Dose-Related Antihypertensive Effects of Irbesartan in Patients With Mild-to-Moderate Hypertension

• Published in: American journal of hypertension 1998-04, Vol.11 (4), p.462-470
• Main Authors: Pool, James L., Guthrie, Robert M., Littlejohn, Thomas W., Raskin, Philip, Shephard, Alexander M.M., Weber, Michael A., Weir, Matthew R., Wilson, Thomas W., Wright, James, Kassler-Taub, Kenneth B., Reeves, Richard A.
• Format: Article
• Language: English
• Subjects: Aged; angiotensin II receptor antagonist; Antihypertensive agents; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - adverse effects; Antihypertensive Agents - therapeutic use; Biological and medical sciences; Biphenyl Compounds - administration & dosage; Biphenyl Compounds - adverse effects; Biphenyl Compounds - therapeutic use; Blood Pressure - drug effects; Cardiovascular system; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; drug withdrawal; Female; Humans; Hydrochlorothiazide - administration & dosage; Hydrochlorothiazide - therapeutic use; hypertension; Hypertension - drug therapy; Hypertension - physiopathology; Irbesartan; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; plasma renin activity; Sodium Chloride Symporter Inhibitors - administration & dosage; Sodium Chloride Symporter Inhibitors - therapeutic use; Tetrazoles - administration & dosage; Tetrazoles - adverse effects; Tetrazoles - therapeutic use; Time Factors; Treatment Outcome
• ISSN: 0895-7061; 1879-1905; 1941-7225
• DOI: 10.1016/S0895-7061(97)00501-3

Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT 1 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 ≥ 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 AT 1 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.