WO1998040067A1

WO1998040067A1 - Use of benzofuran derivatives for reducing death rate after myocardial infarction

Info

Publication number: WO1998040067A1
Application number: PCT/FR1998/000453
Authority: WO
Inventors: Gérald Frangin; Marek Malik
Original assignee: Sanofi
Priority date: 1997-03-10
Filing date: 1998-03-06
Publication date: 1998-09-17
Also published as: FR2760364A1; AR012039A1; AU6840098A

Abstract

The invention concerns the use of benzofuran derivatives with antiarrhythmic activity or one of the pharmaceutically acceptable salts thereof as active principles for preparing pharmaceutical compositions to reduce global death rate among patients having, after myocardial infarction, a reduced left ventricular function and a depressed variability of cardiac rate, without cardiac dysrhythmia requiring an antiarrhythmic treatment.

Description

USE OF BENZOFURAN DERIVATIVES FOR REDUCING MORTALITY AFTER MYOCARDIAL INFECTION

The present invention relates, in general, to the use of antiarrhythmic compounds, for the reduction of mortality after myocardial infarction.

In particular, the subject of the invention is the use of benzofuran derivatives known for their antiarrhythmic activity, in particular amiodarone, or pharmaceutically acceptable salts of these derivatives, for the reduction of mortality after recent myocardial infarction.

Mortality after myocardial infarction appears to be highest, of the order of 15%, in the first 6 to 12 months after the acute accident while it decreases thereafter to align with the mortality recorded in coronary artery disease stable and in chronic.

In this context, an assessment of the patient's chances of survival appears highly desirable.

To this end. different approaches have been proposed based in particular on the estimation of the left ventricular ejection fraction and on parameters which determine the variability of the heart rate.

The extent of the destroyed myocardial mass, which can result in the ejection fraction, as well as ventricular arrhythmias are recognized as major risk factors after myocardial infarction.

Therefore, medical therapy intended to prevent death in these circumstances may be particularly indicated during the first year after the occurrence of this heart attack although there is some discussion as to the duration of this prophylactic therapy itself.

Numerous studies in patients with myocardial infarction, however, attest that left ventricular dysfunction, ventricular arrhythmias and the importance of coronary artery disease independently contribute to the risk of overall mortality and sudden death, ventricular dysfunction left being the essential risk factor (Multicenter Postiπfarction Research Group -N. Engl. J. Med. 1983; 309; 331-336).

Thus, despite the significant progress made in recent years in ^the) treatment of myocardial infarction, the prognosis remains fairly reserved for patients who have a major alteration of ventricular function reflected by a marked lowering of the ejection fraction at this level. Furthermore, the variability of the heart rate which can be considered as the integrated response of the cardiovascular system to various influences such as piasmatic level of catecholamines, baroreflex activity and direct sympathetic and vagal activity, can also be taken advantage of as a factor. predictive of complications related to arrhythmias in patients surviving the acute phase of myocardial infarction

A decrease in the variability of the heart rate is moreover considered not only as a witness to the disturbed vagal cardiac activity but as a complete autonomous deterioration strongly associated with damage to the heart. This decrease in the variability of the heart rate also represents , a powerful and independent prognostic factor for mortality after myocardial infarction (Circulation 1992, 85 2073 - 2079 / Am J Cardiol 1991, 68 434 - 439 / Br Heart J 1991, 65 14-19), this prognostic factor being all the more more potent than the decrease in heart rate variability is associated with other risk factors (Circulation 1996, 93 1043-1065) In particular, a combination of the decrease in heart rate variability has been reported coupled with an increase in heart rate increases the predictive value of post-infarction mortality for these two factors (J Am Coll Cardiol 1996 27 2 70-276) Therefore, patients who show a decrease in heart rate variability have a reduced survival prognosis since they are at increased risk of cardiac mortality and arrhythmic events (Am J Cardiol 1987, 59. 256 - 262)

It therefore seems logical to try to prevent these arrhythmias by administering antiarrhythmic agents Unfortunately, all attempts to reduce post-infarction mortality with class I antiarrhythmic agents

(Vaughan-Williams classification) the most common have failed, especially in patients with arrhythmias or with lowered left ventricular fraction (The CAST Investigators - N Engl. J Med 1989, 321 406-412)

