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Comparison of 3 second line antihypertensive treatment strategies in elderly patients with essential hypertension
46A
POSTERS: Antihypertensive Drugs
antagonist (CA) seems particularly rational on the basis of their mechanism of action. The aim of this study was to determine the antihypertensive effect produced by different combinations of various doses of the ACE-I delapril (D) and the dihydropyridine CA manidipine (M) in patients (pts) with mild to moderate HBP. The study was designed according to a 3x3 factorial design and carried out as a randomised, double-blind, placebo-controlled, multicentre trial. Overall study duration was 8 weeks: 2 of placebo run-in/wash-out, and 6 of active treatment during which 400 pts (231 males, 169 females; mean age 51.8 years) received placebo, D (15 or 30 mg o.i.d.), M (5 or 10 mg o.i.d.), or one of the 4 possible combinations of D and M. In the analysis of final values, all differences between the active treatment groups (grs) and the placebo group (gr) are statistically significant except, for systolic blood pressure (SBP), in the gr M5 and D15, and, for diastolic blood pressure (DBP), in the gr D15. The gr M5⫹D15 showed a significant reduction in SBP and DBP versus both grs treated with either drug alone, while the gr M10⫹D30 showed a reduction in DBP respect to either M10 or D30. In the analysis of the differences between final and baseline values, M5⫹D15 showed a significant difference in SBP and DBP versus both grs treated with either drug alone, while the gr M10⫹D30 showed a reduction in SBP versus the gr receiving D30 alone. Overall, the M10⫹D30 combination gave the best mean reduction in SBP and DBP and appeared to be the more potent of all tested combinations. The rate of pts responders (final-baseline change in DBPⱖ10mmHg) or normalised (DBPⱕ90mmHg) was higher in the grs M10⫹D30 (72.7%) and M5⫹D15 (68.9%) respect to placebo gr and the other grs receiving different combinations of drugs. The number of pts who had to be withdrawn from treatment due to adverse events was low (1%), with no differences among randomised treatment grs. In conclusion, the combination of D and M is more effective than single components and has an additive antihypertensive effect in the treatment of mild to moderate HBP. SBP and DBP are reduced in dose-related manner for each drug as monotherapy and for the two drugs in combination. The combination of M10 and D30 may represent a suitable therapeutic option in HBP, especially in pts not responders to single components. Key Words: Manidipine, Delapril, Combination Therapy
P-36 COMPARISON OF 3 SECOND LINE ANTIHYPERTENSIVE TREATMENT STRATEGIES IN ELDERLY PATIENTS WITH ESSENTIAL HYPERTENSION Roland Asmar, Hani Ghobrial, Laurent Vaur, Isabelle Dubroca. Cardiovascular institut, Paris, France; Aventis Laboratory, Paris, France. The aim of this study was to compare 3 different second line antihypertensive therapeutic strategies on seated systolic blood pressure (SeSBP) in elderly patients (⬎60 years) with mild to moderate essential hypertension with BP being not normalized after 6 weeks first line treatment with 200 mg celiprolol, a cardioselective beta 1 blocker agent. A total of 593 patients (270 males and 323 females), mean aged 69 years ⫾ 8, received