- Email: [email protected]
Ambulatory blood pressure assessment of once-daily candesartan cilexetil versus enalapril in patients with hypertension
116A
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
ASH XV ABSTRACTS
of nicardipine (17 g/kg/min), irbesartan (430 g/kg/min), or nicardipine (17 g/kg/min) preceded by a small dose of irbesartan (600 g/kg). These doses were selected to produce a similar 20 mmHg reduction in mean arterial pressure (MAP) over 30 min. Changes in LSNA during drug-induced decreases in MAP were:
⌬ in MAP
n
ⴚ5
nicardipine irbesartan both
8 8 8
21 ⫾ 4* 6⫾1 8⫾1
⌬ in LSNA (% control) ⴚ10 ⴚ15 35 ⫾ 4* 11 ⫾ 2 21 ⫾ 3
48 ⫾ 5* 17 ⫾ 3 30 ⫾ 4#
ⴚ20 59 ⫾ 5* 21 ⫾ 3 38 ⫾ 4#
*p ⬍ 0.01 compared with other two groups. #p ⬍ 0.05 compared with irbesartan.
These results indicate that irbesartan induces less sympathetic activation than nicardipine and that pretreatment with irbesartan blunts nicardipine-induced increases in sympathetic activation, suggesting that co-administration of a calcium antagonist and an AIIA may have long-term clinical benefits. Key Words: Sympathetic activation; irbesartan; angiotensin II antagonist; calcium channel blocker A014 NICARDIPINE HAS DIRECT SYMPATHOEXCITATORY EFFECT D.A. Calhoun* and S.T. Zhu. University of Alabama at Birmingham, Birmingham, Alabama Sustained sympathetic activation induces left ventricular hypertrophy, smooth muscle cell hyperplasia, and may predispose to sudden death. We recently published that the calcium channel blocker nicardipine induces greater increases in lumbar sympathetic nerve activity (LSNA) and heart rate (HR) in spontaneously hypertensive rats (SHR) than the ACE inhibitor enalaprilat. The present study tested whether this effect is attributable to greater baroreceptor unloading. Recording electrodes were secured to the lumbar nerve of 9-wk old male SHR. Twenty-four hours later in conscious rats, LSNA was recorded during infusion of phenylephrine (10 –21 g/kg/min) sufficient to raise MAP by 20 mmHg followed by nicardipine (6 –12 g/kg/min) or enalaprilat (8 –12 g/kg) sufficient to lower MAP back to baseline. Phenylephrine-induced increase in MAP suppressed LSNA by 47%. Changes in LSNA during nicardipine or enalaprilat-induced reductions in MAP were:
⌬ in MAP
n
ⴚ5
nicardipine enalaprilat
7 9
101 ⫾ 13* 68 ⫾ 7
⌬ in LSNA (% control) ⴚ10 ⴚ15 127 ⫾ 12* 74 ⫾ 9
135 ⫾ 12* 79 ⫾ 8
ⴚ20 143 ⫾ 16* 85 ⫾ 10
*p ⬍ 0.01 compared with enalaprilat. Change in right atrial pressure was not different between the 2 drugs.
These results indicate that nicardipine has a direct sympathoexcitatory effect independent of any change in MAP or right atrial pressure. In contrast, enalaprilat has a sympathoinhibitory effect. These contrasting effects on sympathetic activation may have differential effects on long-term cardiovascular risk.