On the contrary, these antiarrhythmic agents should be contraindicated since instead of reducing mortality after myocardial infarction they actually increase the number of sudden deaths, probably due to their arrhythmogenic effects. Following these observations, the vast majority of cardiologists were skeptical and even opposed to the concept of prevention of sudden death after myocardial infarction by the administration of antiarrhythmic agents

Amiodarone, a powerful corrector of arrhythmias, widely used in this indication, is able to significantly suppress complex premature ventricular contractions and sustained ventricular tachycardia while having only a slight motrope effect and being significantly less arrhythmogenic than class I antiarrhythmics

However, amiodarone differs from other antiarrhythmic agents by a different mechanism of action; its ability to prolong the duration of the action potential and to lengthen the refractory period of the myocardial cell places it in the category of antiarrhythmic drugs of class III. from Vaughan-Wilhams

While it is fully recognized that amiodarone is a beneficial agent in potentially fatal arrhythmias often refractory to other antiarrhythmics, its efficacy has also been evaluated in the prevention of deaths occurring after myocardial infarction

The results of various practical tests in this context have been reported in the literature

In the vast majority of them, the effects of amiodarone have been studied in myocardial infarction survivors with arrhythmias (J Am Coll Cardiol

1992, 20 1056-1062, J Am Coll Cardiol 1990, 16 171 1-1718 N Eπgl J Med 1995, 333 77-82)

However, we have reported in SCRIP N ° 2116 Apπl 2nd 1996 p 18 the preliminary results of the multicentππ clinical trial called EMIAT carried out over a period of 2 years in several hundred patients with reduced left ventricular function, as a factor of risk, essential, but without arrhythmias requiring antiarrhythmic therapy

This trial revealed in particular that the overall mortality, that is to say the mortality due to any cause, did not seem to be modified by amiodarone whereas the arrhythmic mortality was reduced by 35%

Now, it has now surprisingly been found according to the invention, that patients with reduced left ventricular function after myocardial infarction but also with depressed variability in heart rate as an additional risk factor, however without arrhythmias falling under antiarrhythmic therapy, may benefit to a certain extent from a prophylactic effect against overall mortality

Consequently, it can be said to have demonstrated for the first time, in the context of the present invention, the possibility of reducing mortality, after myocardial infarction, whatever its origin, by means of a antiarrhythmic agent in this case amiodarone or its pharmaceutically acceptable salts, in patients with impaired left ventricular function and depressed heart rate variability as major risks but without symptomatic arrhythmias 0

Thus, the invention relates to the use as active ingredient, of a benzofuran derivative with antiarrhythmic activity, in particular amiodarone or dronedarone or of a pharmaceutically acceptable salt of this derivative preferably the hydrochloride, for the preparation of a pharmaceutical composition intended for reducing overall mortality in a patient presenting after myocardial infarction, a reduced left ventricular function and a depressed variability in the heart rate, without arrhythmia necessitating antiarrhythmic treatment

By “benzofuran derivative with antiarrhythmic activity”, is meant, within the framework of the present invention, a benzofuran compound chosen from those described in patents US 3248401, US 5223510 and EP 338746 as well as in patent applications WO 88 / 07996, WO 89/02892, WO 90/02743 and WO 94/29289

Of all of these compounds, there may be mentioned, for example, 2-n-butyl-3- [4- (3-dι- n-butylamιnopropoxy) benzoyl] -5-methylsulfonamιdo-benzofuran or dronedarone and its pharmaceutically acceptable salts described in patent US 5223510 However, as a benzofuran derivative with antiarrhythmic activity, it is generally preferred to use amiodarone and its pharmaceutically acceptable salts described in patent US 3248401

The term “amiodarone” is also understood to mean, in the context of the present invention, 2-n-butyl-3- (4-dιéthylamιnoethoxy-benzoyl) benzofuran in basic form or ^{ι ()} in the form of inclusion complexes in cyclodextnnes, their ethers or their esters

The use of the active metabolites of benzofuran derivatives with antiarrhythmic activity which is discussed above, is also part of the present invention. As examples of such metabolites, mention may be made of 2-n-butyl-3- (4-ethylaminoethoxy-benzoyl) benzofuran or N-desethylamiodarone and its pharmaceutically acceptable salts as described in patent FR 2550091 and 2- n-butyl -3- [4- (3-n-butylamιnopropoxy) benzoyl] -5-methylsulfonamιdo-benzofuran or N-desbutyldronedarone and its pharmaceutically acceptable salts described in US Pat. No. 5,235,510.