celiprolol (200 mg OD) for 6 weeks. After this period, 251 patients (42%) showed persistent uncontrolled BP (SeSBP ⱖ 140 mmHg) and were randomized in 3 parallel groups to receive for an additional 6 weeks either higher dose of celiprolol 300 mg OD, increasing dose strategy (n⫽79), or 200 mg celiprolol ⫹ 12.5 mg hydrochlorothiazide(HCTZ) OD, combination strategy (n⫽85) or 80 mg valsartan OD, substitution strategy (n⫽87). The results showed that the difference in SeSBP reduction (main criterion) adjusted by baseline level was statistically significant between the 3 therapeutic strategies (p⫽0.024). The pairewise comparisons showed higher and more significant decrease of SeSBP with celiprolol 200 mg ⫹ HCTZ 12.5 mg OD (- 14.3 ⫾14.6 mmHg) than with 300 mg
AJH–April 2002–VOL. 15, NO. 4, PART 2
celiprolol OD (- 8.4 ⫾ 12 mmHg ) (p⫽0.007). Comparison of the SeSBP reduction between celiprolol 200 mg ⫹ HCTZ 12.5 mg OD and celiprolol 300 mg OD respectively versus valsartan 80 mg OD (- 10.7 ⫾ 13.9 mmHg) did not reach the statistical significance level. 14 patients (5.6%) were concerned by non serious adverse events (2 patients in the celiprolol 300 mg OD group, 6 patients in the celiprolol 200 mg ⫹ HCTZ 12.5 mg OD group and 4 patients in valsartan 80 mg OD group). In elderly hypertensive patients with BP being not normalized after a first line treatment by betablockers, increasing the dose of betablockers appears to be less effective on BP reduction than the combination with low dose of HCTZ; the combination therapy appears to be more efficient than substituting the betablocker by an angiotensin 2 receptor antagonist. Key Words: Essential Hypertension, Betablockers, Combination Therapy
P-37 LISINOPRIL (L) PHARMACOKINETICS (PK) IN HYPERTENSIVE CHILDREN AND INFANTS W. Shaw, R. Hogg, A. Delucchi, G. Sakihara, T. Wells, F. Tenney, D. Batisky, J. Blumer, B. Vogt, G. Murphy, M. Lo, E. Hand, D. Panebianco, R. Rippley, S. Shahinfar. Merck & Co., Inc., West Point, PA; Medical City Dallas Hospital, Dallas, TX; Luis Calvo Mackenna Hospital, Santiago, Chile; Instituto Nacional de Salud Nino, Lima, Peru; Arkansas Children’s Hospital, Little Rock, AR; LSU Medical Center, Shreveport, LA; Ped. Clinical Trials Int’l, Columbus, OH; Rainbow Babies and Children’s Hosp., Cleveland, OH. We evaluated the PK of L in 4 groups (Grp) of hypertensive infants & children (n⫽46): Grp I: 1 to 24 mos (mean 1.3 yrs); Grp II: 2 to 5 yrs (mean 3.6 yrs); Grp III: 6 to 11 yrs (mean 9.3 yrs); Grp IV: 12 to 15 yrs (mean 14.2 yrs). Grp I & II received oral L suspension (0.15 mg/kg/day). Grp III & IV received L tablets once daily: 2.5 mg if ⬍25 kg, 5 mg if ⱖ25 but ⬍45 kg, and 10 mg if ⱖ45 kg. Actual doses ranged from 0.07 to 0.19 mg/kg once daily. Geometric mean (95%C.I.) steady-state serum PK parameters for L, per RIA, were: There were no statistically significant differences between age groups for any PK parameter. Furthermore, results were comparable to historical observations in adults. There were no drug-related serious adverse experiences, and no pts discontinued due to adverse experiences. We conclude: (1) PK of L do not appear to be different in pediatric patients of different ages, (2) L can be administered in a suspension formulation to children and infants, (3) L was well-tolerated in hypertensive infants & children.
