FR2930148A1 - Use of dronedarone to prepare medicament to prevent mortality and/or cardiovascular hospitalizations in patients having e.g. history of atrial fibrillation/atrial flutter, cerebrovascular accident and non-rheumatic valvular heart disease - Google Patents

Abstract

Use of dronedarone or its salt for the preparation of a medicament for the prevention of mortality and/or cardiovascular hospitalizations in patients having a history of atrial fibrillation or atrial flutter, is claimed. ACTIVITY : Cardiovascular-Gen; Metabolic. MECHANISM OF ACTION : Potassium channel modulator.

Description

The subject of the present invention is the use of dronedarone and its pharmaceutically acceptable salts, for the preparation of a medicament for the preparation of a medicinal product intended for the prevention of cardiovascular hospitalization or of mortality. intended for the prevention of cardiovascular hospitalization and / or mortality. 2-n-butyl-3- [4- (3-di-n-butylaminopropoxy) benzoyl] -5-methylsulfonamidobenziofuran or dronedarone and its pharmaceutically acceptable salts are described in EP 0 471 609 B1. Dronedarone blocks potassium, sodium and calcium channels and also has anti-adrenergic properties. Dronedarone is an antiarrhythmic agent effective in maintaining sinus rhythm in patients with atrial fibrillation or atrial flutter. The Applicant has surprisingly found that dronedarone significantly reduces cardiovascular hospitalizations and / or mortality in patients with a history of atrial fibrillation or atrial flutter due to its ability to modulate serum potassium. Indeed, patent applications WO98 / 40067 and WO97 / 34597 disclose the use of benzofuran derivatives for reducing post-infarction mortality in patients with reduced left ventricular function after myocardial infarction, without requiring rhythm disorder. antiarrhythmic treatment. However, these applications do not disclose or suggest the use of dronedarone to reduce cardiovascular hospitalizations and mortality in patients with a history of atrial fibrillation or atrial flutter, particularly because of its ability to modulate potassium levels in the blood. .

Potassium is the main intracellular ion and plays a vital role in physiology. Indeed, this ion is the main osmotically active intracellular ion and plays an important role in the regulation of intracellular volume. A constant and stable potassium concentration is essential for the functioning of enzymatic systems as well as for good growth and cell division. Potassium contributes to the establishment of the resting potential of the cell membrane, therefore changes in potassium concentration, particularly in the extracellular compartment, have effects on cellular excitability in the nervous, muscular and cardiac systems. The decrease in potassium concentration is known to increase cardiac hyperexcitability at the ventricular level which can lead to severe, life-threatening rhythm disorders. The deleterious role of decreasing potassium concentration has been documented in disparate clinical situations. For example, in patients with heart failure the decrease in potassium concentration may result in fatal rhythm disturbances, diuretic agents having a potassium-sparing effect have demonstrated a beneficial effect in this population. The rapid decrease in potassium levels following abrupt cessation of intense physical activity may also be responsible for some sudden deaths. A possible contribution of decreased potassium levels has been suggested in the sudden death of patients treated with antipsychotics as well as in acute alcohol withdrawal syndromes. Dietary habits with decreased potassium intake may lead to sudden death in susceptible subjects even without structural cardiac pathology. The risk of fatal cardiac hyperexcitability is particularly important in patients who receive anti-arrhythmic therapy that extends the duration of cellular repolarization such as sotalol (Sotalex). These agents may indeed induce torsade de pointe, a severe and potentially fatal ventricular tachycardia. Torsades de pointes are facilitated by the decrease in potassium concentration. Finally, it has been shown that the decrease in potassium concentration induces atrial fibrillations (Manoach M., J. Mol Cell Cardiol, 1998, 30 (6): A4 [8]).

Another clinical situation where the risk of potentially fatal cardiac arrhythmias is high is represented by patients treated with diuretics, these drugs widely prescribed in many indications, the most common being arterial hypertension but also heart failure, the Renal failure, nephrotic syndrome, cirrhosis and glaucoma, are at risk of decreasing potassium concentration, except for potassium-sparing diuretics. The decrease in potassium concentration following diuretic treatment may be complicated by sudden death, particularly in patients with impaired contractile function of the heart or left ventricular dysfunction or after myocardial infarction. The regulation of the potassium concentration could therefore play an important beneficial role, particularly in the patient population that requires anti-arrhythmic treatment (for atrial fibrillation) and possibly other risk factors. However, no antiarrhythmic agent, to date, in therapy, has shown effects as to the regulation of potassium levels in the blood.

The present invention therefore relates to the use of lai dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of cardiovascular hospitalization and / or mortality in patients with a history of atrial fibrillation or atrial flutter.