Similarly, the term "overall mortality" covers, within the framework of the invention, mortality due to any cause whether cardiac, non-cardiac or unknown

It should also be noted that the expression "patient with reduced left ventricular function after myocardial infarction, without rhythm disturbances requiring antiarrhythmic therapy" means a patient, who has a reduced left ventricular function after myocardial infarction, may possibly presenting asymptomatic arrhythmias, that is to say without pathological significance but no arrhythmia falling under antiarrhythmic treatment.

In addition, by "depπmed variability of the heart rate" is essentially meant an altered sympathovagal reflex sympathovagal reflex resulting from a relative decrease in parasympathetic activity compared to sympathetic activity. This variability in heart rate can be expressed by a "triangular index" as defined according to the method described in Eur Heart J 1989, 10

1060-1074 or Br. Heart J. 1991; 65 '14-19

In the context of the present invention, the triangular index of variability of the heart rate is generally <25 units in particular <20 units

Finally, by "reduced left ventricular function" we essentially mean a deficient left ventricular function reflected by an ejection fraction <40%

As will be described in more detail below, it has in particular been noted, following a clinical trial, that amiodarone preferably in the form of its hydrochloride, administered daily reduces overall mortality quite significantly in patients with a reduced ejection fraction, in particular greater than 30% and less than or equal to 40%, and with depressed variability in heart rate, in the post-inaugural infarction period, i.e. in patients with no having not had several infarctions (without history of infarction) For their use in therapy, the benzofuran derivatives with antiarrhythmic activity according to the invention are generally introduced into pharmaceutical compositions.

These pharmaceutical compositions can be presented in any form suitable for their administration in human therapy, in particular for administration by the oral, sublingual, nasal, inhaled, parenteral, topical, transdermal or rectal route.

Generally, the oral or parenteral route is used, but preferably the oral route. As regards the administration unit, this may take the form, for example of a scored tablet or not, a dragee, a capsule, a capsule, a powder, a suspension or syrup for oral administration, a suppository for rectal administration, a solution or suspension for parenteral administration or a device commonly called a "patch" for transdermal administration. The pharmaceutical compositions according to the invention may advantageously comprise, per administration unit, from 50 to 600 mg of active principle in particular from 150 to 250 mg for oral administration, from 10 to 250 mg of active principle for parenteral administration or also from 50 to 200 mg of active ingredient for rectal administration. One can constitute in particular pharmaceutical compositions containing amiodarone, dronedarone or one of their pharmaceutically acceptable salts at a rate of 50 to 500 mg for the oral administration more particularly oral compositions containing from 150 to 250 mg of amiodarone or one of its pharmaceutically acceptable salts or also from 50 to 150 mg of dronedarone or one of its pharmaceutically acceptable salts.

Depending on the chosen route of administration, the pharmaceutical compositions in question will be prepared, in a conventional manner by combining the active principle such as amiodarone or dronedarone or one of their pharmaceutically acceptable salts, with an appropriate pharmaceutical excipient or vehicle, the latter which may consist, for example, of at least one ingredient selected from the following substances: lactose, starches, talc, magnesium stearate, polyvinylpyrrohdone, algmic acid colloidal silica, polysorbate, manmtol, dihydrogen phosphate sodium, distilled water, benzyhque alcohol or sweeteners

For the preparation of an oral pharmaceutical composition, it is possible, for example, to mix the active principle with the selected pharmaceutical excipients or vehicles and then to carry out granulation in the dry or wet state.

Depending on the nature of the excipient used, it is possible, if necessary, to obtain by simple mixing a powder capable of being converted directly into tablets. This powder or this granule can be introduced directly into capsules or gelatin capsules or, preferably, transformed by compression into tablet cores

By way of example, pharmaceutical compositions can be prepared, dosed at 200 mg of amiodarone hydrochloride, for oral administration, for example in the form of tablets, which may or may not be broken, by granulation and compression of the following ingredients

