Combination therapy of angiotensin converting enzyme inhibitor and aldosterone antagonist for reducing morbidity and mortality from cardiovascular disease

Abstract

Combinations of an ACE inhibitor, an aldosterone antagonist, and a loop diuretic are described for use in treatment of circulatory disorders. Of particular interest are therapies using captopril, enalapril or lisinopril co-administered with spironolactone. This co-therapy would be particularly useful to reduce the death rate or the number of non-fatal hospitalizations or prevent the progression of congestive heart failure in patients with cardiovascular disease.

What is claimed is:  
     
         1 . A co-therapy for treating a cardiovascular disorder in a subject, wherein said co-therapy comprises administering a therapeutically-effective amount of an angiotensin converting enzyme inhibitor and administering an aldosterone antagonist in an amount therapeutically effective to antagonize aldosterone to reduce the death rate or the number of non-fatal hospitalizations as compared to monotherapy with an angiotensin converting enzyme inhibitor.  
     
     
         2 . The co-therapy of  claim 1  further characterized by administering said angiotensin converting enzyme inhibitor and said aldosterone antagonist in a sequential manner.  
     
     
         3 . The co-therapy of  claim 1  further characterized by administering said angiotensin converting enzyme inhibitor and said aldosterone antagonist in a substantially simultaneous manner.  
     
     
         4 . The co-therapy of  claim 1  wherein said aldosterone antagonist is a spirolactone-type compound.  
     
     
         5 . The co-therapy of  claim 4  wherein said spirolactone-type compound is spironolactone.  
     
     
         6 . The co-therapy of  claim 1  wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazeptil, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat, spirapril, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590.  
     
     
         7 . The co-therapy of  claim 6  wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril.  
     
     
         8 . The co-therapy of  claim 1  further characterized by said angiotensin converting enzyme inhibitor and said aldosterone antagonist being used in said co-therapy in a weight ratio range from about 0.1-to-one to about twenty-five-to-one of said angiotensin converting enzyme inhibitor to said aldosterone antagonist.  
     
     
         9 . The co-therapy of  claim 8  wherein said weight ratio range is from about 0.5-to-one to about fifteen-to-one.  
     
     
         10 . The co-therapy of  claim 9  wherein said weight ratio range is from about 0.5-to-one to about five-to-one.  
     
     
         11 . The co-therapy of  claim 9  wherein said angiotensin converting enzyme inhibitor is captopril, in a daily dose range from about 30 mg to about 80 mg per dose, or is enalapril in a dose range from about 5 mg to about 25 mg per dose.  
     
     
         12 . The co-therapy of  claim 11  wherein said aldosterone antagonist is spironolactone in a daily dose range from about 1 mg to about 23 mg per dose.  
     
     
         13 . The co-therapy of  claim 12  wherein said spironolactone daily dose is in a range from about 5 mg to about 20 mg.  
     
     
         14 . The co-therapy of  claim 12  wherein said spironolactone daily dose is in a range from about 5 mg to about 15 mg.  
     
     
         15 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination result in a statistically significant reduction in the death rate or the number of non-fatal hospitalizations as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         16 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination result in a statistically significant reduction in the death rate as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         17 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination result in a statistically significant reduction in the number of non-fatal hospitalizations as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         18 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination result in a statistically significant reduction in the rate of deaths resulting from sudden death in subjects afflicted with or susceptible to elevated heart rate variability as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         19 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination result in a statistically significant reduction in the death rate for deaths resulting from progression of heart failure as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         20 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination result in a statistically significant reduction in the death rate or the number of non-fatal hospitalizations in subjects having a left ventricular ejection fraction greater than about 26% as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         21 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination result in a statistically significant reduction in the death rate or the number of non-fatal hospitalizations in subjects having a left ventricular ejection fraction less than about 26% as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         22 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering an angiotensin converting enzyme inhibitor, an aldosterone antagonist and a loop diuretic to the subject, and wherein the angiotensin converting enzyme inhibitor, the aldosterone antagonist and the loop diuretic are administered at doses that in combination suppress clinically significant cough due to elevated pulmonary arterial fibrosis or low levels of pulmonary blood pressure in the subject as compared to said combination therapy without the aldosterone antagonist, and wherein said loop diuretic has no substantial aldosterone antagonistic effect.  
     
