WO2005020971A1 - Use of an angiotensin ii antagonist for the prevention of myocardial infarction - Google Patents

Use of an angiotensin ii antagonist for the prevention of myocardial infarction Download PDF

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Publication number
WO2005020971A1
WO2005020971A1 PCT/SE2004/001228 SE2004001228W WO2005020971A1 WO 2005020971 A1 WO2005020971 A1 WO 2005020971A1 SE 2004001228 W SE2004001228 W SE 2004001228W WO 2005020971 A1 WO2005020971 A1 WO 2005020971A1
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Prior art keywords
angiotensin
type
receptor antagonist
ace inhibitor
daily dose
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PCT/SE2004/001228
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French (fr)
Inventor
John Mcmurray
Jan ÖSTERGREN
Marc Pfeffer
Karl Swedberg
Christopher Granger
Salim Yusef
Peter Held
Eric Michelson
Bertil Olofsson
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Astrazeneca Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor for the prevention of non-fatal myocardial infarction.
  • a myocardial infarction occurs when an area of heart muscle dies or is permanently damaged because of an inadequate supply of oxygen to that area. In non-fatal myocardial infarction, this condition does not result in the death of the subject.
  • an angiotensin II type 1 receptor antagonist and an ACE inhibitor is advantageous for the prevention of non-fatal myocardial infarction.
  • the present invention is thus directed to the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor for the preparation of a medicament for the prevention of non-fatal myocardial infarction.
  • a further aspect of the invention is a method for the prevention of non-fatal myocardial infarction, whereby a pharmaceutically and pharmacologically effective amount of an angiotensin II type 1 receptor antagonist and an ACE inhibitor is administered to a subject in need of such prevention.
  • Still a further aspect of the invention is a method for the prevention of non-fatal myocardial infarction, whereby a pharmaceutically and pharmacologically effective amount of an angiotensin II type 1 receptor antagonist and an ACE inhibitor, is administered to a subject in need of such prevention, wherein said subject is a chronic heart failure patient.
  • a further aspect of the invention is a method for the prevention of non-fatal myocardial infarction, whereby a pharmaceutically and pharmacologically effective amount of an angiotensin II type 1 receptor antagonist and an ACE inhibitor, is administered to a subject in need of such prevention, wherein said subject has a left ventricular ejection fraction equal to or less than 40%.
  • a further of the present invention is the use of an angiotensin IT type 1 receptor antagonist and an ACE inhibitor for the preparation of a medicament for the prevention of myocardial infarction.
  • Angiotensin II type 1 receptor antagonists are compounds which are known to interfere with the renin-angiotensin system (RAS) and are used to treat common cardiovascular diseases, particularly arterial hypertension.
  • A is selected from the group consisting of
  • the compound of the general formula I wherein A is the 1: 1 moiety has the generic name losartan and is known from European Patent No. EP 0 253 310 Bl to du Pont.
  • the compound of the general formula I wherein A is the 1:5 moiety has the generic name candesartan cilexetil and is known from European Patent No. 459 136 B 1 and US 5,196,444 to Takeda Chemical Industries.
  • the compound of the general formula I wherein A is the 1:9 moiety has the generic name irbesartan.
  • the compound of the general formula I wherein A is the 1: 13 moiety has the generic name candesartan and is known from European Patent No. 459 136 B 1 and US 5,703,110 of Takeda Chemical Industries.
  • angiotensin It type 1 receptor antagonists are valsartan, olmesartan, telmisartan and eprosartan.
  • angiotensin IT type 1 receptor antagonists used in accordance with the present invention have several asymmetric carbon atoms, they can exist in several stereochemical forms.
  • the present invention includes the mixture of isomers as well as the individual stereoisomers.
  • the present invention further includes geometrical isomers, rotational isomers, enantiomers, racemates and diastereomers.
  • angiotensin II type 1 receptor antagonists may be used in neutral form, e.g. as a carboxylic acid, or in the form of a salt, preferably a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound at issue.
  • a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound at issue.
  • the compounds listed above can be used in hydrolyzable ester form.
  • the angiotensin II type 1 receptor antagonists are administered by the oral or parenteral route, e.g. by intravenous, subcutaneous or intramuscular administration.
  • Other possible routes of administration include rectal and transdermal administration.
  • the formulation may be given in dosage unit form, especially as tablets or capsules.
