentre, double-blind clinical study with random distribution in two groups of treatment (group treated with dronedarone hydrochloride and group treated with a placebo) of patients having a history of atrial fibrillation or atrial flutter.

I. Patient Selection

[0271] The patients had to have a history of atrial fibrillation or flutter and/or could be in normal sinus rhythm or in atrial fibrillation or flutter at inclusion.

[0272] The patient recruitment was carried out by taking into account the following inclusion criteria:

Inclusion Criteria:

[0273] 1) One of the following risk factors had to be present: [0274] age equal to or greater than 70 years, [0275] hypertension (taking antihypertensives of at least two different classes), [0276] diabetes, [0277] history of cerebral stroke (transient ischemic event or completed cerebral stroke) or of systemic embolism, [0278] left atrial diameter greater than or equal to 50 mm measured by echocardiography, [0279] left ventricular ejection fraction less than 40%, measured by two-dimensional echography;
or [0280] age equal to or above 70, or even above 75, possibly combined with at least one of the risk factors below: [0281] hypertension (taking antihypertensives of at least two different classes), [0282] diabetes, [0283] history of cerebral stroke (transient ischemic event or completed cerebral stroke) or of systemic embolism, [0284] left atrial diameter greater than or equal to 50 mm measured by echocardiography, [0285] left ventricular ejection fraction less than 40%, measured by two-dimensional echography; [0286] 2) availability of an electrocardiogram carried out during the past 6 months in order to document the presence or the history of atrial fibrillation or flutter; [0287] 3) availability of an electrocardiogram carried out during the past 6 months in order to document the presence or absence of normal sinus rhythm.

Exclusion Criteria:

General Criteria:

[0288] Refusal or inability to give informed consent to participate in the study. [0289] Any non cardiovascular illness or disorder that could preclude participation or severely limit survival including cancer with metastasis and organ transplantation requiring immune suppression. [0290] 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. [0291] Breastfeeding women. [0292] Previous (2 preceding months) or current participation in another trial with an investigational drug (under development) or with an investigational device. [0293] Previous participation in this trial.

Criteria Related to a Cardiac Condition:

[0294] Patients in permanent atrial fibrillation [0295] 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 [0296] 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 [0297] Acute myocarditis or constrictive pericarditis [0298] Bradycardia <50 bpm and/or PR-interval ≧0.28 sec on the last 12-lead ECG. [0299] Significant sinus node disease (documented pause of 3 seconds or more) or 2.sup.nd or 3.sup.rd degree atrioventricular block (AV-block) unless treated with a pacemaker.

Criteria Related to Concomitant Medications:

[0300] 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.

Criteria Related to Laboratory Abnormalities:

[0301] Plasma potassium <3.5 mmol/I (as anti-arrhythmic drugs can be arrhythmogenic in patients with hypokalemia, this must be corrected prior to randomization. [0302] A calculated GFR at baseline <10 ml/min using the Cockroft Gault formula (GFR [ml/min]=(140−AGE [years]*WEIGHT [kilograms]*CONSTANT/CREATININE [μmol/L], where CONSTANT is 1 for men and 0.85 for women).

[0303] Furthermore, the concomitant use of grapefruit juice and all potent inhibitors of CYP3A4 such as ketoconazole were prohibited.

II. Duration and Treatment

[0304] Treatment was initiated using tablets containing either the placebo or an amount of dronedarone hydrochloride corresponding to 400 mg of dronedarone at a rate of twice a day with the morning and evening meal and more specifically at a rate of one tablet in the morning during or shortly after breakfast and one tablet in the evening during or shortly after dinner.

[0305] The anticipated duration of the treatment was variable according to the time at which each patient was included in the study, and could range from a minimum of is 12 months for the last patient included up to a maximum corresponding to the entire duration of the study (12 months+duration of inclusion), i.e. approximately 30 months for the first patients included.

III. Results

[0306] The results obtained in this trial were analysed by the Kaplan Meier method for the figures, and the relative risk (RR) was estimated using Cox's proportional-effect regression model.

[0307] The relative risk (RR) is the ratio of the rates of occurrence of a hospitalization or of a death among the patients on dronedarone, relative to the patients on placebo.

[0308] The percentage reduction x of a given event (hospitalization, death, cardiovascular death, etc.) is calculated in the following way:

x=1−relative risk.

