Use of Ace Inhibitors in the Prevention of Congestive Heart Failure

Europäisches Patentamt *EP001212081B1* (19) European Patent Office

Office européen des brevets (11) EP 1 212 081 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 38/55, A61K 31/00, of the grant of the patent: A61K 31/4184, A61P 9/04, 26.10.2005 Bulletin 2005/43 A61P 9/10, A61P 3/10 (21) Application number: 00965898.0 (86) International application number: PCT/EP2000/008341 (22) Date of filing: 25.08.2000

(87) International publication number: WO 2001/015673 (08.03.2001 Gazette 2001/10)

(54) USE OF ACE INHIBITORS IN THE PREVENTION OF CONGESTIVE HEART FAILURE VERWENDUNG VON ACE INHIBITOREN ZUR PROPHYLAXE VON KONGESTIVEM HERZVERSAGEN UTILISATIONS DES INHIBITEURS DE L’ENZYME DE CONVERSION DE L’ANGIOTENSINE POUR PREVENIR L’INSUFFISANCE CARDIAQUE GLOBALE

(84) Designated Contracting States: (56) References cited: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU EP-A- 0 241 201 EP-A- 0 331 014 MC NL PT SE EP-A- 0 426 066 EP-A- 0 474 438 Designated Extension States: EP-A- 0 540 209 EP-A- 0 747 050 AL LT LV MK RO SI EP-A- 0 795 327 WO-A-00/02543 WO-A-00/71751 WO-A-01/15674 (30) Priority: 27.08.1999 SE 9903028 WO-A-93/20839 WO-A-96/24373 WO-A-97/27745 WO-A-97/49392 (43) Date of publication of application: WO-A-98/30216 WO-A-99/20260 12.06.2002 Bulletin 2002/24 WO-A-99/44590 DE-A- 4 308 504 DE-A- 19 913 528 GB-A- 2 308 064 (60) Divisional application: US-A- 5 190 970 US-A- 5 266 583 04006330.7 / 1 437 131 US-A- 5 308 846 US-A- 5 506 361

(73) Proprietor: Aventis Pharma Deutschland GmbH • DATABASE WPI Week 199944 Derwent 65929 Frankfurt am Main (DE) Publications Ltd., London, GB; AN 1999-520858 XP002166044 MASUDA YOSHINOBU, HONDA (72) Inventors: YAYOI, MINATO HISAO: "Inhibitor of cerebral • SCHOELKENS, Bernward vasospasm" & JP 11 222439 A (DAINIPPON 65779 Kelkheim (DE) PHARM CO LTD), 17 August 1999 (1999-08-17) • BENDER, Norbert • OGIKU N ET AL: "Prophylactic effect of imidapril 65719 Hofheim (DE) on stroke in stroke -prone spontaneously • RANGOONWALA, Badrudin hypertensive rats." STROKE, (1993 FEB) 24 (2) 65719 Hofheim (DE) 245-52., XP000997781 • DAGENAIS, Gilles • STIER C T JR ET AL: "ENALAPRIL PREVENTS Quebec, J7A 3P8 (CA) STROKE AND KIDNEY DYSFUNCTION IN • GERSTEIN, Hertzel SALT-LOADED STROKE-PRONE Hamilton, Ontario L8S 4A8 (CA) SPONTANEOUSLY HYPERTENSIVE RATS" • LJUNGGREN, Anders HYPERTENSION (DALLAS), vol. 13, no. 2, 1989, S-431 63 Mölndal (SE) pages 115-121, XP000997775 ISSN: 0194-911X • YUSUF, Salim Carlisle, Ontario L0R 1H2 (CA)