  • the dose of the angiotensin IT type 1 receptor antagonist and in particular a compound according to formula I to be administered in prevention of non-fatal myocardial infarction in subjects suffering from, or susceptible to, such conditions will depend primarily upon the angiotensin II type 1 receptor antagonists used, the route of administration, the severity of the condition to be treated and the status of the subject at issue.
  • the daily dose, especially at oral, rectal as well as parenteral administration can be in the range of from about 0.01 mg to about 1000 mg per day of active substance, such as from 0.1 mg to 750 mg per day of active substance or from 1 mg to 500 mg per day of active substance.
  • the dosage range at oral, rectal as well as parenteral administration can be in the range of from about 0.1 mg to about 300 mg per day, such as from 0.2 mg to 200 mg or from 1 mg to 160 mg per day calculated as candesartan.
  • ACE inhibitors are used, including candesartan cilexetil.
  • ACE inhibitors and pharmaceutically acceptable derivatives thereof, including active metabolites, useful in the present invention include enalapril, lisinopril, captopril, ramipril, alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4
  • the dose of the ACE inhibitor to be administered prevention of non-fatal myocardial infarction in subjects suffering from, or susceptible to, such conditions will depend primarily upon the ACE inhibitor used, the route of administration, the severity of the condition to be treated and the status of the subject at issue.
  • the daily dose of ACE inhibitor is 1-200 mg. In a further aspect of the invention, the daily dose of ACE inhibitor is 1-200 mg. In yet another aspect of the invention, the daily dose of ACE inhibitor is 4-150 mg.
  • the present invention relates to the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor for the prevention of non-fatal myocardial infarction.
  • a “combination” according to the invention may be present as a “fix combination” or as a “kit of parts combination”.
  • a “fix combination” is defined as a combination wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in one unit.
  • a “fix combination” is a pharmaceutical composition wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in admixture, such as in a formulation.
  • Another example of a “fix combination” is a pharmaceutical combination wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in one unit without being in admixture.
  • a “kit of parts combination” is defined as a combination wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in more than one unit.
  • One example of a “kit of parts combination” is a combination wherein the angiotensin IT type 1 receptor antagonist and the ACE inhibitor are present separately.
  • the components of the "kit of parts combination” may be administered simultaneously, sequentially or separately, i.e. separately or together.
  • prevention is meant that non-fatal myocardial infarction is prevented by administering an angiotensin II type 1 receptor antagonist and an ACE inhibitor. This means that the use of an angiotensin IT type 1 receptor antagonist and an ACE inhibitor, provides prevention of a not yet developed non-fatal myocardial infarction.
  • the adjuvants, diluents and carriers used in the pharmaceutical formulations of the present invention may be conventional ones well known to the person skilled in the art.
  • examples of such adjuvants, diluents and carriers include substances used as binders, lubricants, fillers, disintegrants, pH regulants and thickeners as well as substances included for providing isotonic solutions.
  • the wording "daily dose" is defined so that the angiotensin II type 1 receptor antagonist and the ACE inhibitor may be given either as a unit dosage once daily, such as a tablet or a capsule, or alternatively the angiotensin IT type 1 receptor antagonist and the ACE inhibitor may be given twice daily.
  • the daily dose of each of the angiotensin II type 1 receptor antagonist and the ACE inhibitor may vary within the dosage ranges mentioned, and depends on the patient's individual response to treatment.
  • a myocardial infarction is defined herein as the condition that occurs when an area of heart muscle dies or is permanently damaged because of an inadequate supply of oxygen to that area. In non-fatal myocardial infarction, this condition does not result in the death of the subject.
  • the inclusion criteria for the study were: age > 18 years, NYHA functional class II-IV for > 4 weeks (if class IT, the patient must have been hospitalised for a cardiac reason in the previous 6 months), left ventricular ejection fraction (LVEF) ⁇ 40% (measured within the past 6 months) and treatment with an ACE inhibitor at a constant dose for >30 days. Investigators were also asked to state whether each patient was, in their opinion, on an optimum, individualised, dose of ACE inhibitor.
  • the key exclusion criteria were serum creatinine > 265 ⁇ mol/L (> 3 mg/dL), serum potassium > 5.5 mmol/L, symptomatic hypotension and bilateral renal artery stenosis.
  • Patients were randomised to receive candesartan cilexetil or matching placebo which could be started at 4 or 8 mg once daily. Treatment was usually started at a dose of 4 mg once daily and the dose was doubled at two weekly intervals, as tolerated, according to a forced titration protocol with recommended monitoring of blood pressure, serum creatinine and potassium. The target dose was 32 mg once daily from 6 weeks onwards. After randomisation, patients were seen at 2, 4 and 6 weeks, at 6 months and, thereafter, at 4 monthly intervals until the end of the trial.