Grp I (N ⴝ 9)
Grp II (N ⴝ 8)
Mean dose 0.15 0.15 (mg/kg) 3.07 3.59 Mean dose (mg/m2) AUC0–24 hr 101 (72, 142) 84 (59, 120) (ng 䡠 hr/mL)a Cmax (ng/mL)a 7.2 (5.4, 9.7) 6.1 (4.5, 8.3) 5.1 (4.0, 7.0) 5.0 (4.0, 6.0) Median Tmax (hour) Urin. recovery ND 20.4 (14.3, 29.1) (% dose) a
Grp III (N ⴝ 12)
Grp IV (N ⴝ 17)
0.15
0.12
4.50
4.78
129 (96, 173)
117 (91, 150)
10.1 (7.8, 13.1) 5.1 (4.0, 6.2)
9.3 (7.5, 11.5) 6.0 (5.0, 6.1)
35.7 (28.2, 45.2) 26.7 (22.3, 32.1)
Adjusted to 1.0 mg/m2 body surface area
Key Words: Pharmacokinetics, Hypertension, Children
POSTERS: Antihypertensive Drugs
antagonist (CA) seems particularly rational on the basis of their mechanism of action. The aim of this study was to determine the antihypertensive effect produced by different combinations of various doses of the ACE-I delapril (D) and the dihydropyridine CA manidipine (M) in patients (pts) with mild to moderate HBP. The study was designed according to a 3x3 factorial design and carried out as a randomised, double-blind, placebo-controlled, multicentre trial. Overall study duration was 8 weeks: 2 of placebo run-in/wash-out, and 6 of active treatment during which 400 pts (231 males, 169 females; mean age 51.8 years) received placebo, D (15 or 30 mg o.i.d.), M (5 or 10 mg o.i.d.), or one of the 4 possible combinations of D and M. In the analysis of final values, all differences between the active treatment groups (grs) and the placebo group (gr) are statistically significant except, for systolic blood pressure (SBP), in the gr M5 and D15, and, for diastolic blood pressure (DBP), in the gr D15. The gr M5⫹D15 showed a significant reduction in SBP and DBP versus both grs treated with either drug alone, while the gr M10⫹D30 showed a reduction in DBP respect to either M10 or D30. In the analysis of the differences between final and baseline values, M5⫹D15 showed a significant difference in SBP and DBP versus both grs treated with either drug alone, while the gr M10⫹D30 showed a reduction in SBP versus the gr receiving D30 alone. Overall, the M10⫹D30 combination gave the best mean reduction in SBP and DBP and appeared to be the more potent of all tested combinations. The rate of pts responders (final-baseline change in DBPⱖ10mmHg) or normalised (DBPⱕ90mmHg) was higher in the grs M10⫹D30 (72.7%) and M5⫹D15 (68.9%) respect to placebo gr and the other grs receiving different combinations of drugs. The number of pts who had to be withdrawn from treatment due to adverse events was low (1%), with no differences among randomised treatment grs. In conclusion, the combination of D and M is more effective than single components and has an additive antihypertensive effect in the treatment of mild to moderate HBP. SBP and DBP are reduced in dose-related manner for each drug as monotherapy and for the two drugs in combination. The combination of M10 and D30 may represent a suitable therapeutic option in HBP, especially in pts not responders to single components. Key Words: Manidipine, Delapril, Combination Therapy
P-36 COMPARISON OF 3 SECOND LINE ANTIHYPERTENSIVE TREATMENT STRATEGIES IN ELDERLY PATIENTS WITH ESSENTIAL HYPERTENSION Roland Asmar, Hani Ghobrial, Laurent Vaur, Isabelle Dubroca. Cardiovascular institut, Paris, France; Aventis Laboratory, Paris, France. The aim of this study was to compare 3 different second line antihypertensive therapeutic strategies on seated systolic blood pressure (SeSBP) in elderly patients (⬎60 years) with mild to moderate essential hypertension with BP being not normalized after 6 weeks first line treatment with 200 mg celiprolol, a cardioselective beta 1 blocker agent. A total of 593 patients (270 males and 323 females), mean aged 69 years ⫾ 8, received celiprolol (200 mg OD) for 6 weeks. After this period, 251 patients (42%) showed persistent