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Rationale and Safety of ACE-Inhibitor Combination with Calcium Channel Blockers
AIH-APRIL 1996-VOL. 9, NO.4, PART 2
Wednesday, ~ay 15, West Ballroom, 12:30 pm Safety of ~ntihypertensiveTherapies: A Series of InteractIve Panels Cardiovascular Safely of Dihydropyridines: A Hard Look at Real Data. Robert A. Kloner, George Velrovec, Barry l. Materson, Marcia Levenstein. Good Samaritan Hosp. and U. So. Cal., Med. Coli Va., U. Miami, Pfizer USPG, Los Angeles CA Richmond VA Miami Flo New York, NY. ' , Much of the current controversy surrounding use of calcium Channel blockers (CCB's) in hypertension is based on case contr?lIed retrospective studies which have utilized short acting CCB s not FDA approved for hypertension. We reviewed data on myocardial infarction (MI) and death in recent hypertension trials with Slower onset action and longer duration action CCB's that have. minimal peak to trough variability. In the Amlodipine Cardiovascular Community Trial the rate of MI per 1000 patient (pl.) 7e~ w.as 10 - comp:u-ed to the 14.2 MIs/1000 patient years for diuretiCs In the MRC tnal. There were no cardiovascular deaths. Long term results from the trial including 7849 pt-months exposure time revealed 7.6 Ml's per 1000 pl.-years and no cardiovascular deaths. Similar results were reported in the largest mfedipine G1TS trial. In available hypertension clinical trials ofnifedipine GITS MI rate per 1000 patient-years was 6.5. In available hypertension ~linical trials of amlodipine including 89,233 pl.-months exposure tIme rate of MI per 1000 pl.-years was 3.3 and all case mortality was 3.0 per 1000 pl.-years. In comparative trials the MI rate per 1000 pt.-years was 6.1 with amlodipine versus 12.2 for placebo; the mortality rate per 1000 pt.years was 4.1 for amlodipine and 122 for placebo. While not a substitute for the need for long term prospective outcome studies with these newer calcium blockers, the data accumulated so far do not show a signal suggesting an increased rate of MI or death with these agents.
Key Words'
amlodipine. nifedipine GITS. calCium blockers
Wednesday, May 15, West Ballroom, 12:30 pm Safety of Antihypertensive Therapies: A Series of Interactive Panels Title: Rationale and Safely of ACE-Inhibitor Combination wilh , Calcium Cbannel Blockers William B. Applegate, M.D., Mempbls, Tennessee Ahbeugb boIh ACE-inhibitors (ACE) and calcium channel blockers (CCB) are essentially vasodilating antihypertensive agents, !heir basic mecbanisms are somewbat different and possibly synergistic. Calcium channel blockers bave more direcl effects OIl coronary artery smoolh muscle, wbile ACE-inbibitors may bave some specific antiprobferative properlJCS in lbe wall of COrOllary arteries. WIlb regard to lbe bean, calcium channel blockers cause relaxation of lbe myocardium and can increase myocardial filling in diastole. The ACE-inhibitors often cause remodeling of lbe myocardium and lend to prevent congestive heart failure. In Ihe kidney, Ihe calcium channel blockers prtJnary dilale lbe afferent artt..'I'iaI, wblle !he ACEinhibitors primarily block Ihe efferent arterial. Therefore, !be rigbt combinations of a calcium cbannel blocker and an ACE-inhibitor migbl bolb lower blood pressure synergi'lically as well as bave complunenlaJ)' actions on coronary arteries, lbe myocardium, and !he kidney. Dam will be presented on sludies wbicb bave combined enaJapril wilb diltiazem ER and amlod.pine wilb benazepril. In one sludy patients were r.wdomized to eilber placebo, enalapril 5 109 alone or in combination wilh dilliazernER. al doses of 60, 120, 180 or 24Omg. Each of lbe combinations proouced greater blood pressure-Iowenng Ihan lbe placebo and !here was linear a doseresponse relalionsbip. The AmlooipinelBenazepril combination is available in 2.5/10, 5/10, and 5120 mg. capsules. Tbere is a doseresponse relalion,hip wilh regard to blood pressure-lowering in eacb of lbese doses, but most or Ihe blood pressure-lowenng is achieved by Ihe 5/10 dose. Side-effect rates for !be combination drug were similar to lbat of Benazepril alone, but !be combinallon proouced more blood pressure-Iowenng and offsellbe lendency for peripheral etlema in CCB patienlS. Conclusion, lbese dam indicale Ihal calcium cbannel blocker, ACE-inhibitor combinatiOlls are effective and well-lOlerated. In additiOll, !bey offer potential physiologic and bemooynamic synergistic benefits whicb are yet to be fully explored.