Key Words: Sympathetic activation; nicardipine; enalaprilat; ACE inhibitor; calcium channel blocker A015 PHARMACODYNAMIC INTERACTIONS OF SUBLINGUAL APOMORPHINE WITH ORAL ANTIHYPERTENSIVE AGENTS AND NITRATES T.C. Fagan*1, S. Buttler2, C. Schultz2, A. Edmonds2. University of Arizona College of Medicine1, Tucson, AZ, TAP Holdings Inc.2, Deerfield, IL To evaluate potential pharmacodynamic interactions between sublingual apomorphine, (Apo SL) a recently reformulated DA2/DA1 agonist for erectile dysfunction, and antihypertensive and nitrate agents likely to be used concurrently in the clinical setting. Recommended clinical doses of Apo SL are 2– 4 mg. This was a double-blind, randomized, placebo-controlled, crossover trial in 162 male patients with hypertension and/or coronary disease. Apo SL 5 mg and placebo (P) were administered on alternate days to patients chronically receiving therapeutic doses of ACE inhibitors (ACEI), beta blockers (B), alpha blockers (␣B) calcium channel blockers (CCB), diuretics (Du), and short (SAN) and long-acting (LAN) nitrates. Serial supine (Su) and standing (St) systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) were measured by Dinamap® and cardiac rhythm was recorded by 4 hour Holter Monitor. There were no clinically significant interactions between Apo SL and ACEI, B, ␣B, CCB, Du, or SAN. There were no clinically significant interactions between Apo SL and LAN in Su BP or HR. Administration of Apo SL 4 hours after LAN resulted in mean decreases in St SBP of 5–9 mmHg from 30 – 60 minutes post dose (p ⬍ .05); St DBP was decreased by 3– 4 mmHg from 50 – 60 minutes post dose (p ⬍ .05). Both had returned to baseline by 90 minutes post dose. Most common adverse events (AE) (Apo SL:P) were dizziness (11%:2%), nausea (10%:1%), and headache (6%:2%). Significant AE were syncope (1:0) in the B group and symptomatic hypotension in the SAN (2:0) and LAN (2:0) groups. In conclusion, Apo SL is a DA2/DA1 agonist which is effective for male erectile dysfunction. At higher than recommended doses of Apo SL, BP, HR and AE are not altered by coadministration of common classes of antihypertensive agents. In most patients on LAN, decreases in St BP are not clinically significant. A minority of patients receiving nitrates experienced symptomatic St hypotension. Key Words: Apomorphine; adverse effects; hemodynamics; erectile dysfunction; dopamine receptors A016 AMBULATORY BLOOD PRESSURE ASSESSMENT OF ONCE-DAILY CANDESARTAN CILEXETIL VERSUS ENALAPRIL IN PATIENTS WITH HYPERTENSION A. Himmelmann, S. Keina¨nen-Kiukaanniemi, A. Wester, J. Redon, R. Asmar, T. Hedner for the EffECT study group. Sahlgrenska University Hospital, Sweden, University of Oulu, Finland, Midden Twente Ziekenhuis, The Netherlands, University of Valencia, Spain, Institut de Recherche et Formation Cardiovasculaire, France
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
Blood pressure reduction, effect duration and tolerability of the AT1-receptor blocker candesartan and the ACE inhibitor enalapril, once daily, was studied in a multicenter, doubleblind, randomised, parallel group study. A total of 395 patients, aged 20 – 80 years, with mean sitting diastolic blood pressure 95–114 mmHg and mean awake diastolic ambulatory blood pressure (ABP) ⬎85 mmHg after a 4-week placebo run-in period were randomised to 8 weeks treatment. The starting doses were candesartan cilexetil 8 mg or enalapril 10 mg. After 4 weeks the doses were doubled to 16 mg and 20 mg respectively, for all patients. At the end of the study, ABP was measured 0 –36 hours after dose. Trough blood pressure was calculated as ABP 22–24 hours post dose. The mean adjusted reduction from baseline to after 8 weeks of trough diastolic ABP was 8.7 mmHg (95% CI 7.0 –10.5) in the candesartan group vs 5.8 mmHg (95% CI 4.0 –7.6) in the enalapril group (p ⫽ 0.008). For trough systolic ABP 22–24 hours post dose, the mean adjusted reduction in the candesartan group was 13.5 mmHg (95% CI 10.9 –16.1) vs 9.9 mmHg (95% CI 7.3–12.6) in the enalapril group (p ⫽ 0.032). Mean adjusted reduction of diastolic ABP on the day of a missed dose (6 a.m.