The present invention specifically relates to the use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of cardiovascular hospitalization and / or mortality in patients with a history of atrial fibrillation or of atrial flutter by regulating the level of potassium in the blood. Mention may in particular be made of cardiovascular mortality and more particularly sudden death, also known as sudden cardiac death.

More specifically, the present invention relates to the use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of approximately 24% of cardiovascular hospitalizations and / or mortality in patients with a history of atrial fibrillation or atrial flutter by regulating potassium levels in the blood.

The present invention also relates to the use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of approximately 25% of cardiovascular hospitalizations and / or cardiovascular mortality in patients having a history of atrial fibrillation or atrial flutter by regulating the level of potassium in the blood.

The present invention also relates to the use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of approximately 26% of cardiovascular hospitalizations and / or sudden death in patients having a history of atrial fibrillation or atrial flutter by regulating the level of potassium in the blood.

In clinical studies, prevention of cardiovascular hospitalization or cardiovascular mortality or hospitalization or cardiovascular mortality or cardiovascular hospitalization or sudden death is known as composite criteria.

The present invention also relates to the use of dronedarone or a pharmaceutically acceptable salt thereof, in patients with a history of atrial fibrillation or atrial flutter, for the preparation of a medicament for the prevention of: - hospitalizations cardiovascular and more particularly about 25% of cardiovascular hospitalizations and / or - mortality and more specifically about 15% of mortality, and / or - cardiovascular mortality and more specifically about 30% of mortality. cardiovascular, and / or - sudden death and more specifically about 59% of sudden death.

All percentages given above are average values.

Diuretics are widely prescribed for their effectiveness in treating a variety of conditions such as high blood pressure, congestive heart failure, kidney failure, nephrotic syndrome, cirrhosis, glaucoma. One of the major consequences of diuretic therapy, except for potassium-sparing diuretics, is the increased excretion of potassium that may lead to hypokalemia. However, hypokalemia is known to increase cardiac excitability leading, in some patients, to ventricular arrhythmias and sudden deaths (Cooper et al., Circulation, 1999, 100, pages 1311-1315).

Advantageously, the present invention also relates to the use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of cardiovascular hospitalizations and / or mortality in patients with a history of fibrillation auricular or atrial flutter and receiving a treatment based on diuretics including diuretics non-sparing potassium.

The subject of the present invention is also the use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicinal product intended to regulate the level of potassium in the blood, in particular intended for the prevention of hypokalemia, particularly in patients with a history of atrial fibrillation or atrial flutter and / or in patients receiving diuretic-based therapy including potassium-sparing diuretics.

Said diuretic is administered at therapeutically active doses chosen between 1 mg / day and 2 g / day.

Among the pharmaceutically acceptable salts of dronedarone, mention may be made of the hydrochloride.

By non-potassium sparing diuretic is meant a diuretic increasing the excretion of potassium.

By cardiovascular hospitalization is meant a hospitalization resulting from at least one of the following pathologies (Hohnloser et al., Journal of Cardiovascular Electrophysiology, Jan. 2008, 19, No. 1, pages 69-73): relating to atherosclerosis , myocardial infarction or unstable angina pectoris, - stable angina pectoris or atypical chest pain, - syncope, transient ischemic attack or cerebrovascular accident (except intracranial hemorrhage), - atrial fibrillation and other disorders of supraventricular rhythm, - cardiac arrest not fatal, - ventricular arrhythmia, cardiovascular surgery except for cardiac transplantation, - cardiac transplantation, implantation of pacemaker, implantable defibrillator (ICD) or other cardiac device, percutaneous coronary intervention, cerebrovascular or peripheral, changes in blood pressure (hypotension, hypertension, exc epté syncope), cardiovascular infection, - bleeding / major hemorrhage (requiring more or more red blood cells or any intracranial hemorrhage), pulmonary embolism or deep vein thrombosis, - aggravation of congestive heart failure including acute pulmonary edema or dyspnea cardiac origin.

The term mortality covers mortality due to any cause whether it is cardiovascular or non-cardiovascular or unknown.

The term cardiovascular mortality covers, in the context of the invention, the mortality due to all cardiovascular causes (all deaths except those due to a non-cardiovascular cause) including death of arrhythmic origin also known as arrhythmic death, and more cardiovascular death, also known as sudden death.35 The name e: sudden death refers generally to death occurring within one hour or less of one hour after the onset of new symptoms or unexpected death without witnesses.