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 212 081 B1

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• ROBERT MKW LEE, HONG WANG, JOHN S • BLUMENTHAL MEL: "Treatment of congestive SMEDA: "Effects of perindopril on hypertension heart failure: Experience with fosinopril." and stroke prevention in experimental animals" AMERICAN JOURNAL OF HYPERTENSION, vol. CAN. J. CARDIOL., vol. 10, no. Suppl D, 10, no. 10 PART 2, 1997, pages 289S-298S, November 1994 (1994-11), pages 33D-36D, XP001019673 ISSN: 0895-7061 XP000998206 • NAKAMURA FUMIAKI ET AL: "Chronic • J.E.F. REYNOLDS: "Martindale The Extra administration of angiotensin II receptor Pharmacopoeia" 1996 , ROYAL antagonist, TCV-116, in cardiomyopathic PHARMACEUTICAL SOCIETY , LONDON hamsters." AMERICAN JOURNAL OF XP002166043 page 863, column 2 -page 864, PHYSIOLOGY, vol. 267, no. 6 PART 2, 1994, column 2 page 899, column 3 -page 900, column pages H2297-H2304, XP001019610 ISSN: 1 page 940, column 3 -page 941, column 1 0002-9513 • EBERHARDT ROBERT T ET AL: "Angiotensin II • K. PARFITT: "Martindale - The complete drug receptor blockade: An innovative approach to reference - Thirty-second Edition" 1999 , cardiovascular pharmacotherapy." JOURNAL PHARMACEUTICAL PRESS , LONDON UK OF CLINICAL PHARMACOLOGY, vol. 33, no. 11, XP002176301 page 836, column 1 page 865, 1993, pages 1023-1038, XP001019614 ISSN: column 3 page 891, column 3 -page 892, column 0091-2700 1 page 899, column 1 page 951, column 3 page • STIER CHARLES T JR ET AL: "Stroke prevention 960, column 2 -column 3 by losartan in stroke-prone spontaneously hypertensive rats." JOURNAL OF HYPERTENSION, vol. 11, no. SUPPL. 3, 1993, pages S37-S42, XP001019687 Meeting on Losartan: An Orally Active Angiotensin II Antagonist;St. Paul de Vence, France; June 26-27, 1992 ISSN: 0263-6352

2 1 EP 1 212 081 B1 2

Description disease and where the patient exhibits normal or low blood pressure is hitherto unknown. FIELD OF INVENTION SUMMARY OF THE INVENTION [0001] The present invention relates to use of an an- 5 giotensin converting enzyme inhibitor (ACE) or a phar- [0006] The present invention relates to use of an ACE maceutically acceptable salt thereof in the manufacture inhibitor or a pharmaceutically acceptable salt thereof of a medicament for the prevention of congestive heart in the manufacture of a medicament for the prevention failure (CHF), in patients with no preexisting CHF, where of development of CHF in patients with no preexisting the patient is at high risk for a cardiovascular event due 10 CHF, i.e. no signs or symptoms of CHF, where the pa- to a history of previous ischaemic heart disease, stroke tient is at high risk for a cardiovascular event due to a or peripheral arterial disease and where the patient ex- history of previous ischaemic heart disease, stroke or hibits normal or low blood pressure. peripheral aterial disease and where the patient exhibits normal or low blood pressure. BACKGROUND OF THE INVENTION 15 DETAILED DESCRIPTION OF THE INVENTION [0002] Compounds that interfere with the renin angiotensin system (RAS) are well known in the art and are [0007] It has surprisingly been found that cardiovas- used to treat cardiovascular diseases, particularly arte- cular disorders such as CHF can be prevented by use rial hypertension and heart failure. Principally, the RAS 20 of an ACE inhibitor that interferes with the synthesis of can be interferred with by inhibition of the enzymes syn- angiotensin II. The present invention is especially sur- thesizing angiotensins or by blocking the corresponding prising in that especially patients exhibiting a normal or receptors at the effector sites. Available today are inhib- low blood pressure benefit markedly from the preventive itors of the angiotensin converting enzyme (ACE) and action of the ACE inhibitors. The invention describes a angiotensin II type 1 receptor (AT II) antagonists. 25 new method to prevent CHF by administration of an [0003] ACE inhibitors are compounds which inhibit ACE inhibitor to patients with no preexisting CHF, where the conversion of angiotensin I into the active angi- the patient is at high risk for a cardivascular event due otensin II as well as the breakdown of the active vasodi- to a history of previous ischaemic heart disease, stroke lator bradykinin. Both of these mechanisms lead to va- or peripheral arterial disease and where the patient ex- sodilation. Such compounds have been described in, for 30 hibits normal or low blood pressure. example, EP 158927, EP 317878, US 4,743,450, and [0008] Patients exhibiting a normal or low blood pres- US 4,857,520. sure are known as normotensive patients. Examples of [0004] Ramipril (disclosed in EP-A-079022) is a long- guidelines defining blood pressure values for different acting ACE inhibitor. Its active metabolite is the free di- patient groups including different ages, include guide- acid ramiprilat, which is obtained in vivo upon adminis- 35 lines issued by the WHO and JNC (USA). In the present tration of ramipril. In hypertensive patients administra- invention, a suitable definition of a normal or low blood tion of ramipril is known to cause a reduction in periph- pressure can be found in JNC VI, which is hereby incor- eral arterial resistance and thus a reduction of the blood porated by reference. pressure without a compensatory rise in heart rate. It is [0009] In the present invention, "diabetes" include currently being used in the treatment of hypertension 40 both type I diabetes, also known as insulin-dependent, and CHF. Furthermore, ramipril has been shown to re- diabetes mellitus (IDMM), and type II diabetes, also duce mortality in patients with clinical signs of conges- known as non-insulin-dependent diabetes mellitus tive heart failure after surviving an acute myocardial in- (NIDDM). farction. Ramipril has been suggested to have an added [0010] In the present invention, "angiotensin convert- advantage over many other ACE inhibitors due to its 45 ing enzyme (ACE) inhibitor or a pharmaceutically ac- pronounced inhibition of ACE in tissues resulting in or- ceptable salt thereof" includes any compound which in gan protective effects in e.g. the heart, kidney, and blood itself or upon administration interferes with the synthesis vessels. of angiotensin II. [0005] Compounds that interfere with the RAS includ- [0011] When the ACE inhibitor used in the present in- ing ACE inhibitors and AT II antagonists are currently 50 vention have several asymetric carbon atoms, they can used in the treatment of various cardiovascular disor- consequently exist in several stereochemical forms. ders, especially in patients exhibiting a high blood pres- The present invention includes the mixture of isomers sure. Use of said compounds in prevention of cardio- as well as the individual stereoisomers. The present in- vascular disorders is much less common and the use of vention further includes geometrical isomers, rotational said compounds in the prevention of CHF in patients 55 isomers, enantiomers, racemates and diastereomers. with no preexisting CHF, where the patient is at high risk [0012] Where applicable, the ACE inhibitors may be for a cardivascular event due to a history of previous used in neutral form, e.g. as a carboxylic acid, or in the ischaemic heart disease, stroke or peripheral arterial form of a salt, preferably a pharmaceutically acceptable