     
         23 . The combination therapy of  claim 22  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist and loop diuretic are administered at doses that in combination result in a statistically significant reduction in the death rate or the number of non-fatal hospitalizations as compared to said combination therapy without the aldosterone antagonist.  
     
     
         24 . A combination therapy for treating a cardiovascular disorder in a subject, wherein said combination therapy comprises administering a therapeutically-effective amount of an angiotensin converting enzyme inhibitor, a therapeutically-effective amount of an aldosterone antagonist, a therapeutically-effective amount of a loop diuretic and a therapeutically-effective amount of digoxin to the subject.  
     
     
         25 . The combination therapy of  claim 24  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist, loop diuretic and digoxin are administered at doses that in combination result in a statistically significant reduction in the death rate as compared to the combination therapy of  claim 16 .  
     
     
         26 . The combination therapy of  claim 24  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist, loop diuretic and digoxin are administered at doses that in combination result in a statistically significant reduction in the number of non-fatal hospitalizations as compared to the combination therapy of  claim 17 .  
     
     
         27 . The combination therapy of  claim 24  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist, loop diuretic and digoxin are administered at doses that in combination result in a decrease in blood N-terminal atrial natriuretic factor level in the subject as compared to the combination therapy of  claim 15 .  
     
     
         28 . The combination therapy of  claim 24  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist, loop diuretic and digoxin are administered at doses that in combination result in a decrease in blood procollagen type III amino terminal propeptide level in the subject as compared to the combination therapy of  claim 15 .  
     
     
         29 . The combination therapy of  claim 24  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist, loop diuretic and digoxin are administered at doses that in combination result in an increase in left ventricular ejection fraction in the subject as compared to the combination therapy of  claim 15 .  
     
     
         30 . The combination therapy of  claim 15  wherein the subject is a human.  
     
     
         31 . The combination therapy of  claim 15  wherein the subject is susceptible to sudden death.  
     
     
         32 . The combination therapy of  claim 15  wherein the subject is classified in New York Heart Association class III or class IV prior to combination therapy.  
     
     
         33 . The combination therapy of claims  15  wherein the subject has a left ventricular ejection fraction greater than about 26%.  
     
     
         34 . The combination therapy of  claim 15  wherein the subject has a left ventricular ejection fraction less than about 26%.  
     
     
         35 . The combination therapy of  claim 15  wherein the subject is susceptible to or suffering from clinically significant cough due to elevated pulmonary arterial fibrosis or low levels of pulmonary blood pressure.  
     
     
         36 . The combination therapy of  claim 15  wherein the loop diuretic is selected from furosemide and ethynacrylic acid.  
     
     
         37 . The combination therapy of  claim 15  further comprising the administration of a therapeutically-effective amount of digoxin.  
     
     
         38 . The combination therapy of  claim 15  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist and loop diuretic are administered at doses that in combination result in a decrease in blood N-terminal atrial natriuretic factor level in the subject as compared to the combination therapy of  claim 15 .  
     
     
         39 . The combination therapy of  claim 15  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist and loop diuretic are administered at doses that in combination result in a decrease in blood, procollagen type III amino terminal propeptide level in the subject as compared to the combination therapy of  claim 15 .  
     
     
         40 . The combination therapy of  claim 15  wherein the angiotensin converting enzyme inhibitor, aldosterone antagonist and loop diuretic are administered at doses that in combination result in a decrease in blood brain natriuretic peptide level in the subject as compared to the combination therapy of  claim 15 .  
     
     
         41 . The therapy of  claim 15  further characterized by administering said angiotensin converting enzyme inhibitor, aldosterone antagonist and loop diuretic in a sequential manner.  
     
     
         42 . The therapy of  claim 15  further characterized by administering said angiotensin converting enzyme inhibitor, aldosterone antagonist and loop diuretic in a substantially simultaneous manner.  
     
     
         43 . The therapy of  claim 15  wherein said aldosterone antagonist is a spirolactone-type compound.  
     
     
         44 . The therapy of  claim 15  wherein said spirolactone-type compound is spironolactone.  
     
     
         45 . The therapy of  claim 15  wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat, spirapril, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590.  
     