III.1. Results Relating to Cardiovascular Hospitalizations and to Mortality (Principal Judgement Criterion)

[0309] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0310] 917 events were recorded in the placebo group, against 734 in the group treated with dronedarone hydrochloride.

[0311] The calculated relative risk is 0.758 with a p=2×10.sup.8, i.e. a reduction in cardiovascular hospitalizations and deaths of 24.2% on dronedarone hydrochloride, the result being highly significant.

[0312] FIG. 1, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.2. Results Relating to Cardiovascular Hospitalizations and to Cardiovascular Mortality

[0313] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0314] 892 events were recorded in the placebo group, against 701 in the group treated with dronedarone hydrochloride.

[0315] The calculated relative risk is 0.745 with a p=45×10.sup.−10, i.e. a reduction in cardiovascular hospitalizations and cardiovascular deaths of 25.5% on dronedarone hydrochloride, the result being highly significant.

[0316] FIG. 2, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.3. Results Relating to Cardiovascular Hospitalizations and to Sudden Death

[0317] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0318] 873 events were recorded in the placebo group, against 684 in the group treated with dronedarone hydrochloride.

[0319] The calculated relative risk is 0.743 with a p=48×10.sup.−10, i.e. a reduction in cardiovascular hospitalizations and sudden deaths of 25.5% on dronedarone hydrochloride, the result being highly significant.

[0320] FIG. 3, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.4. Results Relating to Cardiovascular Hospitalizations

[0321] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0322] 859 events were recorded in the placebo group, against 675 in the group treated with dronedarone hydrochloride.

[0323] The calculated relative risk is 0.745 with a p=9×10.sup.−9, i.e. a reduction in cardiovascular hospitalizations of 25.5% on dronedarone hydrochloride.

[0324] FIG. 4, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.5. Results Relating to Cardiovascular Hospitalizations for Atrial Fibrillation or Supraventricular Arrhythmia

[0325] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0326] 457 events were recorded in the placebo group, against 296 in the group treated with dronedarone hydrochloride.

[0327] The calculated relative risk is 0.616, i.e. a reduction in cardiovascular hospitalizations for atrial fibrillation of 38.4%

III.6. Results Relating to Cardiovascular Hospitalizations for Transient Ischemic Event or Stroke

[0328] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0329] 61 events were recorded in the placebo group, against 43 in the group treated with dronedarone hydrochloride.

[0330] The calculated relative risk is 0.66 with a p=0.027, i.e. a reduction in cardiovascular hospitalizations for transient ischemic event or stroke of 34% on dronedarone hydrochloride.

III.7. Results Relating to Mortality from any Cause

[0331] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0332] 139 deaths were recorded in the placebo group, against 116 in the group treated with dronedarone hydrochloride.

[0333] The calculated relative risk is 0.844 with a p=0.1758, i.e. a reduction of death of 15.6% on dronedarone hydrochloride.

[0334] FIG. 5, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.8. Results Relating to Cardiovascular Mortality

[0335] Among the 4628 patients included in the study, 2301 were part of the group is treated with dronedarone hydrochloride.

[0336] 94 cardiovascular deaths were recorded in the placebo group, against 65 in the group treated with dronedarone hydrochloride.

[0337] The calculated relative risk is 0.698 with a p=0.0252, i.e. a reduction in cardiovascular mortality of 30.2% on dronedarone hydrochloride.

[0338] FIG. 6, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.9. Results Relating to Arrhythmic Death

[0339] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0340] 48 arrhythmic deaths (deaths from cardiac arrhythmia) were recorded in the placebo group, against 26 in the group treated with dronedarone hydrochloride.

[0341] The calculated relative risk is 0.55 with a p=0.001, i.e. a reduction of arrhythmic death of 45% on dronedarone hydrochloride.

III.10. Results Relating to Sudden Death

[0342] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0343] 35 sudden deaths were recorded in the placebo group, against 14 in the group treated with dronedarone hydrochloride.

[0344] The calculated relative risk is 0.405 with a p=0.0031, i.e. a reduction in sudden death of 59.5% on dronedarone hydrochloride.

