Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial

Background: Recent surveys reveal continuing deficiencies in the awareness, treatment, and control of hyper-tension. In many cases, failure to achieve blood pressure targets may be attributable to the use of antihypertensive monotherapy. Objectives: This study was undertaken to identify combinations of telmisart an, a new oral angiotensin II type I-receptor antagonist, and hydrochloroth iazide (HCTZ) that might provide greater antihypertensive efficacy than mon otherapy with either agent in the treatment of mild to moderate hypertensio n. It also examined the dose-response surface for the 2 drugs alone and in combination. Methods: This was a multicenter, randomized, double-blind, placebo-controll ed, parallel-group study that employed all cells of a 4 x 5 factorial desig n. After a 4-week, single-blind placebo run-in period, men and women betwee n 18 and 80 years of age with mild to moderate hypertension (defined as mea n supine diastolic blood pressure [DBP] between 95 and 114 mm Hg during the last 2 weeks of the placebo run-in period and systolic blood pressure [SBP ] between 114 and 200 mm HE immediately before randomization) were eligible to enter the 8-week, double-blind, double-dummy treatment period. Study co mparisons were between once-daily telmisartan monotherapy (20, 40, 80, or 1 60 mg), HCTZ monotherapy (6.25, 12.5, or 25 mg), 12 combinations of these t elmisartan/HCTZ doses, and placebo. The focus was on 2 combinations: telmis artan 30 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg. The primary ef ficacy variable was change in supine trough DBP from baseline to the last e valuable measurement during double-blind treatment. Plasma renin activity a nd safety parameters, including treatment-emergent adverse events, physical findings, electrocardiograms, and serum electrolyte levels (which are know n to increase with HCTZ treatment), were also assessed. Results: Of 1293 patients screened, 818 (63.3%) were enrolled at 47 centers . Of these 818, 749 (91.6%) completed the study. The intent-to-treat popula tion (randomized with greater than or equal to1 postrandomization blood pre ssure measurement) consisted of 807 patients (98.7%). Telmisartan 80 mg/HCT Z 12.5 mg significantly decreased mean supine trough SBP/DBP by 23.9/14.9 m m Hg, a benefit of 8.5/3.4 mm Hg compared with telmisartan 80 mg and of 17. 0/7.6 mm Hg compared with HCTZ 12.5 mg (both comparisons, P < 0.01). Telmis artan 40 mg/HCTZ 12.5 mg significantly reduced mean supine SEP by 18.8 mm H g, a benefit of 6.6 mm HE compared with telmisartan 40 mg and 11.9 mm Hg co mpared with HCTZ 12.5 mg (both, P < 0.01). This same combination significan tly reduced mean supine DBP by 12.6 mm Hg, a benefit of 5.3 mm Hg compared with HCTZ 12.5 mg (P < 0.01), but was not significantly different from telm isartan 40 mg. Telmisartan 80 mg/HCTZ 12.5 mg was significantly more effect ive than telmisartan 40 mg/HCTZ 12.5 mg in reducing mean supine DBP and SEP (both, P < 0.05). The response surface and responder analyses confirmed th e additive antihypertensive efficacy of the combination of telmisartan and HCTZ. All regimens were well tolerated. Conclusions: Once-daily telmisartan 80 mg/HCTZ 12.5 mg was effective and we ll tolerated when used to reduce SEP and DBP in patients with mild to moder ate hypertension. In addition to enhancing efficacy, this combination prote cted against potassium depletion, a common side effect of thiazide monother apy.