Example 1

Amiodarone hydrochloride 200mg

Lactose 96mg

Corn starch 60mg

Polyvinylpyrrohdone 12mg

2.4mg anhydrous colloidal silica

Magnesium stearate 4.6mg

375mg

Example 2

Amiodarone hydrochloride 200mg

Lactose 71mg Corn starch 66mg

Polyvinylpyrrolidone 6mg

2.4mg anhydrous colloidal silica

Magnesium stearate 4.6mg

350mg

Likewise, a pharmaceutical composition containing 106 mg of dronedarone hydrochloride can be constituted for oral administration in particular in the form of a capsule:

Example 3

Dronedarone hydrochloride 106mg

(i.e. 100mg of dronedarone base)

Corn starch 138.5mg

Talc 50mg

Colloidal anhydrous silica 1, 25mg

Magnesium stearate 2.5mg

Lactose 201, 75mg

500mg

For parenteral administration, pharmaceutical compositions can also be prepared, dosed with 150 mg of amiodarone hydrochloride or 10.6 mg of dronedarone hydrochloride, for example in the form of an injectable solution of formulation; O 98/40067

Example 4

Amiodarone hydrochloride 150mg

Polysorbate 80 300mg

Benzyl alcohol 60mg

Water for injection QS ^* 3ml

Example 5

Dronedarone hydrochloride 10.6mg

(i.e. 10mg of dronedarone base)

Mannitol 200mg

Anhydrous sodium dihydrogen phosphate 120mg

Water for injection Q.S. 10ml

^* QS. sufficient quantity to

When seeking a prophylactic effect on post-infarction mortality, in accordance with the invention, the active principle, more especially amiodarone or its pharmaceutically acceptable salts, can be administered at daily doses varying from 100 to 800 mg per oral, preferably 200 to 400 mg

In the particular case of the administration of amiodarone by the oral route, or of its pharmaceutically acceptable salts, daily doses greater than 400 mg, for example doses of 400 to 800 mg, in particular doses of 600 to 800 mg, are reserved for treatment of short duration, for example in attack treatments requiring a large loading dose of active principle, while daily doses less than or equal to 400 mg, for example doses of 200 to 300 mg, preferably doses of 200 mg represent more maintenance doses

In particular, the following therapeutic regimen can be used which comprises the administration of amiodarone hydrochloride as active ingredient first in a loading dose then in a maintenance dose, namely ^: • Attack treatment: 800 mg / day or 4 tablets each dosed with 200 mg of amiodarone hydrochloride for 2 weeks, treatment starting early after the acute phase of myocardial infarction, for example from

• Maintenance treatment: 400 mg / day or 2 tablets each dosed with 200 mg of amiodarone hydrochloride for 3 to 4 months then 200 mg of amiodarone hydrochloride for at least 12 months.

According to another aspect of the invention, the administration of the benzofuran derivative with antiarrhythmic activity or of a pharmaceutically acceptable salt thereof can be carried out in close association, that is to say simultaneous or sequential with the administration of at least one additional cardioactive agent in order to reinforce the desired prophylactic effect and or to treat the underlying cardiac disease.

Consequently, another subject of the invention relates to the use of a benzofuran derivative with antiarrhythmic activity, preferably amiodarone or dronedarone, or of a pharmaceutically acceptable salt of this derivative for the preparation of pharmaceutical compositions to be administered in simultaneous or sequential association, with at least one additional cardioactive agent, for the reduction of the overall mortality in patients presenting after myocardial infarction a reduced left ventricular function and a depressed variability of the heart rate, without disturbances of the rhythm requiring antiarrhythmic therapy.

According to this variant, it is possible to combine the active principle, for example amiodarone, dronedarone or one of their pharmaceutically acceptable salts, and at least one additional cardioactive agent chosen from a diuretic, an inhibitor of the enzyme converting angiotensin, an angiotensin II receptor antagonist, a caicic inhibitor, a cardiotonic agent, a β-blocking agent, a nitro derivative or a vitamin K inhibitor By way of nonlimiting examples, there will subsequently be mentioned cardioactive agents which may be associated with the active principle in question, these agents being named by their International Common Name (INN).

Thus, one can select: • the diuretic from furosemide, hydrochlorothiazide, metolazone, amilonde and spironolactone, these compounds being administered at therapeutically active doses chosen between 1 and 200 mg / day

• the angiotensin converting enzyme inhibitor among captopπl, enalapril, fosinopril, quinapπl, ramipnl, lisinopπl, cilazapπl and permdopril, these compounds being administered at selected therapeutically active doses between 2 and 150mg / day.