– 6 p.m.) was 8.0 mmHg (95% CI 6.7–9.3) in the candesartan group vs 4.5 mmHg (95% CI 3.2–5.9) in the enalapril group (p ⬍ 0.001). The corresponding reductions in systolic ABP were 11.4 mmHg (95% CI 9.3–13.5) with candesartan and 7.2 mmHg (95% CI 5.1– 9.4) with enalapril (p ⫽ 0.002). The proportion of patients who discontinued due to adverse events was 2.0% and 3.6% in the candesartan and enalapril groups, respectively. Once-daily candesartan cilexetil, 16 mg, was superior to enalapril, 20 mg, in reducing blood pressure at trough. At least 12 hours after a missed dose there was a persistent reduction of blood pressure during treatment with candesartan. Both treatments were well tolerated. Key Words: Candesartan; cilexetil; enalapril; ambulatory blood pressure; missed dose A017 THE ANTIPROTEINURIC EFFECT OF ENALAPRIL IS POTENTIATED BY LOSARTAN IN NORMOTENSIVE PATIENTS WITH DIABETIC NEPHROPATHY J. Arteaga*, E. Petrina, E. Anda, D. Calderon, M. Sorbet, M. Asiro´n. Dept. of Nephrology. Hospital de Navarra. Pamplona. Spain It is well known that enalapril and losartan play an important role in decreasing proteinuria in diabetic nephropathy. The aim of this work was to analyze if the addition of losartan 50 mg/day to normotensive diabetic patients with normal renal function in treatment with enalapril could be beneficial in terms of decreasing proteinuria. We selected 10 patients (4M, 6F) with type 2 diabetes, normotensives, proteinuric and with normal renal function in treatment with enalapril 10 –20 mg/day (6 –14 months). We added Losartan 50 mg/day for two months and then, enalapril was discontinued for another two months. They were their own control. There were no significant changes in weight, serum creatinine, sistolic and diastolic blood pressure.
POSTERS: Antihypertensive Drugs
Enalapril Proteinuria gr/24 h (Paired t-test)
117A
enalapril ⴙ losartan
Losartan
1,955 ⫾ 0,334
2,458 ⫾ 0,428
2,396 ⫾ 0,535 p ⬍ 0,05
p ⬍ 0,01
A decrease in proteinuric levels was observed during the combination time period. After stopping enalapril there was an increase of proteinuria that reached similar levels to the first period ones. We suggest that the additive effect of enalapril and losartan could be an elective treatment in patients with diabetic nephropathy. Long term studies are necessary to confirm the useful effect of this association. Key Words: Diabetic nephropathy; enalapril; losartan hypertension
A018 CONTROL OF BLOOD PRESSURE IN A POPULATION OF WOMEN WITH HYPERTENSION AND CAD USING AN INTERNET-BASED ELECTRONIC PRESCRIBING SYSTEM R.M. Cooper-DeHoff, E.M. Handberg-Thurmond, R.G. Marks, M. Conlon, H.R. Kolb, C.J. Pepine for the INVEST Investigators. University of Florida, Gainesville, FL Background: Adequate BP control in patients with hypertension is difficult as various reports document that only 16 –24% of patients actually achieve control despite treatment. Because coronary artery disease (CAD) is the #1 killer of women, it is imperative that focus be placed on adequate BP control in women who are hypertensive and have CAD. Data for CAD & women are lacking. To determine what is required to control BP using JNC VI criteria with lower targets for special populations, we examined data from a cohort of women with CAD enrolled in an ongoing trial. Methods: The INternational VErapamil/trandolapril Study (INVEST) utilizes a unique internet-based all electronic data management system to collect data and randomly assign and prescribe antihypertensive medications (HCTZ, atenolol, verapamil SR and trendolapril). CAD is defined as either a remote confirmed MI, abnormal coronary angiogram, abnormal stress tests or classic angina pectoris. Physicians, primarily in the community, utilize the internet to generate electronic prescriptions from the assigned strategy. The system guides physicians, based on blood pressure control, to up-titrate dose and number of medications as necessary. Patients are seen every 6 weeks for the first 6 months and then biannually. Results: Data from the first 3766 women enrolled reveal an elderly population (60% ⬎65 yo), 58% Caucasian, 23% African American, 19% Hispanic, and 28% with a history of diabetes. BP data reveal diastolic and systolic control in 83% and 46% respectively, during the first year, with very few reported episodes of hypotension. BP control however, required ⱖ2 different medications in 74% of the women. Daily doses of medications ranged from: Verapamil SR 240 – 480 mg, trandolapril 2– 8 mg, atenolol 50 –100 mg and hydrochlorothiazide 25–50 mg.