[0345] FIG. 7, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.11. Regulation of the Blood Potassium Level

[0346] The potassium concentration-modulating effect is clearly documented in the study by virtue of the results of analyses of regular blood samples taken throughout the duration of the study in the context of the monitoring of vital parameters.

[0347] The variations in potassium (in mmol/l) between the first and the last is administration of the medicament of the study are included in FIG. 8, in which B signifies basal level, D signifies day and M signifies month.

[0348] An analysis of covariance of the change in blood potassium level, taking into account the starting value during the study after the 24.sup.th month, shows a significant different in favour of dronedarone compared to the placebo (p<0.0001).

[0349] Dronedarone therefore makes it possible to regulate the potassium level in the blood.

III.12. Results Relating to the Patients in the Study Receiving, in Addition, a Diuretic-Based Treatment

[0350] The clinical results of the study corroborate the hypothesis that modulating potassium decreases the risk of sudden death, in particular in patients exposed to the risk of a decrease in potassium exacerbated by the administration of a diuretic treatment: the reduction in the risk of sudden death by dronedarone, i.e. the prevention of sudden death compared with the placebo, was 70.4% in the patients on diuretics and 34% in the patients not taking diuretics.

[0351] Furthermore, the reduction in the risk was greater in the groups of patients liable to be treated with diuretics, such as hypertensive patients, where the reduction in the risk was 62%, against a reduction of 45.5% observed in the patients who were not hypertensive.

III.13. Results Relating to Cardiovascular Hospitalizations and to Mortality in Patients Who Developed “Permanent Atrial Fibrillation/Flutter”

[0352] Among the 4628 patients included in the study, 2301 were part of the group treated with dronedarone hydrochloride.

[0353] 294 patients who developed permanent atrial fibrillation/flutter in the group treated with placebo versus 178 patients in the group treated with dronedarone hydrochloride (p<0.001).

[0354] 74 events were recorded in the placebo group versus 29 in the group treated with dronedarone hydrochloride.

[0355] The calculated relative risk is 0.67 with a p=0.06, i.e. a reduction in cardiovascular hospitalizations and to mortality in patients with permanent atrial fibrillation/flutter of 33% on dronedarone hydrochloride.

[0356] FIG. 9, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the beginning of the treatment, this separation persisting over time throughout the duration of the study.

III.14. Results Relating to the Prevention of Cardiovascular Hospitalization or Death in Patients with a Structural Heart Disease

[0357] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0358] 629 events were reported in the placebo group versus 486 in the group treated with dronedarone hydrochloride.

[0359] Calculated relative risk was equal to 0.76, i.e. a decrease of cardiovascular hospitalization or death of 24%.

III.15. Results Relating to the Prevention of Cardiovascular Hospitalization in Patients with a Structural Heart Disease

[0360] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0361] 583 events were reported in the placebo group versus 452 in the group treated with dronedarone hydrochloride.

[0362] Calculated relative risk was equal to 0.76, i.e. a decrease of cardiovascular hospitalization of 24%.

III.16. Results Relating to the Prevention of Death in Patients with a Structural Heart Disease

[0363] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0364] 106 events were reported in the placebo group versus 77 in the group treated with dronedarone hydrochloride.

[0365] Calculated relative risk was equal to 0.76, i.e. a decrease of death of 24%.

III.17. Results Relating to the Prevention of Cardiovascular Death in Patients with a Structural Heart Disease

[0366] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0367] 75 events were reported in the placebo group versus 48 in the group treated with dronedarone hydrochloride.

[0368] Calculated relative risk was equal to 0.67, i.e. a decrease of cardiovascular deaths of 33%.

III.18. Results Relating to the Prevention of Cardiovascular Hospitalization and Death in Patients with a Congestive Heart Failure Defined as NYHA Class III in a Stable Hemodynamic Condition

[0369] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0370] At randomization, 109 patients with NYHA class III congestive heart failure in a stable hemodynamic condition were part of the placebo group and 91 patients with NYHA class III congestive heart failure in a stable hemodynamic condition were part of the group treated with dronedarone hydrochloride.

[0371] 71 events were reported in the placebo group versus 40 in the group treated with dronedarone hydrochloride.

[0372] Calculated relative risk was equal to 0.56, i.e. a decrease of cardiovascular hospitalization or death of 44%.

[0373] FIG. 10 shows that the effect of dronedarone occurred early and increased over time.