• the angiotensin II receptor antagonist among irbesartaπ, losartan, candesartan, valsartan, zolasartan, telminsartan, eprosartan, these compounds being administered at therapeutically active doses chosen between 1 and 200 mg / day. However, irbesartan represents a preferred angiotensin II receptor antagonist.

• the calcium channel blocker among nifedipine, nicardipine, lacidipine, felodipine, amlodipine, diltiazem and verapa il, these compounds being administered in therapeutically active doses chosen between 1 and 500 mg / day.

• the cardiotonic agent among acetyldigitoxm, digitoxin and digoxin, these compounds being administered in therapeutically active doses chosen between

0.1 and 2mg / day.

Β-blocking agent among timolol, atenolol, pindolol, bisoprolol, acebutolol, propranolol, metoprolol, nadolol, tertatolol, alprenolol, betaxolol, celiprolol and oxprenolol , these compounds being administered at therapeutically active doses chosen between 10 and 500 mg / day. • the nitre derivative among nicorandil, isosorbide mononitrate, isosorbide dinitrate and tnnitπne, these compounds being administered at therapeutically active doses chosen between 2 and 200 mg / day

• the vitamin K antagonist among warfaπne, acenocoumarole and phenprocoumon, these compounds being administered at therapeutically active doses chosen between 1 and 50 mg / day

However, associations with an angiotensin converting enzyme inhibitor or with an angiotensin II receptor antagonist or with a β-blocking agent represent preferred associations.

However, amiodarone or its pharmaceutically acceptable salts does not represent the product of benzofuran with antiarrhythmic activity of choice for the constitution for example of a simultaneous association represented by a single administration unit being given its particularly prolonged lifespan compared other cardioactive agents associated with it

The prophylactic efficacy of benzofuran derivatives with antiarrhythmic activity and their pharmaceutically acceptable salts vis-à-vis post-infarction mortality was demonstrated via amiodarone hydrochloride following a prospective clinical study , multicenter and double blind (with a triple blind approach) with randomization (random assignment) of patients

This study, which was carried out over a period of several years, was carried out in high-risk patients presenting as a compulsory inclusion criterion a deficient left ventricular function after recent myocardial infarction and reduced variability in the heart rate

CLINICAL STUDY

I. Patient selection

The patients were randomized between the 5th and 21st days after myocardial infarction. During this period, the inclusion criteria were checked and following exclusion for each patient of both sexes likely to be enrolled in the trial namely

Inclusion criteria

1) presence of a myocardial infarction

2) ejection fraction less than or equal to 40% by standardized radionuclide ventilation o

3) reduced variability of the heart rate determined according to the so-called "triangular index of heart rate variability (HRV)" method (Eur Heart J 1989, 10 1060 - 1074)

This method is based on the histogram of the distribution of RR intervals between normal QRS determined from Holter records over 24 hours, the value of the triangular index of HRV being calculated by dividing the area of the histogram by its height , in other words the triangular index VFC corresponds to the total number of RR intervals of the analyzable sinus rhythm divided by their modal frequency 0

4) age over 18 and under 75

Exclusion criteria

5 1) Amiodarone contraindications

2) special status of the patient, in particular women of childbearing age, non-cardiac or preexisting disease likely to significantly shorten a 2-year survival or any condition requiring treatment with tricyclic antidepressants, phenytoin, hdoflazine, prenylamine or vmcamine 3) need for antiarrhythmic therapy other than β-blockers or digitalis at the time of inclusion in the trial

4) severe angina not responding to conventional treatment

5) severe heart failure not responding to conventional treatment

6) need for heart surgery

Each of the patients selected according to these criteria were included in the study and randomized between 5 and 21 days after the myocardial infarction to receive either amiodarone hydrochloride or placebo.

Duration and treatment

The trial lasted for 4 years, the recruitment period spanning 3 years so that patients recruited during the first 2 years were treated for 2 years and those recruited in the last year were treated until the end of test. The minimum salary was, therefore, 1 year. This treatment was started double blind from tablets containing either the placebo or 200 mg of amiodarone hydrochloride, according to the following therapeutic scheme:

a) Exchange dose ^• 800mg or 4 tablets / day in two divided doses for 2 weeks

b) Maintenance dose:

* 400mg or 2 co pnmes / jour in two intakes from the 3rd week for 3 months and 2 weeks. ^* 200mg or 1 tablet per day for 20 months.