uncontrolled BP (SeSBP ⱖ 140 mmHg) and were randomized in 3 parallel groups to receive for an additional 6 weeks either higher dose of celiprolol 300 mg OD, increasing dose strategy (n⫽79), or 200 mg celiprolol ⫹ 12.5 mg hydrochlorothiazide(HCTZ) OD, combination strategy (n⫽85) or 80 mg valsartan OD, substitution strategy (n⫽87). The results showed that the difference in SeSBP reduction (main criterion) adjusted by baseline level was statistically significant between the 3 therapeutic strategies (p⫽0.024). The pairewise comparisons showed higher and more significant decrease of SeSBP with celiprolol 200 mg ⫹ HCTZ 12.5 mg OD (- 14.3 ⫾14.6 mmHg) than with 300 mg
AJH–April 2002–VOL. 15, NO. 4, PART 2
celiprolol OD (- 8.4 ⫾ 12 mmHg ) (p⫽0.007). Comparison of the SeSBP reduction between celiprolol 200 mg ⫹ HCTZ 12.5 mg OD and celiprolol 300 mg OD respectively versus valsartan 80 mg OD (- 10.7 ⫾ 13.9 mmHg) did not reach the statistical significance level. 14 patients (5.6%) were concerned by non serious adverse events (2 patients in the celiprolol 300 mg OD group, 6 patients in the celiprolol 200 mg ⫹ HCTZ 12.5 mg OD group and 4 patients in valsartan 80 mg OD group). In elderly hypertensive patients with BP being not normalized after a first line treatment by betablockers, increasing the dose of betablockers appears to be less effective on BP reduction than the combination with low dose of HCTZ; the combination therapy appears to be more efficient than substituting the betablocker by an angiotensin 2 receptor antagonist. Key Words: Essential Hypertension, Betablockers, Combination Therapy
P-37 LISINOPRIL (L) PHARMACOKINETICS (PK) IN HYPERTENSIVE CHILDREN AND INFANTS W. Shaw, R. Hogg, A. Delucchi, G. Sakihara, T. Wells, F. Tenney, D. Batisky, J. Blumer, B. Vogt, G. Murphy, M. Lo, E. Hand, D. Panebianco, R. Rippley, S. Shahinfar. Merck & Co., Inc., West Point, PA; Medical City Dallas Hospital, Dallas, TX; Luis Calvo Mackenna Hospital, Santiago, Chile; Instituto Nacional de Salud Nino, Lima, Peru; Arkansas Children’s Hospital, Little Rock, AR; LSU Medical Center, Shreveport, LA; Ped. Clinical Trials Int’l, Columbus, OH; Rainbow Babies and Children’s Hosp., Cleveland, OH. We evaluated the PK of L in 4 groups (Grp) of hypertensive infants & children (n⫽46): Grp I: 1 to 24 mos (mean 1.3 yrs); Grp II: 2 to 5 yrs (mean 3.6 yrs); Grp III: 6 to 11 yrs (mean 9.3 yrs); Grp IV: 12 to 15 yrs (mean 14.2 yrs). Grp I & II received oral L suspension (0.15 mg/kg/day). Grp III & IV received L tablets once daily: 2.5 mg if ⬍25 kg, 5 mg if ⱖ25 but ⬍45 kg, and 10 mg if ⱖ45 kg. Actual doses ranged from 0.07 to 0.19 mg/kg once daily. Geometric mean (95%C.I.) steady-state serum PK parameters for L, per RIA, were: There were no statistically significant differences between age groups for any PK parameter. Furthermore, results were comparable to historical observations in adults. There were no drug-related serious adverse experiences, and no pts discontinued due to adverse experiences. We conclude: (1) PK of L do not appear to be different in pediatric patients of different ages, (2) L can be administered in a suspension formulation to children and infants, (3) L was well-tolerated in hypertensive infants & children.
Grp I (N ⴝ 9)
Grp II (N ⴝ 8)
Mean dose 0.15 0.15 (mg/kg) 3.07 3.59 Mean dose (mg/m2) AUC0–24 hr 101 (72, 142) 84 (59, 120) (ng 䡠 hr/mL)a Cmax (ng/mL)a 7.2 (5.4, 9.7) 6.1 (4.5, 8.3) 5.1 (4.0, 7.0) 5.0 (4.0, 6.0) Median Tmax (hour) Urin. recovery ND 20.4 (14.3, 29.1) (% dose) a
Grp III (N ⴝ 12)
Grp IV (N ⴝ 17)
0.15
0.12
4.50
4.78
129 (96, 173)
117 (91, 150)
10.1 (7.8, 13.1) 5.1 (4.0, 6.2)
9.3 (7.5, 11.5) 6.0 (5.0, 6.1)
35.7 (28.2, 45.2) 26.7 (22.3, 32.1)
Adjusted to 1.0 mg/m2 body surface area
Key Words: Pharmacokinetics, Hypertension, Children