KeyWords:
SPECIAL SYMPOSIA
Wednesday, May 15, West Ballroom, 12:30 pm Safety of Antihypertensive Therapies: A Series of Interactive Panels LESSONS FROM COMBINATION THERAPY IN V A STUDIES. B.J. Materson, Miami VA Medical Center University of Miami, Miami, FL. ' Combination antihypertensive therapy has been a part of VA Cooperative Study protocols from the very beginning. The greatest early impact derived from the success of the combination of reserpine, hydrochlorothiazide (HCTZ) and hydralazine in a population of patients ranging from what would today be classified as stage 1 to 4. The commercial product, Ser-Ap·Es, was popular for many years thereafter. In a later study propranolol alone achieved goal in 52% of the patients, propranolol plus hydralazine in 72%, and propranolol plus HCTZ in 81 %. A series of studies demonstrated the benefit of combination of HCTZ with a variety of drugs: prazosin, hydralazine, propranolol, oxprenolol, nadolol, and captopri!. Reserpine in very low doses was safe and effective when combined with a low dose of chlorthalidone. The VA Cooperative Study on Monotherapy of Hypertension incorporated a substudy of patients who had not achieved goal blood pressure with two different single drugs. In this study, the two drugs that had failed to achieve goal were combined. Systolic BP was reduced in 77% of the patients for whom one of the two drugs was HCTZ compared to 46% of those whose combination did not include I1CTZ (p=O.002); for diastolic BP. the results were 69% vs 51 % (p=O.067). The BP reduction was 22.4±IO.4/14.1±6.6 with HCTZ and 17.8±I9.3/13.6±9.l without HCTZ. Key Words:
Hypertension, monotherapy, combination
Wednesday, May 15, West Ballroom, 12:30 pm Safety of Antihypertensive Therapies: A Series of Interactive Panels THE INFLUENCE OF DIETARY SALT AND INSULIN RESISTANCE ON THE RISK FOR HYPERTENSIVE RENAL INJURY. MR Weir, Division of Nephrology, University of Maryland School of Medicine. Hypertensive renal injury is a major identifiable cause of end-stage renal disease in salt sensitive popUlations such as African-Americans, older patients and diabetics. A complex nexus of sociological, biological, environmental, and sociocultural variables are involved in mediating this risk. It is likely that dietary salt intake and salt sensitivity are linked in influencing the risk of hypertensive renal injury, since it has been demonstrated that increasing insulin resistance with an increase in glomerular filtration fraction and proteinuria. The inter-relationship between dietary sodium and nonpharmacologic and pharmacologic interventions may prove to be an important issue that needs to be addressed on a patient-by-patient basis, since the efficacy of these therapies may be dependent on the degree of dietary salt intake. It is also likely that the pathophysiologic disturbances induced by greater dietary salt intake may be more specifically corrected by some of these intervention compared to others, Since dietary salt has identifiable influences on blood pressure, renal hemodynamics and metabolism, its overall effect on c~rdiovascular risk, particularly in highr1sk groups such as African-Americans, older ~atients and diabetics assumes increasing 1mportance.