Co-medication has also been established, namely: angiotensin converting enzyme inhibitors in 77% of patients, β-blockers in 44%, vitamin K antagonists in 29%, digoxin in 23%. calcium antagonists in 14%.

Holter recordings performed during the trial revealed that approximately 40% of patients had more than 10 ventricular extrasystoles per hour or 3 bi- or tri-twin extrasystoles

III. Results

The results obtained during this trial were analyzed by Kaplan Meyer's method and are reported below: • either in the form of Tables showing the percentages of reduction in overall mortality after 24 months for the group of patients with a triangular index of HRV <20 units and for the group of patients with a triangular index of HRV <19, the majority of patients in the study who showed an index less than or equal to this dichotomy limit. • either in the form of attached drawings.

In all cases, the abbreviations used have the following meanings ^•

"PL" means "placebo"

"Am" means "amiodarone hydrochloride".

A) Group of patients with triangular index of HRV <20 units a) Figure 1 represents the rate of patients surviving for 24 months at overall mortality.

Among the 365 patients included in the study (278 men of 61.7 + 8.5 years of average age), 184 of them belonging to the placebo group, a triangular index of HRV <20 units was highlighted .

Following the two years of the trial, 21.7% of deaths were recorded in the placebo group and 16.6% of deaths in the group treated with amiodarone hydrochloride.

Figure 1, which reproduces the results obtained, also shows a clear separation of the two cumulative survival curves. b) Other results relating to the reduction in overall mortality were determined during this test from 3 subgroups of patients formed from the group of patients with triangular index of HRV <20 units included in the Ces test. subgroups were made up of patients with specific characteristics, namely patients:

1) with inaugural myocardial infarction, or

2) treated with β-blockers at the time of inclusion in the trial, or

3) with basic heart rate (HR)> 75 beats / min These results are listed in Table 1 below

TABLE 1

The reduction in arrhythmic cardiac mortality with amiodarone hydrochloride was 66% after 24 months (p = 0.0054) (arrhythmic cardiac mortality with placebo = 12.8% and with hydrochloride d 'amiodarone = 4.4%)

B) Group of patients with triangular index of HRV <19 units a) Figure 2 represents the rate of patients surviving for 24 months at the global mortality after inaugural myocardial infarction

In the 235 patients with inaugural myocardial infractus included in the study, namely 116 patients on palcebo and 119 patients on amiodarone hydrochloride, a triangular index of HRV <19 units was highlighted at the time of inclusion. O 98/40067

17

Following the two years of the trial, this group recorded 18.93% of deaths in patients on placebo and 9.57% of deaths in patients treated with amiodarone hydrochloride, which is equivalent to a 49% reduction in mortality (p = 0.05).

Figure 2, which reproduces the results obtained, shows a statistically significant reduction in the mortality of the group treated with amiodarone hydrochloride (p = 0.05). b) Other results relating to the reduction of overall mortality were determined during this test:

• from the total group of patients with triangular index of VFC 19 units included in the trial,

• from two subgroups formed from the total group of patients with triangular index of VFC <19 units included in the test.

These subgroups were made up of patients with special characteristics, namely patients:

1) treated with β-blockers at the time of inclusion in the trial or

2) with basic heart rate (HR)> 75 pulses / min These results are listed in Table 2 below ^•

TABLE 2

Claims

1. Use of benzofuran derivatives with antiarrhythmic activity or of a pharmaceutically acceptable salt thereof as active principles for the preparation of pharmaceutical compositions intended to reduce overall mortality in patients with reduced left ventricular function after myocardial infarction and depressed heart rate variability with no arrhythmia requiring antiarrhythmic therapy.

2. Use according to Claim 1 characterized in that the benzofuran derivative is amiodarone or one of its pharmaceutically acceptable salts.

3. Use according to Claim 1 characterized in that the benzofuran derivative is dronedarone or one of its pharmaceutically acceptable salts. 4. Use according to Claim 1 characterized in that the benzofuran derivative is desethylamiodarone or one of its pharmaceutically acceptable salts. 5. Use according to Claim 1 characterized in that the benzofuran derivative is N-desbutyldronedarone. 6. Use according to one of Claims 1 to 5 characterized in that the pharmaceutically acceptable salt is the hydrochloride.

