Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension.
Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT1 subtype) antagonist irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan were also assessed. After a placebo lead-in phase, all patients were randomized to 8 weeks of double-blind therapy with either placebo (n = 158) or irbesartan at doses of 1, 5, 10, 25, 50, 100, 200, or 300 mg (n = 731 total) orally once daily. Irbesartan reduced blood pressure in a dose-related manner. Reductions from baseline in trough seated diastolic blood pressure ranged from 7.5 mm Hg for 50 mg irbesartan to 11.6 mm Hg for 300 mg irbesartan. At week 8, statistically significant reductions over placebo were observed in trough seated blood pressure with all irbesartan doses > or = 50 mg. These reductions reached statistical significance versus placebo within 2 weeks with 100, 200, and 300 mg irbesartan. Plasma irbesartan concentrations correlated with dose. Angiotensin II and aldosterone levels generally showed dose-related changes, consistent with AT1 receptor blockade. In patients not controlled at 8 weeks, the addition of 12.5 mg HCTZ resulted in further dose-related reductions in blood pressure. Irbesartan demonstrated a placebo-like safety profile and no dose-related toxicity. Irbesartan, administered alone or in combination with HCTZ, was well tolerated. Withdrawal of irbesartan did not result in rebound hypertension or adverse events. Thus, once-daily irbesartan is both an effective and safe antihypertensive agent for the treatment of mild-to-moderate hypertension.
Pool
J L
JL
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. jpool@bcm.tmc.edu
Guthrie
R M
RM
Littlejohn
T W
TW
Raskin
P
P
Shephard
A M
AM
Weber
M A
MA
Weir
M R
MR
Wilson
T W
TW
Wright
J
J
Kassler-Taub
K B
KB
Reeves
R A
RA
D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D000077405:Irbesartan; D008297:Male; D008875:Middle Aged; D049993:Sodium Chloride Symporter Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000077405:Irbesartan