III.19. Results Relating to the Prevention of Cardiovascular Hospitalization and Death in Patients with Congestive Heart Failure Defined with a Reduced Left Ventricular Ejection Fraction Below 0.35 in a Stable Hemodynamic Condition

[0374] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0375] At randomization, 87 patients with congestive heart failure in a stable hemodynamic condition as defined by a reduced left ventricular ejection fraction below 0.35 were part of the placebo group and 92 patients with congestive heart failure in a stable hemodynamic condition defined with a reduced left ventricular ejection fraction below 0.35 were part of the group treated with dronedarone hydrochloride.

[0376] 47 events were reported in the placebo group versus 39 in the group treated with dronedarone hydrochloride.

[0377] Calculated relative risk was equal to 0.68, i.e. a decrease of cardiovascular hospitalization or death 32%.

III.20. Results Relating to the Prevention of Death in Patients with Congestive Heart Failure Defined as NYHA Class III

[0378] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0379] At randomization, 109 patients with NYHA class III congestive heart failure in a stable hemodynamic condition were part of the placebo group and 91 patients with NYHA class III congestive heart failure in a stable hemodynamic condition were part of the group treated with dronedarone hydrochloride.

[0380] 21 events were reported in the placebo group versus 12 in the group treated with dronedarone hydrochloride.

[0381] Calculated relative risk was equal to 0.66, i.e. a decrease of death of 34%.

III.21. Results Relating to the Prevention of Death in Patients with Congestive Heart Failure in a Stable Hemodynamic Condition as Defined by a Reduced Left Ventricular Ejection Fraction Below 0.35

[0382] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0383] At randomization, 87 patients with congestive heart failure in a stable hemodynamic conditions defined by a reduced left ventricular ejection fraction below 0.35 were part of the placebo group and 92 patients with congestive heart failure in a stable hemodynamic condition as defined by a reduced defined with a left ventricular ejection fraction below 0.35 were part of the group treated with dronedarone hydrochloride.

[0384] 16 events were reported in the placebo group versus 10 in the group treated with dronedarone hydrochloride.

[0385] Calculated relative risk was equal to 0.55, i.e. a decrease of death of 45%.

III.22. Results Relating to the Prevention of Death in Patients with Congestive Heart Failure in a Stable Hemodynamic Condition as Defined as NYHA Class III and by a Reduced Left Ventricular Ejection Fraction Below 0.35

TABLE-US-00005 Dronedarone Placebo 400 mg BID (N = 23) (N = 24) Number of events, n 19  13  Median survival [95% 254.0 [131.0; 293.0] 487.0 [182.0; NA].sup.    CI](day) Cumulative incidence of 0.348 [0.153; 0.542] 0.292 [0.110; 0.474] events at 6 months [95% CI] Cumulative incidence of 0.696 [0.508; 0.884] 0.375 [0.181; 0.569] events at 1 year [95% CI] Cumulative incidence of 0.837 [0.680; 0.993] 0.578 [0.368; 0.788] events at 2 years [95% CI] Endpoint's composition: Cardiovascular hospitalization 15  10  Death from any cause 4 3 Cardiovascular death 3 2 Non cardiovascular death 1 1 Log-rank test p-value 0.0711 Relative risk [95% CI]a 0.523 [0.256; 1.070]
III.23. Results Relating to the Prevention of Hospitalizations Associated with Congestive Heart Failure, that is for Patients Who Developed Congestive Heart Failure

[0386] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0387] 132 events were reported in the placebo group versus 112 in the group treated with dronedarone hydrochloride.

[0388] Calculated relative risk was equal to 0.855, i.e. a decrease of cardiovascular hospitalization associated with congestive heart failure of 14.5%.

III.24. Results Relating to the Prevention of Hospitalizations Associated with Class IV Congestive Heart Failure, that is for Patients Who Developed Congestive Heart Failure

[0389] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0390] 54 events were reported in the placebo group versus 42 in the group treated with dronedarone hydrochloride.

[0391] Calculated relative risk was equal to 0.78, i.e. a decrease of cardiovascular hospitalization associated with class IV congestive heart failure of 22%.