  • CV cardiovascular
  • the planned sample size of 2,500 patients was designed to provide approximately 80% power to detect an 16% relative reduction in the primary outcome.
  • the analysis was carried out on an intention-to-teat basis and included all randomised patients. All major outcomes were analysed using a time to first event approach.
  • the primary analysis used the log-rank test for comparing the time to event distributions.
  • the hazard ratios were estimated, together with 95% confidence intervals.
  • a Cox regression model with treatment and other prospectively defined covariates was performed to adjust the hazard ratio for these pre-specified baseline factors which might influence the event rates. P-values were two-sided and values of less than 0.05 were considered significant.
  • Enalapril, lisinopril, captopril and ramipril were the most commonly used ACE inhibitors, together accounting for 74% of all ACE inhibitors used.
  • the mean daily doses of these in the candesartan group were 16.8, 17.7, 82.2 and 6.8 mg, respectively, and in the placebo group, 17.2, 17.7, 82.7 and 7.3 mg, respectively.

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Abstract

The present invention relates to the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor for the prevention of non-fatal myocardial infarction.

Description

USE OF AN ANGIOTENSIN II ANTAGONIST FOR THE PREVENTION OF MYOCARDIAL INFARCTION
Field of the invention
The present invention relates to the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor for the prevention of non-fatal myocardial infarction.
Background of the invention
A myocardial infarction occurs when an area of heart muscle dies or is permanently damaged because of an inadequate supply of oxygen to that area. In non-fatal myocardial infarction, this condition does not result in the death of the subject.
Outline of the invention
It has now surprisingly been found that the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor is advantageous for the prevention of non-fatal myocardial infarction. The present invention is thus directed to the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor for the preparation of a medicament for the prevention of non-fatal myocardial infarction.
A further aspect of the invention is a method for the prevention of non-fatal myocardial infarction, whereby a pharmaceutically and pharmacologically effective amount of an angiotensin II type 1 receptor antagonist and an ACE inhibitor is administered to a subject in need of such prevention.
Still a further aspect of the invention is a method for the prevention of non-fatal myocardial infarction, whereby a pharmaceutically and pharmacologically effective amount of an angiotensin II type 1 receptor antagonist and an ACE inhibitor, is administered to a subject in need of such prevention, wherein said subject is a chronic heart failure patient.
A further aspect of the invention is a method for the prevention of non-fatal myocardial infarction, whereby a pharmaceutically and pharmacologically effective amount of an angiotensin II type 1 receptor antagonist and an ACE inhibitor, is administered to a subject in need of such prevention, wherein said subject has a left ventricular ejection fraction equal to or less than 40%.
A further of the present invention is the use of an angiotensin IT type 1 receptor antagonist and an ACE inhibitor for the preparation of a medicament for the prevention of myocardial infarction.
Angiotensin II type 1 receptor antagonists
Angiotensin II type 1 receptor antagonists are compounds which are known to interfere with the renin-angiotensin system (RAS) and are used to treat common cardiovascular diseases, particularly arterial hypertension.
In one aspect of the present invention use is made of an angiotensin LI type 1 receptor antagonist of the general formula I:
Figure imgf000003_0001
wherein A is selected from the group consisting of
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000004_0004
Figure imgf000004_0005
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
and
Figure imgf000006_0001
or pharmaceutically acceptable salts, solvates or stereochemical isomers of any of these, or solvates of such salts.
The compound of the general formula I wherein A is the 1: 1 moiety has the generic name losartan and is known from European Patent No. EP 0 253 310 Bl to du Pont.
The compound of the general formula I wherein A is the 1:5 moiety has the generic name candesartan cilexetil and is known from European Patent No. 459 136 B 1 and US 5,196,444 to Takeda Chemical Industries.
The compound of the general formula I wherein A is the 1:9 moiety has the generic name irbesartan.
The compound of the general formula I wherein A is the 1: 13 moiety has the generic name candesartan and is known from European Patent No. 459 136 B 1 and US 5,703,110 of Takeda Chemical Industries.
Further useful examples of angiotensin It type 1 receptor antagonists are valsartan, olmesartan, telmisartan and eprosartan.