It should also be pointed out that the term having a history of atrial fibrillation or atrial flutter means a patient who has in the past had one or more episodes of atrial fibrillation or flutter and / or who is in atrial fibrillation or atrial flutter at the time of use of dronedarone or a pharmaceutically acceptable salt thereof.

Patients with a history of atrial fibrillation or atrial flutter may also include patients with at least one of the following risk factors: - hypertension, - diabetes, - history of stroke, or systemic embolism, - left atrial diameter greater than or equal to 50 mm measured by echocardiography, - left ventricular ejection fraction less than 40% as measured by two-dimensional ultrasound.

Patients with a history of atrial fibrillation or atrial flutter may also include patients with additional risk factors, namely at least one of the following conditions: hypertension, underlying structural heart disease, tachycardia, coronary heart disease, non-rheumatic heart valve disease, - dilated cardiomyopathy of ischemic origin, fibrillation ablation or atrial flutter e.g. by catheter or endomyocardial ablation, supraventricular tachycardia other than atrial fibrillation or flutter, 35 - history of cardiac surgery valvular, - non-ischemic dilated cardiomyopathy, hypertrophic cardiomyopathy, rheumatic heart disease, sustained ventricular tachycardia, congenital heart disease, catheter ablation for example for tachycardia other than for atrial fibrillation or flutter, - ventricular fibrillation, and / or at least one of cardiac device selected from: - a pacemaker, - an implantable defibrillator (ICD).

Regulating the level of potassium in the blood means preventing the decrease or a possible increase in said rate.

The main classes of non-sparing potassium diuretics are: thiazides, - loop diuretics, proximal diuretics (osmotic, carbonic anhydrase inhibitors).

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

These pharmaceutical compositions contain an effective dose of dronedarone or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, 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 its salt, may be administered in unit dosage form. , in admixture with conventional pharmaceutical excipients, to animals and to humans in the cases mentioned above. Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, dronedarone and its pharmaceutically acceptable salts can be used in creams, gels, ointments or lotions.

For example, a unit dosage form of dronedarone or a pharmaceutically acceptable salt thereof in tablet form may correspond to one of the following examples: Ingredients mg% dronedarone hydrochloride (corresponding 426 65.5 to 400 mg of base) _ Methylhydroxypropylcellulose 21.1 3.2.5 Lactose monohydrate 46.55 7.9 Corn starch 45.5 7_ Polyvinylpyrrolidone 65 10 Poloxamer 407 40 6.15 Colloidal silica anhydrous 2.6 04 Magnesium stearate 3.25 0 , 5,650 100 Ingredients mg% - Dronedarone hydrochloride (corresponding to 426 65.5 to 400 mg base) Microcrystalline cellulose 65 10 Anhydrous colloidal silica 2.6 0.4 Anhydrous lactose 42.65 _ 6, G_ Polyvinylpyrrolidone 13 2 Poloxamer 407 40 6.15 Macrogol 6000 57.5 8.85 Magnesium Stearate 3.25 05 650 100 20 Ingredients mg Dronedarone Hydrochloride (corresponding to 426 to 400 mg base) Microcrystalline Cellulose 26 Corn Starch 45.5 Polyvinylpyrrolidone 65 Poloxamer 407 40 Silica c olloidal anhydrous 3.25 Magnesium stearate 3.25 Lactose monohydrate 41.65 650 Ingredients mg Dronedarone hydrochloride (equivalent 213 to 400 mg base) Microcrystalline cellulose 13 Corn starch 22.75 Polyvinylpyrrolidone 32.5 Poloxamer 407 20 Colloidal anhydrous silica 1,3 Magnesium stearate 1,625 Lactose monohydrate 20,825 650 Orally, the dose of dronedarone administered per day can be as high as 800 mg in one or more doses.

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

The present invention, according to another of its aspects, also relates to a method of treatment of 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 following data with reference to the accompanying drawings in which:

Figure 1 represents a Kaplan Meier curve with the cumulative rate of hospitalization or death any cause over a period of 30 months; Figure 2 shows a Kaplan Meier curve with the cumulative rate of hospitalization or cardiovascular death over a 30-month period; Figure 3 represents a Kaplan Meier curve with the cumulative rate of hospitalization or sudden death over a 30-month period; Figure 4 shows a Kaplan Meier curve with the cumulative rate of hospitalization over a 30-month period; Figure 5 shows a Kaplan Meier curve with the cumulative rate of all-cause death over a 30-month period; Figure 6 shows a Kaplan Meier curve with the cumulative rate of cardiovascular death over a 30-month period; Figure 7 shows a Kaplan Meier curve with the cumulative rate of sudden death over a 30-month period; Figure 8 shows the average changes in potassium between the first and the last administration over a period of 30 months.