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
ASH XV ABSTRACTS
of nicardipine (17 g/kg/min), irbesartan (430 g/kg/min), or nicardipine (17 g/kg/min) preceded by a small dose of irbesartan (600 g/kg). These doses were selected to produce a similar 20 mmHg reduction in mean arterial pressure (MAP) over 30 min. Changes in LSNA during drug-induced decreases in MAP were:
⌬ in MAP
n
ⴚ5
nicardipine irbesartan both
8 8 8
21 ⫾ 4* 6⫾1 8⫾1
⌬ in LSNA (% control) ⴚ10 ⴚ15 35 ⫾ 4* 11 ⫾ 2 21 ⫾ 3
48 ⫾ 5* 17 ⫾ 3 30 ⫾ 4#
ⴚ20 59 ⫾ 5* 21 ⫾ 3 38 ⫾ 4#
*p ⬍ 0.01 compared with other two groups. #p ⬍ 0.05 compared with irbesartan.
These results indicate that irbesartan induces less sympathetic activation than nicardipine and that pretreatment with irbesartan blunts nicardipine-induced increases in sympathetic activation, suggesting that co-administration of a calcium antagonist and an AIIA may have long-term clinical benefits. Key Words: Sympathetic activation; irbesartan; angiotensin II antagonist; calcium channel blocker A014 NICARDIPINE HAS DIRECT SYMPATHOEXCITATORY EFFECT D.A. Calhoun* and S.T. Zhu. University of Alabama at Birmingham, Birmingham, Alabama Sustained sympathetic activation induces left ventricular hypertrophy, smooth muscle cell hyperplasia, and may predispose to sudden death. We recently published that the calcium channel blocker nicardipine induces greater increases in lumbar sympathetic nerve activity (LSNA) and heart rate (HR) in spontaneously hypertensive rats (SHR) than the ACE inhibitor enalaprilat. The present study tested whether this effect is attributable to greater baroreceptor unloading. Recording electrodes were secured to the lumbar nerve of 9-wk old male SHR. Twenty-four hours later in conscious rats, LSNA was recorded during infusion of phenylephrine (10 –21 g/kg/min) sufficient to raise MAP by 20 mmHg followed by nicardipine (6 –12 g/kg/min) or enalaprilat (8 –12 g/kg) sufficient to lower MAP back to baseline. Phenylephrine-induced increase in MAP suppressed LSNA by 47%. Changes in LSNA during nicardipine or enalaprilat-induced reductions in MAP were:
⌬ in MAP
n
ⴚ5
nicardipine enalaprilat
7 9
101 ⫾ 13* 68 ⫾ 7
⌬ in LSNA (% control) ⴚ10 ⴚ15 127 ⫾ 12* 74 ⫾ 9
135 ⫾ 12* 79 ⫾ 8
ⴚ20 143 ⫾ 16* 85 ⫾ 10
*p ⬍ 0.01 compared with enalaprilat. Change in right atrial pressure was not different between the 2 drugs.
These results indicate that nicardipine has a direct sympathoexcitatory effect independent of any change in MAP or right atrial pressure. In contrast, enalaprilat has a sympathoinhibitory effect. These contrasting effects on sympathetic activation may have differential effects on long-term cardiovascular risk.