In one aspect of the present invention, use is made of a compound of the general formula I wherein A is 1:5 (candesartan cilexetil) or A is 1:13 (candesartan). Candesartan cilexetil is ® ccuurrrreennttllyy mmaannufactured and sold worldwide e.g. under the trade names Atacand , Amias and Blopress When the angiotensin IT type 1 receptor antagonists used in accordance with the present invention have several asymmetric carbon atoms, they can exist in several stereochemical forms. The present invention includes the mixture of isomers as well as the individual stereoisomers. The present invention further includes geometrical isomers, rotational isomers, enantiomers, racemates and diastereomers.
Where applicable, the angiotensin II type 1 receptor antagonists may be used in neutral form, e.g. as a carboxylic acid, or in the form of a salt, preferably a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound at issue. Where applicable the compounds listed above can be used in hydrolyzable ester form.
Normally, the angiotensin II type 1 receptor antagonists are administered by the oral or parenteral route, e.g. by intravenous, subcutaneous or intramuscular administration. Other possible routes of administration include rectal and transdermal administration. The formulation may be given in dosage unit form, especially as tablets or capsules.
The dose of the angiotensin IT type 1 receptor antagonist and in particular a compound according to formula I to be administered in prevention of non-fatal myocardial infarction in subjects suffering from, or susceptible to, such conditions, will depend primarily upon the angiotensin II type 1 receptor antagonists used, the route of administration, the severity of the condition to be treated and the status of the subject at issue. The daily dose, especially at oral, rectal as well as parenteral administration, can be in the range of from about 0.01 mg to about 1000 mg per day of active substance, such as from 0.1 mg to 750 mg per day of active substance or from 1 mg to 500 mg per day of active substance.
In one embodiment, where candesartan and derivatives thereof are used, including candesartan cilexetil, the dosage range at oral, rectal as well as parenteral administration can be in the range of from about 0.1 mg to about 300 mg per day, such as from 0.2 mg to 200 mg or from 1 mg to 160 mg per day calculated as candesartan. ACE inhibitors
ACE inhibitors and pharmaceutically acceptable derivatives thereof, including active metabolites, useful in the present invention, include enalapril, lisinopril, captopril, ramipril, alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lyciumin A, lyciumin B, muracein B, pentopril, perindopril, perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramiprilat, spirapril, spirapril hydrochloride, spriraprilat, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril and zofenoprilat.
The dose of the ACE inhibitor to be administered prevention of non-fatal myocardial infarction in subjects suffering from, or susceptible to, such conditions, will depend primarily upon the ACE inhibitor used, the route of administration, the severity of the condition to be treated and the status of the subject at issue.
In one aspect of the present invention, the daily dose of ACE inhibitor is 1-200 mg. In a further aspect of the invention, the daily dose of ACE inhibitor is 1-200 mg. In yet another aspect of the invention, the daily dose of ACE inhibitor is 4-150 mg.
Combination of angiotensin II type 1 receptor antagonist and ACE inhibitor
The present invention relates to the use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor for the prevention of non-fatal myocardial infarction. A "combination" according to the invention may be present as a "fix combination" or as a "kit of parts combination".
A "fix combination" is defined as a combination wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in one unit. One example of a "fix combination" is a pharmaceutical composition wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in admixture, such as in a formulation. Another example of a "fix combination" is a pharmaceutical combination wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in one unit without being in admixture.
A "kit of parts combination" is defined as a combination wherein the angiotensin II type 1 receptor antagonist and the ACE inhibitor are present in more than one unit. One example of a "kit of parts combination" is a combination wherein the angiotensin IT type 1 receptor antagonist and the ACE inhibitor are present separately. The components of the "kit of parts combination" may be administered simultaneously, sequentially or separately, i.e. separately or together.
With the wording "prevention" as used herein, is meant that non-fatal myocardial infarction is prevented by administering an angiotensin II type 1 receptor antagonist and an ACE inhibitor. This means that the use of an angiotensin IT type 1 receptor antagonist and an ACE inhibitor, provides prevention of a not yet developed non-fatal myocardial infarction.
The adjuvants, diluents and carriers used in the pharmaceutical formulations of the present invention, may be conventional ones well known to the person skilled in the art. Examples of such adjuvants, diluents and carriers include substances used as binders, lubricants, fillers, disintegrants, pH regulants and thickeners as well as substances included for providing isotonic solutions. The wording "daily dose" is defined so that the angiotensin II type 1 receptor antagonist and the ACE inhibitor may be given either as a unit dosage once daily, such as a tablet or a capsule, or alternatively the angiotensin IT type 1 receptor antagonist and the ACE inhibitor may be given twice daily. The daily dose of each of the angiotensin II type 1 receptor antagonist and the ACE inhibitor may vary within the dosage ranges mentioned, and depends on the patient's individual response to treatment.