The efficacy, compared to placebo, of dronedarone and its pharmaceutically acceptable salts for the prevention of cardiovascular hospitalization or mortality was demonstrated by means of dronedarone hydrochloride in a prospective clinical study. , multinational, multi-centric and double-blind with hasarcl distribution in two treatment groups (dronedarone hydrochloride treated group and placebo treated group) of patients with a history of atrial fibrillation or atrial flutter.

I. Selection of patients

Patients should have a history of atrial fibrillation or flutter and / or could be in normal sinus rhythm or atrial fibrillation or flutter at baseline.35 Patient recruitment was performed taking into account the following inclusion criteria:

Inclusion Criteria 1) One of the following risk factors should be present: age ≥ 70 years or greater than 75 years, with or without at least one of the following risk factors o hypertension (taking antihypertensive agents) at least two different classes), o diabetes, history of stroke (transient ischemic attack or cerebral stroke) or systemic embolism, 15 o left atrial diameter greater than or equal to 50 mm as measured by echocardiography , o left ventricular ejection fraction less than 40% measured by two-dimensional ultrasound.

2) availability of an electrocardiogram performed in the last 6 months to document the presence or history of atrial fibrillation or flutter.

3) Availability of an electrocardiogram performed in the last 6 months to document the presence or absence of normal sinus rhythm. II. Duirée and treatment

The treatment was initiated from tablets containing either placebo or a quantity of dronedarone hydrochloride corresponding to 400 mg of dronedarone 30 at the rate of one tablet in the morning during or shortly after breakfast and one tablet during the evening or shortly after dinner. The duration of the planned treatment was variable according to the inclusion rate of each patient in the study and could range from 12 months minimum for the last patient included up to a maximum corresponding to the entire duration of the study (12 months + duration of inclusion) is about 30 months for the first included patients. III. Results

The results obtained in this test were analyzed by the Kaplan Meyer method for the figures and the relative risk (RR) was estimated using the proportional proportional regression model of Cox.

Relative risk (RR) is the ratio of the rates of occurrence of hospitalization or death in dronedarone patients compared to placebo-treated patients.

The percentage reduction x of a given event (hospitalization, death, cardiovascular death, etc.) is calculated as follows: x = 1 - relative risk.

III. 1. Results for cardiovascular hospitalization and mortality (criterion 15 of principle)

Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group. There were 917 events in the placebo group versus 734 in the dronedarone hydrochloride group. The calculated relative risk is 0.758 with a p = 2.10-8, a reduction of cardiovascular hospitalizations and 24.2% deaths from dronedarone hydrochloride, the result being highly significant.

FIG. 1, which reproduces the results obtained, shows a clear separation of the two cumulative curves very soon after the start of treatment, this separation being persistent over time throughout the duration of the study. :

III. 2. Results for Cardiovascular Hospitalization and Cardiovascular Mortality

Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group. There were 892 events in the placebo group versus 701 in the dronedarone hydrochloride group. 13 The calculated relative risk is 0.745 with a p = 45.1010, a reduction of cardiovascular hospitalizations and cardiovascular deaths of 25.5% in dronedarone hydrochloride, the result being highly significant.

Figure 2, which reproduces the results obtained, shows a clear separation of the two cumulative curves very early after the start of treatment, this separation persisting over time throughout the duration of the study. :

III. 3. Results for cardiovascular hospitalization and sudden death In the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group. There were 873 events in the placebo group versus 684 in the dronedarone hydrochloride group. The calculated relative risk is 0.743 with a p = 48.10-10, a reduction in cardiovascular hospitalizations and sudden death of 25.5% in dronedarone hydrochloride, the result being highly significant. FIG. 3, which reproduces the results obtained, shows a clear separation of the two cumulative curves very early after the start of the treatment, this separation being persistent over time throughout the duration of the study. :

III. 4. Results for cardiovascular hospitalizations

Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group. There were 859 events in the placebo group versus 675 in the dronedarone hydrochloride group. The calculated relative risk is 0.745 with a p = 9.109, a reduction of 30 cardiovascular hospitalizations by 25.5% in dronedarone hydrochloride.

Figure 4, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the start of the treatment, this separation persisting in time throughout the duration of the study. III. 5. Results for all-cause mortality

Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group.

There were 139 deaths in the placebo group versus 116 in the dronedarone hydrochloride group. The calculated relative risk is 0.844 with p = 0.1758, a reduction in cardiovascular hospitalizations of 15.6% in dronedarone hydrochloride.

Figure 5, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the beginning of the treatment, this separation persisting in time throughout the duration of the study.