7. Use of amiodarone hydrochloride as active ingredient for the preparation of pharmaceutical compositions intended to reduce overall mortality in patients with reduced left ventricular function and depressed heart rate variability after heart attack, without disturbances rhythm requiring antiarrhythmic therapy.

8. Use according to one of Claims 1 to 7, characterized in that the pharmaceutical compositions are intended to reduce overall mortality in patients with reduced left ventricular function reflected by an ejection fraction <40%.

9. Use according to Claim 8 characterized in that the ejection fraction is greater than 30% and equal to or less than 40%. 10 Use according to one of Claims 1 to 9 characterized in that pharmaceutical compositions are prepared for oral administration sublingual, nasal, inhaled, parenteral, topical, transdermal or rectal

11 Use according to Claim 10 characterized in that pharmaceutical compositions for oral administration are prepared

12 Use according to Claim 10 characterized in that pharmaceutical compositions are prepared for parenteral administration

13. Use according to Claim 10 or 1 1, characterized in that pharmaceutical compositions are prepared containing from 50 to 600 mg of active principle for oral administration.

14 Use according to Claim 10 or 12 characterized in that pharmaceutical compositions are prepared containing from 10 to 250 mg of active principle for parenteral administration

15 Use according to Claim 11 or 13 characterized in that pharmaceutical compositions are prepared for the oral administration of daily doses of 100 to 800 mg of amiodarone or one of its pharmaceutically acceptable salts

16 Use according to Claim 15 characterized in that pharmaceutical compositions are prepared for the oral administration of daily loading doses of 400 to 800 mg of amiodarone or one of its pharmaceutically acceptable salts

17 Use according to Claim 15 characterized in that pharmaceutical compositions are prepared for the oral administration of daily maintenance doses of 200 to 300 mg of amiodarone or one of its pharmaceutically acceptable salts

18 Use according to Claim 17 characterized in that the daily maintenance dose is 200 mg of amiodarone or one of its pharmaceutically acceptable salts

19 Use according to one of Claims 1 to 18 characterized in that the pharmaceutical compositions are administered in simultaneous or sequential association with at least one additional cardioactive agent 20. Use according to Claim 19 characterized in that the additional cardioactive agent is chosen from one diuretic, an enzyme inhibitor conversion of angiotensin, an angiotensin II receptor blocker, a calcium channel blocker, a cardiotonic agent, a β-blocking agent, a nitre derivative and a vitamin K 21 inhibitor Use according to Claim 20 characterized in that

• the diuretic is chosen from furosemide, hydrochlorothiazide, metolazone, amiloπde and spironolactone

• the angiotensin converting enzyme inhibitor is chosen from captopnl, enalapril, fosinopπl, qumapril, ramipπl, lisinopril, cilazapril and peπndopril

• the angiotensin II receptor antagonist is chosen from irbesartan, losartan, candesartan, valsartan, zolasartan, telminsartan and eprosartan

• the calcium channel blocker is chosen from nifedipine, nicardipine, lacidipine, felodipine, amlodipine, diltiazem and verapamil • the cardiotonic agent is chosen from acetyldigitoxin, digitoxin and digoxin

• the β-blocking agent is chosen from timolol, atenolol, pindolol, bisoprolol, acebutolol, propranolol, metoprolol, nadolol, tertatolol, alprenolol, betaxolol, celiprolol and l 'oxprenolol

• the nitro derivative is chosen from nicorandil, isosorbide mononitrate, isosorbide dinitrate and trinitπne

• the vitamin K antagonist is chosen from warfaπne, acenocoumarole and phenprocoumon

22. Use according to one of Claims 19 to 21 characterized in that the pharmaceutical compositions are administered in simultaneous or sequential combination with an inhibitor of the angiotensin converting enzyme or with an angiotensin II receptor antagonist 23. Use according to Claim 22 characterized in that the pharmaceutical compositions are administered in simultaneous or sequential association with irbesartan 24. Use according to one of Claims 19 to 23 characterized in that the pharmaceutical compositions contain amiodarone or one of its salts pharmaceutically acceptable

25. Use according to one of Claims 19 to 23 characterized in that the pharmaceutical compositions contain dronedarone or one of its pharmaceutically acceptable salts.

26. Use according to Claim 24 or 25 characterized in that the pharmaceutically acceptable salt is the hydrochloride.