A myocardial infarction is defined herein as the condition that occurs when an area of heart muscle dies or is permanently damaged because of an inadequate supply of oxygen to that area. In non-fatal myocardial infarction, this condition does not result in the death of the subject.
Examples
A parallel, placebo-controlled cinical study was performed.
The inclusion criteria for the study were: age > 18 years, NYHA functional class II-IV for > 4 weeks (if class IT, the patient must have been hospitalised for a cardiac reason in the previous 6 months), left ventricular ejection fraction (LVEF) < 40% (measured within the past 6 months) and treatment with an ACE inhibitor at a constant dose for >30 days. Investigators were also asked to state whether each patient was, in their opinion, on an optimum, individualised, dose of ACE inhibitor. The key exclusion criteria were serum creatinine > 265 μmol/L (> 3 mg/dL), serum potassium > 5.5 mmol/L, symptomatic hypotension and bilateral renal artery stenosis.
Patients were randomised to receive candesartan cilexetil or matching placebo which could be started at 4 or 8 mg once daily. Treatment was usually started at a dose of 4 mg once daily and the dose was doubled at two weekly intervals, as tolerated, according to a forced titration protocol with recommended monitoring of blood pressure, serum creatinine and potassium. The target dose was 32 mg once daily from 6 weeks onwards. After randomisation, patients were seen at 2, 4 and 6 weeks, at 6 months and, thereafter, at 4 monthly intervals until the end of the trial.
The primary outcome in the study was cardiovascular (CV) death or unplanned admission to hospital for the management of worsening CHF.
Statistical methods
The planned sample size of 2,500 patients was designed to provide approximately 80% power to detect an 16% relative reduction in the primary outcome. The analysis was carried out on an intention-to-teat basis and included all randomised patients. All major outcomes were analysed using a time to first event approach. The primary analysis used the log-rank test for comparing the time to event distributions. The hazard ratios were estimated, together with 95% confidence intervals. In addition, a Cox regression model with treatment and other prospectively defined covariates was performed to adjust the hazard ratio for these pre-specified baseline factors which might influence the event rates. P-values were two-sided and values of less than 0.05 were considered significant.
Results
Of the 2548 patients enrolled, 1276 were randomised to candesartan and 1272 to placebo. The median duration of follow up was 41 months.
Enalapril, lisinopril, captopril and ramipril were the most commonly used ACE inhibitors, together accounting for 74% of all ACE inhibitors used. The mean daily doses of these in the candesartan group were 16.8, 17.7, 82.2 and 6.8 mg, respectively, and in the placebo group, 17.2, 17.7, 82.7 and 7.3 mg, respectively. Investigators stated that they thought 96% of patients in each group were on an optimum, individualised, dose of ACE inhibitor at randomisation.
483 (37.9%) patients in the candesartan group and 538 (42.3%) patients in the placebo group experienced the primary outcome of CV death or hospitalisation for CHF, representing a hazard ratio (HR) of 0.85 (95% CI 0.75, 0.96), p=0.011 unadjusted, p=0.010 covariate adjusted. The annualised event rates were 14.1% in the candesartan group and 16.6% in the placebo group.
49 patients in the placebo group experienced non-fatal myocardial infarction, whereas in the candesartan group only 26 experienced non-fatal myocardial infarction. Thus, the risk of non-fatal myocardial infarction was 48.8% (p=0.006) lower in the candesartan group than in the placebo group (see also figure 1, showing the proportion of patients with confirmed non-fatal myocardial infarction over time).

Claims

Claims
1. Use of an angiotensin II type 1 receptor antagonist and an ACE inhibitor, for the manufacture of a medicament for the prevention of myocardial infarction.
2. Use according to claim 1, wherein the myocardial infarction is non-fatal myocardial infarction.
3. Use according to claim 1 or 2, wherein the prevention is in a chronic heart failure patient.
4. Use according to any one of claims 1-3, wherein the prevention is in a patient having a left ventricular ejection fraction equal to or less than 40%.