Key Words: Sympathetic activation; nicardipine; enalaprilat; ACE inhibitor; calcium channel blocker A015 PHARMACODYNAMIC INTERACTIONS OF SUBLINGUAL APOMORPHINE WITH ORAL ANTIHYPERTENSIVE AGENTS AND NITRATES T.C. Fagan*1, S. Buttler2, C. Schultz2, A. Edmonds2. University of Arizona College of Medicine1, Tucson, AZ, TAP Holdings Inc.2, Deerfield, IL To evaluate potential pharmacodynamic interactions between sublingual apomorphine, (Apo SL) a recently reformulated DA2/DA1 agonist for erectile dysfunction, and antihypertensive and nitrate agents likely to be used concurrently in the clinical setting. Recommended clinical doses of Apo SL are 2– 4 mg. This was a double-blind, randomized, placebo-controlled, crossover trial in 162 male patients with hypertension and/or coronary disease. Apo SL 5 mg and placebo (P) were administered on alternate days to patients chronically receiving therapeutic doses of ACE inhibitors (ACEI), beta blockers (B), alpha blockers (␣B) calcium channel blockers (CCB), diuretics (Du), and short (SAN) and long-acting (LAN) nitrates. Serial supine (Su) and standing (St) systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) were measured by Dinamap® and cardiac rhythm was recorded by 4 hour Holter Monitor. There were no clinically significant interactions between Apo SL and ACEI, B, ␣B, CCB, Du, or SAN. There were no clinically significant interactions between Apo SL and LAN in Su BP or HR. Administration of Apo SL 4 hours after LAN resulted in mean decreases in St SBP of 5–9 mmHg from 30 – 60 minutes post dose (p ⬍ .05); St DBP was decreased by 3– 4 mmHg from 50 – 60 minutes post dose (p ⬍ .05). Both had returned to baseline by 90 minutes post dose. Most common adverse events (AE) (Apo SL:P) were dizziness (11%:2%), nausea (10%:1%), and headache (6%:2%). Significant AE were syncope (1:0) in the B group and symptomatic hypotension in the SAN (2:0) and LAN (2:0) groups. In conclusion, Apo SL is a DA2/DA1 agonist which is effective for male erectile dysfunction. At higher than recommended doses of Apo SL, BP, HR and AE are not altered by coadministration of common classes of antihypertensive agents. In most patients on LAN, decreases in St BP are not clinically significant. A minority of patients receiving nitrates experienced symptomatic St hypotension. Key Words: Apomorphine; adverse effects; hemodynamics; erectile dysfunction; dopamine receptors A016 AMBULATORY BLOOD PRESSURE ASSESSMENT OF ONCE-DAILY CANDESARTAN CILEXETIL VERSUS ENALAPRIL IN PATIENTS WITH HYPERTENSION A. Himmelmann, S. Keina¨nen-Kiukaanniemi, A. Wester, J. Redon, R. Asmar, T. Hedner for the EffECT study group. Sahlgrenska University Hospital, Sweden, University of Oulu, Finland, Midden Twente Ziekenhuis, The Netherlands, University of Valencia, Spain, Institut de Recherche et Formation Cardiovasculaire, France
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
Blood pressure reduction, effect duration and tolerability of the AT1-receptor blocker candesartan and the ACE inhibitor enalapril, once daily, was studied in a multicenter, doubleblind, randomised, parallel group study. A total of 395 patients, aged 20 – 80 years, with mean sitting diastolic blood pressure 95–114 mmHg and mean awake diastolic ambulatory blood pressure (ABP) ⬎85 mmHg after a 4-week placebo run-in period were randomised to 8 weeks treatment. The starting doses were candesartan cilexetil 8 mg or enalapril 10 mg. After 4 weeks the doses were doubled to 16 mg and 20 mg respectively, for all patients. At the end of the study, ABP was measured 0 –36 hours after dose. Trough blood pressure was calculated as ABP 22–24 hours post dose. The mean adjusted reduction from baseline to after 8 weeks of trough diastolic ABP was 8.7 mmHg (95% CI 7.0 –10.5) in the candesartan group vs 5.8 mmHg (95% CI 4.0 –7.6) in the enalapril group (p ⫽ 0.008). For trough systolic ABP 22–24 hours post dose, the mean adjusted reduction in the candesartan group was 13.5 mmHg (95% CI 10.9 –16.1) vs 9.9 mmHg (95% CI 7.3–12.6) in the enalapril group (p ⫽ 0.032). Mean adjusted reduction of diastolic ABP on the day of a missed dose (6 a.m.