     
         46 . The therapy of  claim 15  wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril.  
     
     
         47 . The therapy of  claim 15  further characterized by said angiotensin converting enzyme inhibitor and said aldosterone antagonist being used in said combination therapy in a weight ratio range from about 0.1-to-one to about twenty-five-to-one of said angiotensin converting enzyme inhibitor to said aldosterone antagonist.  
     
     
         48 . The therapy of  claim 15  wherein said weight ratio range is from about 0.5-to-one to about fifteen-to-one.  
     
     
         49 . The therapy of  claim 15  wherein said weight ratio range is from about 0.5-to-one to about five-to-one.  
     
     
         50 . The therapy of  claim 15  wherein said angiotensin converting enzyme inhibitor is captopril, in a daily dose range from about 30 mg to about 80 mg per dose, or is enalapril in a dose range from about 5 mg to about 25 mg per dose.  
     
     
         51 . The therapy of  claim 15  wherein said aldosterone antagonist is spironolactone in a daily dose range from about 1 mg to about 23 mg per dose.  
     
     
         52 . The therapy of  claim 15  wherein said spironolactone daily dose is in a range from about 5 mg to about 20 mg.  
     
     
         53 . The therapy of  claim 15  wherein said spironolactone daily dose is in a range from about 5 mg to about 15 mg.  
     
     
         54 . The method of  claim 15  wherein the aldosterone antagonist is an epoxy-steroidal aldosterone antagonist.  
     
     
         55 . The method of  claim 15  wherein the epoxy-containing compound has an epoxy moiety fused to the “C” ring of the steroidal nucleus of a 20-spiroxane compound.  
     
     
         56 . The method of  claim 15  wherein the 20-spiroxane compound is characterized by the presence of a 9-alpha,11-beta-substituted epoxy moiety.  
     
     
         57 . The method of  claim 15  wherein the epoxy-containing compound is selected from the group consisting of: 
 Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-,γ-lactone, methyl ester, (7α,11α,17α)-;  
 Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-dimethyl ester, (7α,11α,17α)-;  
 3′H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone, (6β, 7β,11β,17β)-;  
 Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo, 7-(1-methylethyl) ester, monopotassium salt, (7α,11α,17α)-;.  
 Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, 7-methyl ester, monopotassium salt, (7α, 11α,17α)-;  
 3′H-cyclopropa[6,7]pregna-1,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone, (6α,7α,11α)-;  
 3′H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, methyl ester, (6′,7′,11α,17α)-;  
 3′H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotassium salt, (6′,7′,11α,17α)-;  
 3′H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone, (6α, 7α,11α,17α)-;  
 Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, ethyl ester, (7′,11α,17α)-; and  
 Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, 1-methylethyl ester, (7α,11α, 17α)-.  
 
     
     
         58 . The method of  claim 15  wherein the aldosterone antagonist is eplerenone.  
     
     
         59 . The method of  claim 15  wherein the aldosterone antagonist is eplerenone in.a daily dose range from about 0.5 mg to about 500 mg.  
     
     
         60 . The method of  claim 15  wherein the aldosterone antagonist is an aldosterone antagonist other than spironolactone.  
     
     
         61 . A composition comprising an angiotensin converting enzyme inhibitor, an aldosterone antagonist, a loop diuretic and digoxin, and the pharmaceutically acceptable salts, esters and prodrugs thereof.  
     
     
         62 . A composition of  claim 63  comprising: 
 a first amount of an angiotensin converting enzyme inhibitor, or a pharmaceutically acceptable salt, ester or prodrug thereof;  
 a second amount of an aldosterone antagonist, or a pharmaceutically acceptable salt, ester or prodrug thereof;  
 a third amount of a loop diuretic, or a pharmaceutically acceptable salt, ester or prodrug thereof;  
 a fourth amount of digoxin, or a pharmaceutically acceptable salt, ester or prodrug thereof; and  
 a pharmaceutically acceptable carrier;  
 wherein the first, second, third and fourth amounts in combination comprise a therapeutically effective amount of said inhibitor, antagonist, loop diuretic and digoxin.  
 
     
     
         63 . A composition of  claim 64  wherein the aldosterone antagonist is spironolactone.  
     
     
         64 . A composition of  claim 64  wherein the aldosterone antagonist is eplerenone.