111.6 Results relating to cardiovascular mortality.

Of the 4628 patients included in the study, 2301 were in the dronedarone hydrochloride group. There were 94 cardiovascular deaths in the placebo group compared to 65 in the dronedarone hydrochloride group. The calculated relative risk is 0.698 with p = 0.0252, a reduction in cardiovascular mortality of 30.2% in dronedarone hydrochloride.

Figure 6, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the start of treatment, this separation persisting over time throughout the study. 111.7 Sudden Death Results 4628 patients included in the study, 2301 were part of the group treated with 3C) dronedarone hydrochloride. There were 35 sudden deaths in the placebo group compared to 14 in the dronedarone hydrochloride group. The calculated relative risk is 0.405 with a p = 0.0031, a reduction in sudden death of 59.5% in dronedarone hydrochloride. FIG. 7, which reproduces the results obtained, shows a clear separation of the two cumulative curves, very early after the start of the treatment, this separation persisting over time during the entire duration of the study. 111.8 Requalification of serum potassium

The modulatory effect of potassium concentration is clearly documented in the study by the results of regular blood tests carried out throughout the duration of the study as part of the monitoring of vital parameters.

The potassium changes (in mmol / L) between the first and last administration of the study drug are included in Figure 8 in which B means basal level, J means day and M, month.

An analysis of the covariance of the change in serum potassium taking into account the baseline value during the study up to the 24th month shows a significant difference in favor of dronedarone compared to placebo (p <0.0001).

The dronedarone thus makes it possible to regulate the level of potassium in the blood. 111.9. Results for patients in the study receiving a diuretic-based regimen

The clinical results of the study support the hypothesis that potassium modulation decreases the risk of sudden death, particularly in patients at risk of decreased potassium exacerbated by diuretic therapy: risk reduction Sudden death of dronedarone, ie the prevention of sudden death compared with placebo, was 70.4% in patients taking diuretics and 34% in patients without diuretics.

In addition, the risk reduction was greater in groups of patients likely to be treated with diuretics such as hypertensives where the risk reduction was 62% compared to a reduction of 45.5% observed in non-hypertensive patients. 20 35

Claims (12)

REVENDICATIONS1. Use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention of mortality and / or cardiovascular hospitalization in patients with a history of atrial fibrillation or atrial flutter. 2. Use according to claim 1 for the preparation of a medicament for the prevention of mortality and / or cardiovascular hospitalizations in patients with a history of atrial fibrillation or atrial flutter by regulating the level of potassium in the blood. 3. Use according to one of claims 1 or 2 for the preparation of a medicament for the prevention of approximately 24% of mortality and / or cardiovascular hospitalizations in patients with a history of atrial fibrillation or atrial flutter . 4. Use according to one of claims 1 or 2 for the preparation of a medicament for the prevention of cardiovascular hospitalizations. 5. Use according to one of claims 1 or 2 for the preparation of a medicament for the prevention of mortality. 6. Use according to one of claims 1 or 2 characterized in that the mortality 25 is a cardiovascular mortality. 7. Use according to one of claims 1 or 2 characterized in that the mortality is a sudden death. 30 8. Use according to claim 1 characterized in that the patients receive a treatment based on diuretics. 9. Use according to claim 8 characterized in that the diuretics are non-sparing potassium diuretics. Page: 17 10. Use according to one of the preceding claims, characterized in that the patients have, in addition, at least one of the following risk factors: - hypertension, - diabetes, - history of cerebrovascular accident or systemic embolism, left atrial diameter greater than or equal to 50 mm measured by echocardiography, left ventricular ejection fraction less than 40% measured by two-dimensional ultrasound. 11. Use according to one of the preceding claims, characterized in that the patients have, in addition, additional risk factors, namely at least one of the following pathologies: hypertension, underlying structural heart disease, tachycardia, coronary artery disease, non-rheumatic heart valve disease, dilated cardiomyopathy of ischemic origin, - atrial fibrillation or flutter removal by catheter, supraventricular tachycardia other than atrial fibrillation or flutter, - past history of valvular surgery, non-ischemic dilated cardiomyopathy 25 - cardiomyopathy hypertrophic, rheumatic valvular heart disease, sustained ventricular tachycardia, congenital heart disease, - catheter ablation for tachycardia other than for atrial fibrillation or flutter, - ventricular fibrillation, and / or at least one cardiac device selected from: - a pacemaker, - a implant defibrillator able (ICD). 35 Page: 18 12. Use according to one of the preceding claims characterized in that the dose of dronedarone administered per day orally may reach 800 mg, in one or more doses. Page: 19