3 3 EP 1 212 081 B1 4 salt such as the sodium, potassium, ammonium, calci- being mixed to form a formulation. um or magnesium salt of the compound at issue. Where [0019] Soft gelatine capsules may be prepared with applicable the compounds listed above can be used in capsules containing a mixture of the active ingredient of hydrolyzable ester form. the invention, vegetable oil, fat, or other suitable vehicle [0013] In the present invention, the ACE inhibitors 5 for soft gelatine capsules. Hard gelatine capsules may may exhibit a long term duration, medium term duration contain granules of the active ingredients. Hard gelatine or short term duration. capsules may also contain the active ingredients in com- [0014] ACE inhibitors or pharmaceutically acceptable bination with solid powdered ingredients such as lac- salts thereof, including active metabolites, which can be tose, saccharose, sorbitol, mannitol, potato starch, corn used for the prevention of CHF indude, but is not limited 10 starch, amylopectin, cellulose derivatives or gelatine. to, the following compounds: [0020] Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain alacepril, alatriopril, altiopril calcium, ancovenin, the active substance mixed with a neutral fat base; (ii) benazepril, benazepril hydrochloride, benazeprilat, in the form of a gelatine rectal capsule which contains benzoylcaptopril, captopril, captopril-cysteine, cap- 15 the active substance in a mixture with a vegetable oil, topril-glutathione, ceranapril, ceranopril, ceronapril, paraffin oil or other suitable vehicle for gelatine rectal cilazapril, cilazaprilat, delapril, delapril-diacid, enal- capsules; (iii) in the form of a ready-made micro enema; april, enalaprilat, enapril, epicaptopril, foroxymith- or (iv) in the form of a dry micro enema formulation to ine, fosfenopril, fosenopril, fosenopril sodium, fosi- be reconstituted in a suitable solvent just prior to admin- nopril, fosinopril sodium, fosinoprilat, fosinoprilic 20 istration. acid, glycopril, hemorphin-4, idrapril, imidapril, in- [0021] Liquid preparations may be prepared in the dolapril, indolaprilat, libenzapril, lisinopril, lyciumin form of syrups or suspensions, e.g. solutions or suspen- A, lyciumin B, mixanpril, moexipril, moexiprilat, sions containing the active ingredients and the remain- moveltipril, muracein A, muracein B, muracein C, der consisting, for example, of sugar or sugar alcohols pentopril, perindopril, perindoprilat, pivalopril, pivo- 25 and a mixture of ethanol, water, glycerol, propylene gly- pril, quinapril, quinapril hydrochloride, quinaprilat, col and polyethylene glycol. If desired, such liquid prep- ramipril, ramiprilat, spirapril, spirapril hydrochloride, arations may contain coloring agents, flavoring agents, spiraprilat, spiropril, spiropril hydrochloride, temoc- preservatives, saccharine and carboxymethyl cellulose april, temocapril hydrochloride, teprotide, trandol- or other thickening agents. Liquid preparations may also april, trandolaprilat, utibapril, zabicipril, zabiciprilat, 30 be prepared in the form of a dry powder to be recon- zofenopril and zofenoprilat. stituted with a suitable solvent prior to use. [0022] Solutions for parenteral administration may be [0015] Preferred ACE inhibitors for use in the present prepared as a solution of a formulation of the invention invention are ramipril, ramiprilat, lisinopril, enalapril and in a pharmaceutically acceptable solvent. These solu- enalaprilat. More preferred ACE inhibitors for uses in the 35 tions may also contain stabilizing ingredients, preserv- present invention are ramipril and ramiprilat. Information atives and/or buffering ingredients. Solutions for about ramipril and ramiprilat can be obtained e.g. from parenteral administration may also be prepared as a dry the Merck Index., 12th ed., 1996, pp. 1394-1395. preparation to by reconstituted with a suitable solvent [0016] For clinical use, the ACE inhibitor is formulated before use. into a pharmaceutical formulation for oral, intravenous, 40 [0023] The total amount of active ingredient suitably subcutaneous, tracheal, bronchial, intranasal, pulmo- lies in the range of from about 0.1 % (w/w) to about 95 nary, transdermal, buccal, rectal, parenteral or some % (w/w) of the formulation, suitably from 0.5 % to 50 % other mode of administration. The pharmaceutical for- (w/w) and preferably from 1 % to 25 % (w/w). mulation may contain the inhibitor in admixture with a [0024] The pharmaceutical formulations may contain pharmaceutically acceptable adjuvant, diluent and/or 45 between about 0.1 mg and about 1000 mg of active in- carrier. gredient, preferably between 1 mg and 100 mg of active [0017] In the preparation of the pharmaceutical for- ingredient. mulations of the present invention the active ingredient [0025] The dose of the active ingredient to be admin- may be mixed with solid, powdered ingredients, such as istered will depend on the relevant indication, the age, lactose, saccharose, sorbitol, mannitol, starch, amylo- 50 weight and sex of the patient and may be determined pectin, cellulose derivatives, gelatin, or another suitable by a physician. The dosage will suitably be in the range ingredient, as well as with disintegrating agents and lu- of from about 0.01 mg/kg to about 20 mg/kg, preferably bricating agents such as magnesium stearate, calcium between 0.1 mg/kg and 10 mg/kg. stearate, sodium stearyl fumarate and polyethylene gly- [0026] The typical daily dose of the active ingredients col waxes. The mixture may then be processed into 55 varies within a wide range and will depend on various granules or pressed into tablets. factors such as the relevant indication, the route of ad- [0018] The active ingredient may be separately ministration, the age, weight and sex of the patient and premixed with the other, non-active ingredients, before may be determined by a physician. In general, dosages,