5. Use according to any one of claims 1-4, wherein the angiotensin IT type 1 receptor antagonist is a compound of the general formula I:
Figure imgf000013_0001
wherein A is selected from the group consisting of
Figure imgf000013_0002
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
10
Figure imgf000014_0004
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000015_0004
and
Figure imgf000015_0005
or pharmaceutically acceptable salts, solvates or stereochemical isomers of any of these, or solvates of such salts.
6. Use according to claim 5, wherein A is 1:5.
7. Use according to claim 5 , wherein A is 1: 13.
8. Use according to any of claims 1-7, wherein the ACE inhibitor is selected from any one of enalapril, lisinopril, captopril, ramipril, alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lyciumin A, lyciumin B, muracein B, pentopril, perindopril, perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramiprilat, spirapril, spirapril hydrochloride, spriraprilat, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril and zofenoprilat, as well as, in each case, a pharmaceutically acceptable salt thereof.
9. Use according to claim 8, wherein the ACE inhibitor is selected from any one of enalapril, lisinopril, captopril, trandolapril and ramipril.
10. Use according to any one of claims 1-9, wherein the daily dose of the angiotensin IT type 1 receptor antagonist is from about 0.01 mg to about 1000 mg.
11. Use according to claim 10 wherein the daily dose of the angiotensin II type 1 receptor antagonist is from about 0.1 mg to 750 mg.
12. Use according to claim 11, wherein the daily dose of the angiotensin IT type 1 receptor antagonist is from about 1 mg to 500 mg.
13. Use according to claim 12, wherein the daily dose of the angiotensin II type 1 receptor antagonist is from aout 0.1 mg to about 300 mg per day calculated as candesartan.
14. Use according to any one of claims 1-13, wherein the daily dose of ACE inhibitor is 1- 500 mg.
15. Use according to claim 14, wherein the daily dose of ACE inhibitor is 4-150 mg.
16. A method for the prevention of myocardial infarction, whereby a pharmaceutically and pharmacologically effective amount of an angiotensin IT type 1 receptor antagonist and an ACE inhibitor is administered to a subject in need of such prevention.
17. A method according to claim 16, wherein the myocardial infarction is non-fatal myocardial infarction.
18. A method according to claim 16 or 17, wherein the prevention is in a chronic heart failure patient.
19. A method according any one of claims 16-18, wherein the prevention is in a patient having a left ventricular ejection fraction equal to or less than 40%.
20. A method according to any one of claims 16-19, wherein the angiotensin II type 1 receptor antagonist is a compound of the general formula I:
Figure imgf000018_0001
wherein A is selected from the group consisting of
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000018_0004
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000020_0001
Figure imgf000020_0002
and
Figure imgf000020_0003
or pharmaceutically acceptable salts, solvates or stereochemical isomers of any of these, or solvates of such salts.
21. A method according to claim 20, wherein A is 1:5.
22. A method according to claim 20, wherein A is 1:13.
23. A method according to any one of claims 16-22, wherem the ACE inhibitor is selected from any one of enalapril, lisinopril, captopril, ramipril, alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lyciumin A, lyciumin B, muracein B, pentopril, perindopril, perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramiprilat, spirapril, spirapril hydrochloride, spriraprilat, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril and zofenoprilat, as well as, in each case, a pharmaceutically acceptable salt thereof.
24. A method according to claim 23, wherein the ACE inhibitor is selected from any one of enalapril, lisinopril, captopril, trandolapril and ramipril.
25. The method according to any one of claims 16-24, wherein the daily dose of the angiotensin IT type 1 receptor antagonist is from about 0.01 mg to about 1000 mg.
26. The method according to claim 25, wherein wherein the daily dose of the angiotensin IT type 1 receptor antagonist is from about 0.1 mg to 750 mg.
27. The method according to claim 26, wherem the daily dose of the angiotensin II type 1 receptor antagonist is from about 1 mg to 500 mg.
28. The method according to claim 27, wherein the daily dose of the angiotensin II type 1 receptor antagonist is from about 0.1 mg to about 300 mg per day calculated as candesartan.
29. The method according to any one of claims 16-28, wherein the daily dose of ACE inhibitor is 1-500 mg.
30. The method according to claim 29, wherein the daily dose of ACE inhibitor is 4-150 mg.
PCT/SE2004/001228 2003-08-29 2004-08-25 Use of an angiotensin ii antagonist for the prevention of myocardial infarction WO2005020971A1 (en)

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WO2007028524A2 (en) * 2005-09-06 2007-03-15 Prous Institute For Biomedical Research S.A. Use of a derivative of imidazole for the treatment of leukotriene related disorders
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