KeyWords:
Salt, insulin resistance. hypertension. kidney
199A
Wednesday, ~ay 15, West Ballroom, 12:30 pm Safety of ~ntihypertensiveTherapies: A Series of InteractIve Panels Cardiovascular Safely of Dihydropyridines: A Hard Look at Real Data. Robert A. Kloner, George Velrovec, Barry l. Materson, Marcia Levenstein. Good Samaritan Hosp. and U. So. Cal., Med. Coli Va., U. Miami, Pfizer USPG, Los Angeles CA Richmond VA Miami Flo New York, NY. ' , Much of the current controversy surrounding use of calcium Channel blockers (CCB's) in hypertension is based on case contr?lIed retrospective studies which have utilized short acting CCB s not FDA approved for hypertension. We reviewed data on myocardial infarction (MI) and death in recent hypertension trials with Slower onset action and longer duration action CCB's that have. minimal peak to trough variability. In the Amlodipine Cardiovascular Community Trial the rate of MI per 1000 patient (pl.) 7e~ w.as 10 - comp:u-ed to the 14.2 MIs/1000 patient years for diuretiCs In the MRC tnal. There were no cardiovascular deaths. Long term results from the trial including 7849 pt-months exposure time revealed 7.6 Ml's per 1000 pl.-years and no cardiovascular deaths. Similar results were reported in the largest mfedipine G1TS trial. In available hypertension clinical trials ofnifedipine GITS MI rate per 1000 patient-years was 6.5. In available hypertension ~linical trials of amlodipine including 89,233 pl.-months exposure tIme rate of MI per 1000 pl.-years was 3.3 and all case mortality was 3.0 per 1000 pl.-years. In comparative trials the MI rate per 1000 pt.-years was 6.1 with amlodipine versus 12.2 for placebo; the mortality rate per 1000 pt.years was 4.1 for amlodipine and 122 for placebo. While not a substitute for the need for long term prospective outcome studies with these newer calcium blockers, the data accumulated so far do not show a signal suggesting an increased rate of MI or death with these agents.
Key Words'
amlodipine. nifedipine GITS. calCium blockers
Wednesday, May 15, West Ballroom, 12:30 pm Safety of Antihypertensive Therapies: A Series of Interactive Panels Title: Rationale and Safely of ACE-Inhibitor Combination wilh , Calcium Cbannel Blockers William B. Applegate, M.D., Mempbls, Tennessee Ahbeugb boIh ACE-inhibitors (ACE) and calcium channel blockers (CCB) are essentially vasodilating antihypertensive agents, !heir basic mecbanisms are somewbat different and possibly synergistic. Calcium channel blockers bave more direcl effects OIl coronary artery smoolh muscle, wbile ACE-inbibitors may bave some specific antiprobferative properlJCS in lbe wall of COrOllary arteries. WIlb regard to lbe bean, calcium channel blockers cause relaxation of lbe myocardium and can increase myocardial filling in diastole. The ACE-inhibitors often cause remodeling of lbe myocardium and lend to prevent congestive heart failure. In Ihe kidney, Ihe calcium channel blockers prtJnary dilale lbe afferent artt..'I'iaI, wblle !he ACEinhibitors primarily block Ihe efferent arterial. Therefore, !be rigbt combinations of a calcium cbannel blocker and an ACE-inhibitor migbl bolb lower blood pressure synergi'lically as well as bave complunenlaJ)' actions on coronary arteries, lbe myocardium, and !he kidney. Dam will be presented on sludies wbicb bave combined enaJapril wilb diltiazem ER and amlod.pine wilb benazepril. In one sludy patients were r.wdomized to eilber placebo, enalapril 5 109 alone or in combination wilh dilliazernER. al doses of 60, 120, 180 or 24Omg. Each of lbe combinations proouced greater blood pressure-Iowenng Ihan lbe placebo and !here was linear a doseresponse relalionsbip. The AmlooipinelBenazepril combination is available in 2.5/10, 5/10, and 5120 mg. capsules. Tbere is a doseresponse relalion,hip wilh regard to blood pressure-lowering in eacb of lbese doses, but most or Ihe blood pressure-lowenng is achieved by Ihe 5/10 dose. Side-effect rates for !be combination drug were similar to lbat of Benazepril alone, but !be combinallon proouced more blood pressure-Iowenng and offsellbe lendency for peripheral etlema in CCB patienlS. Conclusion, lbese dam indicale Ihal calcium cbannel blocker, ACE-inhibitor combinatiOlls are effective and well-lOlerated. In additiOll, !bey offer potential physiologic and bemooynamic synergistic benefits whicb are yet to be fully explored.
