A search of the medical literature using MEDLINE and EMBASE (English-language articles only) was conducted using the keywords [olmesartan] AND [hydrochlorothiazide] AND [hypertension OR high blood pressure] AND [efficacy]. The full articles were retrieved and the results were then manually filtered to identify studies in which the efficacy of olmesartan/hydrochlorothiazide combination was evaluated in hypertensive patients, including “high-risk” patients subgroups, such as elderly and diabetic patients. Additional references were identified from the reference list of published articles. Searches were last updated on 31 December 2014.
Table 1 summarizes the study design, patients, interventions, and endpoints of the most relevant studies included in this review, in which blood pressure changes in patients treated with olmesartan medoxomil-based therapy were reported.
In some clinical studies, the efficacy of OM/HCTZ combination has been evaluated both in terms of reduction of office seated BP and 24-hour ambulatory monitoring (ABPM). In hypertensive patients, in fact, there is often a difference in efficacy outcomes when blood pressure reduction (obtained by treatment) is determined as office seated BP vs
24-hour ambulatory monitoring. For example, renal denervation has been shown to induce a marked reduction in office BP, which has been found to be sustained up to 3 years following the denervation procedure, but only limited reductions have been observed on 24-hour ambulatory BP [1
In a randomized, double-blind, factorial design multicenter study, conducted by Chrysant et al. [6
], the efficacy and safety of OM/HCTZ at various doses were evaluated vs
placebo and monotherapy with either OM or HCTZ. After an initial single-blind, 4-week, placebo run-in period, eligible patients were randomized to 8 weeks of double-blind treatment with placebo, OM monotherapy (at doses of 10, 20, or 40 mg/day), HCTZ monotherapy (at doses of 12.5 or 25 mg/day), or OM/HCTZ combination therapy including all possible combinations of doses used in the monotherapy groups. A total of 502 patients were randomized to one of the 12 treatment groups (35/47 patients per group). All OM/HCTZ combinations significantly reduced both seated diastolic blood pressure (SeDBP) and seated systolic blood pressure (SeSBP) compared with placebo, in a dose-dependent manner. The mean SeSBP and SeDBP reductions from baseline for OM/HCTZ ranged from -20.5/-16.0 mmHg to -28.3/-22.3 mmHg. Reductions from baseline in mean trough SeSBP/SeDBP were -3.3/-8.2 mmHg, -20.1/-16.4 mmHg, and -26.8/-21.9 mmHg with placebo, OM/HCTZ 20/12.5 mg, and OM/HCTZ 40/25 mg, respectively.
The greatest reduction in SeDBP, about -22 mmHg, was observed in the group treated with the combination of OM/HCTZ 40/25 mg/day. Evidence of efficacy for all active treatments was observed as early as after 1 week of treatment, and increased throughout the course of the study. When analyzing responder rates (defined as trough SeDBP <90 mmHg or ≥ 10 mmHg reduction in SeDBP), these were found to increase after switching from OM to OM/HCTZ, progressively increasing with up-titration of OM/HCTZ to OM/HCTZ 40/25 mg/day (92.3%) (Figure 1).
All doses of OM, either alone or in combination with HCTZ, were safe and well tolerated, and there were no significant or clinically relevant differences between different doses in the incidence of treatment-emergent adverse events (AEs) [7
]. The combination of OM/HCTZ has demonstrated blood pressure changes and responder rates comparable to, and in some cases significantly higher than, other antihypertensive combinations.
A comparative review of four similarly designed factorial studies investigating the relative efficacy of 8 weeks of olmesartan, irbesartan, telmisartan or valsartan, each with or without HCTZ, showed that the magnitude of reductions in BP [both in DBP (Figure 2) and SBP (Figure 3)] was greater with the combination OM/HTCZ 20/25 mg/day than with any other combination of ARB/HCTZ [3
Additional evidence for the efficacy of OM/HCTZ has been provided by a series of clinical studies included in a review by Punzi [8
]. The BENIFORCE study, a 12-week, randomized, double-blind, placebo-controlled trial, was conducted in 276 patients with stage 1 or stage 2 hypertension [9
]. After a run-in phase with placebo, patients were randomized to placebo (12 weeks) or to OM 20 mg/day (1-3 weeks). The OM-based treatment regimen was up-titrated in a stepwise fashion to OM 40 mg (4-6 week), OM/HCTZ 40/12.5 mg (7-9 weeks), and OM/HCTZ 40/25 mg (10-12 weeks) in patients whose BP remained >120/80 mmHg for each dosing interval.
The OM-based treatment regimen produced significantly greater reductions in mean seated BP (SeBP) from baseline compared with placebo (22.3/12.1 mmHg vs
0.1/-0.8, p<0.0001). The cumulative percentage of patients achieving the BP goal of <140/90 mmHg was significantly higher with the OM-based treatment regimen compared with placebo (74.1% vs
30.7%, p<0.0001) [10
]. In addition, a significantly greater percentage of patients treated with the OM-based regimen achieved BP normalization (<120/80 mmHg) compared with placebo (27.3% vs
1.5%; p<0.0001). Recently, a subgroup analysis of the BENIFORCE study indicated that the significant BP improvements achieved with OM/HCTZ treatment compared with placebo were independent of race, age, or sex [8
A European study investigated the safety and tolerability of OM/HCTZ in 1226 patients with stage 2 hypertension [12
]. Patients were initially treated with OM 40 mg/day during an 8-week open label phase. Patients who failed to achieve BP control (trough seated cuff SBP [SeSBP] of 140-180 mmHg and SeDBP of 90-115 mmHg, mean 24-hour DBP ≥ 80 mmHg and >30% of daytime DBP>85 mmHg) entered a randomized double-blind treatment phase of 8 weeks. In this phase, patients were randomized in a 2:2:2:1 scheme to OM 40 mg, OM/HCTZ 20/12.5 mg, OM/HCTZ 40/12.5 mg, and OM/HCTZ 40/25 mg. The primary endpoint was the change from baseline in SeDBP from week 8 to the end of week 16; with the highest dosage of OM/HCTZ (40/25 mg) the change in SeDBP was -11.2 mmHg compared with -5.7 mmHg in patients who remained on OM 40 mg monotherapy (p<0.0001). The change in SeSBP for the same time period was -16.2 mmHg for OM/HCTZ 40/25 mg compared with -8.9 mmHg for OM 40 mg (p<0.0001). The SeBP goal of <140/90 mmHg (<130/80 mmHg for patients with diabetes) was achieved by 42.1% of patients treated with OM/HCTZ 40/25 mg compared with 24.8% of those treated with OM 40 mg.