III.25. Results Relating to the Prevention of Cardiovascular Hospitalization or Death in Patients with Coronary Heart Disease

[0392] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0393] At randomization, 737 patients with coronary heart disease were part of the placebo group and 668 patients with coronary heart disease were part of the group treated with dronedarone hydrochloride.

[0394] 350 events were reported in the placebo group versus 252 in the group treated with dronedarone hydrochloride.

[0395] Calculated relative risk was equal to 0.733, i.e. a decrease of cardiovascular hospitalization or death of 27% in patients with coronary heart disease (P=0.0002).

III.26. Results Relating to the Prevention of Cardiovascular Hospitalization for Patients with Coronary Heart Disease

[0396] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0397] At randomization, 737 patients with coronary heart disease were part of the placebo group and 668 patients with coronary heart disease were part of the group treated with dronedarone hydrochloride.

[0398] 321 events were reported in the placebo group versus 233 in the group treated with dronedarone hydrochloride.

[0399] Calculated relative risk was equal to 0.740, i.e. a decrease of cardiovascular hospitalization of 26% for patients with coronary heart disease (P=0.0005).

III.27. Results Relating to the Prevention of Death for Patients with Coronary Heart Disease

[0400] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0401] At randomization, 737 patients with coronary heart disease were part of the placebo group and 668 patients with coronary heart disease were part of the group treated with dronedarone hydrochloride.

[0402] 66 events were reported in the placebo group versus 39 in the group treated with dronedarone hydrochloride.

[0403] Calculated relative risk was equal to 0.643, i.e. a decrease of death of 36% for patients with coronary heart disease (P=0.0273).

III.28. Results Relating to the Prevention of Cardiovascular Death for Patients with Coronary Heart Disease

[0404] From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

[0405] At randomization, 737 patients with coronary heart disease were part of the placebo group and 668 patients with coronary heart disease were part of the group treated with dronedarone hydrochloride.

[0406] 47 events were reported in the placebo group versus 26 in the group treated with dronedarone hydrochloride.

[0407] Calculated relative risk was equal to 0.602, i.e. a decrease of cardiovascular death of 40% (P=0.0355).

III.29. Results Relating to the Prevention of Cardiovascular Hospitalization and Death in Patients with Cardiovascular Risk Factors

TABLE-US-00006 N HR (95% CI) Age ≧ 75 years 1925 0.75 (0.65, 0.87) Hypertension 3995 0.77 (0.69, 0.85) Diabetes 945 0.75 (0.61, 0.91) Prior cerebrovascular accident 616 0.80 (0.62, 1.02) or systemic embolism Left atrium diameter >= 50 mm 955 0.77 (0.63, 0.94) LVEF < 0.40 338 0.72 (0.51, 1.00)

[0408] Consequently, these results show a decrease of respectively 25%, 23%, 25%, 20%, 23%, 28% of cardiovascular hospitalization and death in patients with at least one of each above cardiovascular risk factors.

III.30. Results Relating to the Prevention of Cardiovascular Hospitalization

[0409]

TABLE-US-00007 Placebo Dronedarone (N = 2327) (N = 2301) HR (95% CI) Any cardiovascular 859 (36.9%)  675 (29.3%)  0.745 [0.673-0.824] hospitalization Atherosclerosis related (if not 8 (0.3%) 11 (0.5%) 1.282 [0.516-3.187] otherwise specified) Myocardial infarction or 61 (2.6%) 48 (2.1%) 0.742 [0.508-1.083] unstable angina Stable angina pectoris or 41 (1.8%) 45 (2.0%) 1.042 [0.682-1.591] atypical chest pain Syncope 24 (1.0%) 21 (0.9%) 0.836 [0.465-1.501] TIA or stroke (except 35 (1.5%) 28 (1.2%) 0.751 [0.457-1.235] intracranial hemorrhage) Atrial fibrillation and other 457 (19.6%)  296 (12.9%)  0.616 [0.532-0.713] supraventricular rhythm disorders Non-fatal cardiac arrest 2 (<0.1%)  3 (0.1%) 1.442 [0.241-8.632] Cardiovascular surgery 23 (1.0%) 21 (0.9%) 0.852 [0.472-1.540] except cardiac transplantation Implantation of a pacemaker, 29 (1.2%) 32 (1.4%) 1.041 [0.630-1.721] ICD or any other cardiac device Transcutaneous coronary, 31 (1.3%) 27 (1.2%) 0.817 [0.488-1.369] cerebrovascular or peripheral procedure Blood pressure related 21 (0.9%) 21 (0.9%) 0.949 [0.518-1.738] (hypotension, hypertension; except syncope) Cardiovascular infection 0 .sup. (0%) 4 (0.2%) NA Major bleeding (requiring two 24 (1.0%) 21 (0.9%) 0.816 [0.454-1.466] or more units of blood or any intracranial hemorrhage) Pulmonary embolism or 3 (0.1%) 10 (0.4%)  3.159 [0.869-11.478] deep vein thrombosis Worsening heart failure, 92 (4.0%) 78 (3.4%) 0.805 [0.595-1.089] including pulmonary edema or dyspnea of cardiac origin Ventricular extrasystoles 1 (<0.1%)  1 (<0.1%)   0.973 [0.061-15.560] Ventricular tachycardia (non- 6 (0.3%) 6 (0.3%) 0.952 [0.307-2.951] sustained and sustained) Ventricular fibrillation 1 (<0.1%)  1 (<0.1%)   0.943 [0.059-15.083] Other ventricular arrhythmia 0 .sup. (0%) 1 (<0.1%)  NA