– 6 p.m.) was 8.0 mmHg (95% CI 6.7–9.3) in the candesartan group vs 4.5 mmHg (95% CI 3.2–5.9) in the enalapril group (p ⬍ 0.001). The corresponding reductions in systolic ABP were 11.4 mmHg (95% CI 9.3–13.5) with candesartan and 7.2 mmHg (95% CI 5.1– 9.4) with enalapril (p ⫽ 0.002). The proportion of patients who discontinued due to adverse events was 2.0% and 3.6% in the candesartan and enalapril groups, respectively. Once-daily candesartan cilexetil, 16 mg, was superior to enalapril, 20 mg, in reducing blood pressure at trough. At least 12 hours after a missed dose there was a persistent reduction of blood pressure during treatment with candesartan. Both treatments were well tolerated. Key Words: Candesartan; cilexetil; enalapril; ambulatory blood pressure; missed dose A017 THE ANTIPROTEINURIC EFFECT OF ENALAPRIL IS POTENTIATED BY LOSARTAN IN NORMOTENSIVE PATIENTS WITH DIABETIC NEPHROPATHY J. Arteaga*, E. Petrina, E. Anda, D. Calderon, M. Sorbet, M. Asiro´n. Dept. of Nephrology. Hospital de Navarra. Pamplona. Spain It is well known that enalapril and losartan play an important role in decreasing proteinuria in diabetic nephropathy. The aim of this work was to analyze if the addition of losartan 50 mg/day to normotensive diabetic patients with normal renal function in treatment with enalapril could be beneficial in terms of decreasing proteinuria. We selected 10 patients (4M, 6F) with type 2 diabetes, normotensives, proteinuric and with normal renal function in treatment with enalapril 10 –20 mg/day (6 –14 months). We added Losartan 50 mg/day for two months and then, enalapril was discontinued for another two months. They were their own control. There were no significant changes in weight, serum creatinine, sistolic and diastolic blood pressure.
POSTERS: Antihypertensive Drugs
Enalapril Proteinuria gr/24 h (Paired t-test)
117A
enalapril ⴙ losartan
Losartan
1,955 ⫾ 0,334
2,458 ⫾ 0,428
2,396 ⫾ 0,535 p ⬍ 0,05
p ⬍ 0,01
A decrease in proteinuric levels was observed during the combination time period. After stopping enalapril there was an increase of proteinuria that reached similar levels to the first period ones. We suggest that the additive effect of enalapril and losartan could be an elective treatment in patients with diabetic nephropathy. Long term studies are necessary to confirm the useful effect of this association. Key Words: Diabetic nephropathy; enalapril; losartan hypertension
A018 CONTROL OF BLOOD PRESSURE IN A POPULATION OF WOMEN WITH HYPERTENSION AND CAD USING AN INTERNET-BASED ELECTRONIC PRESCRIBING SYSTEM R.M. Cooper-DeHoff, E.M. Handberg-Thurmond, R.G. Marks, M. Conlon, H.R. Kolb, C.J. Pepine for the INVEST Investigators. University of Florida, Gainesville, FL Background: Adequate BP control in patients with hypertension is difficult as various reports document that only 16 –24% of patients actually achieve control despite treatment. Because coronary artery disease (CAD) is the #1 killer of women, it is imperative that focus be placed on adequate BP control in women who are hypertensive and have CAD. Data for CAD & women are lacking. To determine what is required to control BP using JNC VI criteria with lower targets for special populations, we examined data from a cohort of women with CAD enrolled in an ongoing trial. Methods: The INternational VErapamil/trandolapril Study (INVEST) utilizes a unique internet-based all electronic data management system to collect data and randomly assign and prescribe antihypertensive medications (HCTZ, atenolol, verapamil SR and trendolapril). CAD is defined as either a remote confirmed MI, abnormal coronary angiogram, abnormal stress tests or classic angina pectoris. Physicians, primarily in the community, utilize the internet to generate electronic prescriptions from the assigned strategy. The system guides physicians, based on blood pressure control, to up-titrate dose and number of medications as necessary. Patients are seen every 6 weeks for the first 6 months and then biannually. Results: Data from the first 3766 women enrolled reveal an elderly population (60% ⬎65 yo), 58% Caucasian, 23% African American, 19% Hispanic, and 28% with a history of diabetes. BP data reveal diastolic and systolic control in 83% and 46% respectively, during the first year, with very few reported episodes of hypotension. BP control however, required ⱖ2 different medications in 74% of the women. Daily doses of medications ranged from: Verapamil SR 240 – 480 mg, trandolapril 2– 8 mg, atenolol 50 –100 mg and hydrochlorothiazide 25–50 mg.