4 5 EP 1 212 081 B1 6 and especially oral and parenteral dosages, will be in 2. The use according to claim 1, where the patient is the range of from about 0.1 to about 100 mg per day of diabetic. active ingredient, preferably between 1 and 50 mg per day of active ingredient. 3. The use according to claims 1-2, wherein the angi- [0027] The following Example is intended to illustrate, 5 otensin converting enzyme inhibitor or a pharma- but in no way limit the scope of the invention. ceutically acceptable salt thereof is selected from the group consisting of alacepril, alatriopril, altiopril EXAMPLE calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, [0028] A large-scale clinical trial was designed to ex- 10 captopril-cysteine, captopril-glutathione, cerana- amine the effect of the ACE inhibitor ramipril versus pla- pril, ceranopril, ceronapril, cilazapril, cilazaprilat, cebo in reducing cardiovascular events. delapril, delapril-diacid, enalapril, enalaprilat, en- [0029] The study was conducted in 267 centres in 19 april, epicaptopril, foroxymithine, fosfenopril, fose- countries over a six year period and included 9,541 par- nopril, fosenopril sodium, fosinopril, fosinopril sodi- ticipants who are at high risk for cardiovascular events 15 um, fosinoprilat, fosinoprilic acid, glycopril, hemor- due to a history of previous ischaemic heart disease, phin-4, idrapril, imidapril, indolapril, indolaprilat, stroke, peripheral arterial disease or individuals with di- libenzapril, lisinopril, lyciumin A, lyciumin B, mixan- abetes. pril, moexipril, moexiprilat, moveltipril, muracein A, [0030] The systolic blood pressure at inclusion of the muracein B, muracein C, pentopril, perindopril, patients was on average 138 mm Hg and thus the pa- 20 perindoprilat, pivalopril, pivopril, quinapril, quinapril tients were normotensive at study start. After one month hydrochloride, quinaprilat, ramipril, ramiprilat, spir- of therapy with either ramipril or placebo, the systolic april, spirapril hydrochloride, spiraprilat, spiropril, blood pressure had decreased by 5.48 mm Hg and 1.59 spiropril hydrochloride, temocapril, temocapril hy- mm Hg, respectively. drochloride, teprotide, trandolapril, trandolaprilat, [0031] The primary endpoint of the study was myo- 25 utibapril, zabicipril, zabiaprilat, zofenopril and cardial infarction (MI), stroke and cardiovascular (CV) zofenoprilat. death (mortality). [0032] The number of patients who developed CHF 4. The use according to claim 3, wherein the angi- was significantly reduced by 21% in the ramipril group, otensin converting enzyme inhibitor is selected which is unexpected since patients had no signs or 30 from the group consisting of ramipril, ramiprilat, lisi- symptoms of CHF at study start. nopril, enalapril and enalaprilat.