III.31. Results Relating to the Prevention of Cardiovascular Hospitalization not Due to a Supraventricular Arrhythmia Such as Atrial Fibrillation or Flutter

[0410]

TABLE-US-00008 Placebo Dronedarone (N = 2327) (N = 2301) HR (95% CI) Any non-AF cardiovascular 511 (22.0%)  438 (19.0%)  0.855 [0.753-0.972] hospitalization Atherosclerosis related (if not 10 (0.4%) 11 (0.5%) 1.094 [0.464-2.575] otherwise specified) Myocardial infarction or unstable 71 (3.1%) 52 (2.3%) 0.730 [0.511-1.045] angina Stable angina pectoris or 53 (2.3%) 51 (2.2%) 0.962 [0.655-1.412] atypical chest pain Syncope 28 (1.2%) 23 (1.0%) 0.822 [0.474-1.427] TIA or stroke (except intracranial 43 (1.8%) 32 (1.4%) 0.742 [0.469-1.172] hemorrhage) Non-fatal cardiac arrest 2 (<0.1) 3 (0.1%) 1.504 [0.251-9.000] Cardiovascular surgery except 28 (1.2%) 24 (1.0%) 0.853 [0.495-1.472] cardiac transplantation Implantation of a pacemaker, 56 (2.4%) 46 (2.0%) 0.819 [0.555-1.210] ICD or any other cardiac device Transcutaneous coronary, 40 (1.7%) 31 (1.3%) 0.773 [0.484-1.235] cerebrovascular or peripheral procedure Blood pressure (hypotension, 26 (1.1%) 25 (1.1%) 0.960 [0.554-1.662] hypertension, not syncope) Cardiovascular infection 0 .sup. (0%) 4 (0.2%) NA Major bleeding (requiring two or 28 (1.2%) 27 (1.2%) 0.960 [0.566-1.628] more units of blood or any intracranial hemorrhage) Pulmonary embolism or deep 4 (0.2%) 11 (0.5%) 2.713 [0.864-8.521] vein thrombosis Worsening heart failure, 113 (4.9%) 89 (3.9%) 0.787 [0.596-1.039] including pulmonary edema or dyspnea of cardiac origin Ventricular extrasystoles 1 (<0.1) 1 (<0.1)  1.005 [0.063-16.062] Ventricular tachycardia (non- 7 (0.3%) 6 (0.3%) 0.857 [0.288-2.550] sustained and sustained) Ventricular fibrillation 1 (<0.1) 1 (<0.1)  0.997 [0.062-15.940] Other ventricular arrhythmia 0 .sup. (0%) 1 (<0.1) NA

[0411] For example, dronedarone was associated with a 14.5% reduction in the risk of a first cardiovascular hospitalization not due to a supraventricular arrhythmia (HR [95% Cl] 0.855 [0.753−0.972]). As noted below, the lower number of non-AF/AFL hospitalizations on dronedarone was mainly due to fewer hospitalizations for worsening heart failure, MI or unstable angina, or stroke or TIA