KeyWords:
SPECIAL SYMPOSIA
Wednesday, May 15, West Ballroom, 12:30 pm Safety of Antihypertensive Therapies: A Series of Interactive Panels LESSONS FROM COMBINATION THERAPY IN V A STUDIES. B.J. Materson, Miami VA Medical Center University of Miami, Miami, FL. ' Combination antihypertensive therapy has been a part of VA Cooperative Study protocols from the very beginning. The greatest early impact derived from the success of the combination of reserpine, hydrochlorothiazide (HCTZ) and hydralazine in a population of patients ranging from what would today be classified as stage 1 to 4. The commercial product, Ser-Ap·Es, was popular for many years thereafter. In a later study propranolol alone achieved goal in 52% of the patients, propranolol plus hydralazine in 72%, and propranolol plus HCTZ in 81 %. A series of studies demonstrated the benefit of combination of HCTZ with a variety of drugs: prazosin, hydralazine, propranolol, oxprenolol, nadolol, and captopri!. Reserpine in very low doses was safe and effective when combined with a low dose of chlorthalidone. The VA Cooperative Study on Monotherapy of Hypertension incorporated a substudy of patients who had not achieved goal blood pressure with two different single drugs. In this study, the two drugs that had failed to achieve goal were combined. Systolic BP was reduced in 77% of the patients for whom one of the two drugs was HCTZ compared to 46% of those whose combination did not include I1CTZ (p=O.002); for diastolic BP. the results were 69% vs 51 % (p=O.067). The BP reduction was 22.4±IO.4/14.1±6.6 with HCTZ and 17.8±I9.3/13.6±9.l without HCTZ. Key Words:
Hypertension, monotherapy, combination
Wednesday, May 15, West Ballroom, 12:30 pm Safety of Antihypertensive Therapies: A Series of Interactive Panels THE INFLUENCE OF DIETARY SALT AND INSULIN RESISTANCE ON THE RISK FOR HYPERTENSIVE RENAL INJURY. MR Weir, Division of Nephrology, University of Maryland School of Medicine. Hypertensive renal injury is a major identifiable cause of end-stage renal disease in salt sensitive popUlations such as African-Americans, older patients and diabetics. A complex nexus of sociological, biological, environmental, and sociocultural variables are involved in mediating this risk. It is likely that dietary salt intake and salt sensitivity are linked in influencing the risk of hypertensive renal injury, since it has been demonstrated that increasing insulin resistance with an increase in glomerular filtration fraction and proteinuria. The inter-relationship between dietary sodium and nonpharmacologic and pharmacologic interventions may prove to be an important issue that needs to be addressed on a patient-by-patient basis, since the efficacy of these therapies may be dependent on the degree of dietary salt intake. It is also likely that the pathophysiologic disturbances induced by greater dietary salt intake may be more specifically corrected by some of these intervention compared to others, Since dietary salt has identifiable influences on blood pressure, renal hemodynamics and metabolism, its overall effect on c~rdiovascular risk, particularly in highr1sk groups such as African-Americans, older ~atients and diabetics assumes increasing 1mportance.
KeyWords:
Salt, insulin resistance. hypertension. kidney
199A