Abbrevations 5. The use according to claim 3, wherein the angiotensin converting enzyme inhibitor is ramipril or [0033] 35 ramiprilat.

ACE = angiotensin converting enzyme AT II = angiotensin II type 1 receptor Patentansprüche CHF = congestive heart failure IDMM = insulin-dependent, diabetes mellitus 40 1. Verwendung eines Angiotensin-Konversions En- JNC = Joint National Committee zym-Hemmer oder eines pharmazeutisch verträgli- MI = myocardial infarction chen Salzes davon zur Herstellung eines Arzneimit- NIDDM = non-insulin-dependent diabetes mellitus tels für die Verhinderung oder Verminderung des WHO = World Health Organization Risikos von Stauungsinsuffizienz (CHF) bei einem 45 Patienten ohne vorher vorliegender CHF, wobei der Patient ein hohes Risiko für ein cardiovaskuläres Claims Ereignis aufgrund einer Historie von früherer ischä- mischer Herzerkrankung, Schlaganfall oder peri- 1. The use of an angiotensin converting enzyme inhib- pherer arterieller Erkrankung aufweist und wobei itor or a pharmaceutically acceptable salt thereof in 50 der Patient einen normalen oder niedrigen Blut- the manufacture of a medicament for the prevention druck zeigt. or reduction of the risk of congestive heart failure (CHF) in a patient with no preexisting CHF, where 2. Verwendung nach Anspruch 1, wobei der Patient the patient is at high risk for a cardiovascular event Diabetiker ist. due to a history of previous ischaemic heart dis- 55 ease, stroke or peripheral arterial disease, and 3. Verwendung nach Ansprüchen 1-2, wobei der An- where the patient exhibits normal or low blood pres- giotensin-Konversions Enzym-Hemmer oder ein sure. pharmazeutisch verträgliches Salz davon ausge-

