Dose-Response Characteristics of Olmesartan Medoxomil and Other Angiotensin Receptor Antagonists

Abstract

Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are an effective initial antihypertensive monotherapy in many patients. However, when initial ARB monotherapy fails to achieve the recommended BP goal, there is some controversy as to whether dose uptitration or the addition of a diuretic is more appropriate. This article addresses this issue by reviewing the dose-response characteristics of olmesartan medoxomil and other ARBs, as well as the relationship between ARB uptitration and BP goal attainment.

Two types of trial designs are used to assess dose response: dose-ranging studies (usually a parallel design using different doses across different patient groups), which are used to establish the optimal dose for US FDA registration purposes, and dose-titration studies (increased dosing within the same patients and treating to goal BP). Since dose titration is within the same patient, it may be considered more appropriate for demonstrating dose-response characteristics and demonstration of BP goal attainment. While results from dose-ranging studies suggest that the dose-response curve for some ARBs may be flat, dose-titration studies indicate that significant improvements in BP control and BP goal attainment can be achieved with ARB uptitration.

In an integrated analysis of seven US and European randomized, placebo-controlled, dose-ranging trials involving 3055 patients with stage 2 hypertension treated with olmesartan medoxomil 2.5–80 mg/day or placebo for 8 weeks, all olmesartan medoxomil doses were significantly more effective than placebo in lowering the mean DBP and mean SBP (p ↓0.001); notably, optimal BP-lowering efficacy was observed at higher dosages. In fact, the 20 mg/day (recommended starting dose) and 40 mg/day (maximum approved dose) dosages were significantly (p ↓0.001) more effective in lowering mean BP than the 5 mg/day dosage (optional starting dose in volume-depleted patients), and the 40 mg/day dosage was significantly (p <0.01) more effective than the 20 mg/day dosage. The BP decreases observed with the uptitration of olmesartan medoxomil from 20 to 40 mg/day doses resulted in substantial additional mean BP reductions from baseline. Such BP reductions have been shown to translate into a clinically relevant increase in the number of patients who achieve BP goal.

In conventional clinical studies, the shallow dose-response findings often attributed to ARBs may be an artifact resulting from the inclusion of both treatment responders and nonresponders within each dose group. However, this may not accurately reflect the results that are actually obtained in clinical practice. The efficacy of certain ARBs, such as olmesartan medoxomil, is dose-dependent, with greater reductions being attained at higher doses; higher BP goal attainment rates are achieved with the higher doses. Thus, ARB monotherapy, with appropriate uptitration as needed, is an excellent initial treatment option for patients with hypertension.