5 7 EP 1 212 081 B1 8

wählt ist aus der Gruppe, bestehend aus Alacepril, lazaprilat, le délapril, le délapril-diacide, l'énalapril, Alatriopril, Altioprilcalcium, Ancovenin, Benazepril, l'énalaprilat, l'énapril, l'épicaptopril, la foroxymithi- Benazeprilhydrochlorid, Benazeprilat, Benzoylcap- ne, le fosfénopril, le fosénopril, le fosénopril sodium, topril, Captopril, Captopril-Cystein, Captopril-Gluta- le fosinopril, le fosinopril sodium, le fosinoprilat, thion, Ceranapril, Ceranopril, Ceronapril, Cilazapril, 5 l'acide fosinoprilique, le glycopril, l'hémorphine-4, Cilazaprilat, Delapril, Delapril-disäure, Enalapril, l'idrapril, l'imidapril, l'indolapril, l'indolaprilat, le li- Enalaprilat, Enapril, Epicaptopril, Foroxymithin, benzapril, le lisinopril, la lyciumine A, la lyciumine Fosfenopril, Fosenopril, Fosenoprilnatrium, Fosi- B, le mixanpril, le moexipril, le moexiprilat, le mo- nopril, Fosinoprilnatrium, Fosinoprilat, Fosinopril- veltipril, la muracéine A, la muracéine B, la mura- säure, Glycopril, Hemorphin-4, Idrapril, Imidapril, 10 céine C, le pentopril, le perindopril, le perindoprilat, Indolapril, Indolaprilat, Libenzapril, Lisinopril, Lyci- le pivalopril, le pivopril, le quinapril, le chlorhydrate umin A, Lyciumin B, Mixanpril, Moexipril, Moexi- de quinapril, le quinaprilat, le ramipril, le ramiprilat, prilat, Moveltipril, Muracein A, Muracein B, Mura- le spirapril, le chlorhydrate de spirapril, le spirapri- cein C, Pentopril, Perindopril, Perindoprilat, Pivalo- lat, le spiropril, le chlorhydrate de spiropril, le témo- pril, Pivopril, Quinapril, Quinaprilhydrochlorid, Qui- 15 capril, le chlorhydrate de témocapril, le téprotide, le naprilat, Ramipril, Ramiprilat, Spirapril, Spiraprilhy- trandolapril, le trandolaprilat, l'utibapril, le zabicipril, drochlorid, Spiraprilat, Spiropril, Spiroprilhydrochlo- le zabiciprilat, le zofénopril et le zofénoprilat. rid, Temocapril, Temocaprilhydrochlorid, Teprotid, Trandolapril, Trandolaprilat, Utibapril, Zabicipril, 4. Utilisation selon la revendication 3, dans laquelle Zabiciprilat, Zofenopril und Zofenoprilat. 20 l'inhibiteur de l'enzyme de conversion de l'angiotensine est choisi dans le groupe constitué par le rami- 4. Verwendung nach Anspruch 3, wobei der Angioten- pril, le ramiprilat, le lisinopril, l'énalapril et l'énalapri- sin-Konversions Enzym-Hemmer aus der Gruppe, lat. bestehend aus Ramipril, Ramiprilat, Lisinopril, En- alapril und Enalaprilat, ausgewählt ist. 25 5. Utilisation selon la revendication 3, dans laquelle l'inhibiteur de l'enzyme de conversion de l'angioten- 5. Verwendung nach Anspruch 3, wobei der Angioten- sine est le ramipril ou le ramiprilat. sin-Konversions Enzym-Hemmer Ramipril oder Ra- miprilat ist. 30

Revendications

1. Utilisation d'un inhibiteur de l'enzyme de conversion de l'angiotensine ou d'un sel pharmaceutiquement 35 acceptable de ce composé dans la fabrication d'un médicament destiné à la prévention ou à la réduc- tion du risque d'insuffisance cardiaque congestive (CHF) chez un patient sans CHF préexistante lorsque le patient présente un risque élevé d'accident 40 cardiovasculaire en raison d'antécédents de maladie cardiaque ischémique, d'accident vasculaire cé- rébral ou de maladie artérielle périphérique anté- rieurs, et lorsque le patient présente une tension ar- térielle normale ou basse. 45

2. Utilisation selon la revendication 1, dans laquelle le patient est diabétique.

3. Utilisation selon les revendications 1-2 dans laquel- 50 le l'inhibiteur de l'enzyme de conversion de l'angiotensine ou un sel pharmaceutiquement acceptable de ce composé est choisi dans le groupe constitué par l'alacépril, l'alatriopril, l'altiopril calcium, l'anco- vénine, le bénazépril, le chlorhydrate de bénazépril, 55 le benazéprilat, le benzoylcaptopril, le captopril, la captopril-cystéine, la captopril-glutathione, le céra- napril, le céranopril, le céronapril, le cilazapril, le ci-