Abstract

Background:

Most patients with hypertension require more than one agent to control blood pressure (BP). The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide (HCTZ).

Methods:

This was a randomized, double-blind, factorial design study. After a placebo run-in period, eligible patients (n = 502) with a baseline mean seated diastolic blood pressure (SeDBP) of 100 to 115 mm Hg were randomized to one of 12 groups: placebo, olmesartan medoxomil monotherapy (10, 20, or 40 mg/day, HCTZ monotherapy (12.5 or 25 mg/day), or one of six groups of olmesartan medoxomil/HCTZ combination therapy. The primary endpoint was the change in mean trough SeDBP from baseline at week 8. Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses, but did not compare BP reductions with different combination doses.

Results:

Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure (SeSBP) at week 8 than did monotherapy with either component. All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner. Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg, 20.1/16.4 mm Hg, and 26.8/21.9 mm Hg with placebo, olmesartan medoxomil/HCTZ 20/12.5 mg, and olmesartan medoxomil/HCTZ 40/25 mg, respectively. All treatments were well tolerated.

Conclusions:

Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated.

With only up to 34% of Americans with hypertension achieving a goal blood pressure (BP) of <140/90 mm Hg, more aggressive and multifaceted modes of therapy are required.1–3 Major studies have shown that most patients with hypertension need two or more antihypertensive drugs to achieve BP control.4–7 Substantial evidence supports the efficacy of angiotensin II blockade using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) to lower BP and to protect the heart and kidneys.8–16 Based on these data, the American Diabetes Association recommends the use of ACE inhibitors as first-line therapy for hypertensive patients with type 1 diabetic renal disease, and ARB for those with type 2 diabetes and renal disease.17

Placebo-controlled clinical trials have shown that the BP-lowering efficacy of olmesartan medoxomil monotherapy, a long-acting, once-daily ARB, at its starting dosage (20 mg/day) and maximal dosage (40 mg/day) compares favorably with that of other antihypertensive agents such as atenolol, captopril, felodipine, and amlodipine besylate, as well as other ARBs, in clinical efficacy trials.18–22

Hydrochlorothiazide (HCTZ) is a thiazide diuretic that is commonly used in combination with other antihypertensive agents, including ARBs.23,24 Hydrochlorothiazide is known to activate the renin-angiotensin-aldosterone system (RAAS), providing a strong rationale for the combination of an ARB with HCTZ.25–29 The objective of this factorial design study was to assess the efficacy and safety of olmesartan medoxomil in combination with HCTZ at various dosages compared with monotherapy with each drug and with placebo.

Methods

Study population

This was a randomized, double-blind, factorial design study conducted at 48 investigational sites in the United States. Eligibility criteria for randomization included the following: average SeDBP ≥100 and ≤115 mm Hg at both week 3 and week 4 placebo run-in visits, with at least 4 days between the two visits; a difference of ≤7 mm Hg between the two SeDBP measurements; and at least 80% compliance with the study drug regimen during the placebo run-in period. Patients with serious medical disorders, and those with a body weight ≥50% of ideal body weight for height and frame size (calculated according to the 1983 Metropolitan Life Insurance table), were excluded. The protocol and one amendment were reviewed and approved by either a central or local institutional review board at each of the investigational sites. The study was conducted in accordance with institutional review board committee and informed consent regulations of 21 Code of Federal Regulations parts 50 and 56, and principles of the Declaration of Helsinki and its amendments. Written informed consent was obtained from each study participant at the screening visit.

Study design

After an initial single-blind, 4-week, placebo run-in period, eligible patients (n = 502) were randomized to one of 12 treatment groups for 8 weeks of double-blind treatment with placebo, olmesartan medoxomil monotherapy (at doses of 10, 20, or 40 mg/day), HCTZ monotherapy (at doses of 12.5 or 25 mg/day), or olmesartan medoxomil/HCTZ combination therapy (including all possible combinations of doses used in the monotherapy groups). The factorial design was used to assess the efficacy and safety of olmesartan medoxomil in combination with HCTZ across a range of doses for each therapy. Patients were evaluated for therapeutic efficacy and safety on day 1 and at weeks 1, 4, and 8. Patients were instructed to take their study medication once daily in the morning with breakfast. On the day of a scheduled visit, they were instructed not to take their dose of study medication until after BP measurements were recorded and all tests were performed.

Body weight was measured at screening and at day 1. Blood pressure and heart rate were measured before the daily dose of study medication was taken on day 1 and at weeks 1, 4, and 8 (all BP measurements were to be obtained before 12 noon on the day of the scheduled study visit, and within 20 to 28 h after the previous dose of study medication). Duplicate readings were taken of seated and standing cuff BP at trough; the average of the two seated BP and the two standing BP measurements were used as the seated and standing readings, respectively, for the visit.

Safety was monitored by assessing the occurrence of adverse events (AEs) at every visit and by performing clinical laboratory tests (ie, hematology, blood chemistry, and urinalysis). All patients who were randomly assigned to study drug treatment and received at least one dose of randomized study drug were included in the safety analysis.

Efficacy variables

The primary efficacy variable was the change from baseline in mean trough SeDBP at week 8, using the last observation carried forward (LOCF) for patients who did not complete the protocol. Secondary efficacy variables included the change from baseline in mean seated systolic blood pressure (SeSBP) at week 8 and in mean standing diastolic blood pressure (StDBP) and systolic blood pressure (StSBP) at week 8, and responder rates, defined as an SeDBP <90 mm Hg or a ≥10 mm Hg reduction in SeDBP at week 8.

Statistical analysis

The sample size was calculated for a two-sided significance level of .05, based on the primary efficacy variable (change from baseline in mean SeDBP at week 8), to achieve 90% power for the AVE procedure proposed by Hung and colleagues.30

Baseline and demographic characteristics were presented for each treatment group. Categorical demographic variables were summarized as percentages and compared between treatments using a χ2 test. Continuous variables including baseline vital signs, age, height, weight, and duration of hypertension history were compared using one-way analysis of variance with treatment as a factor.

Criteria for antihypertensive efficacy included the following: 1) determination of whether at least one combination dose produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses; 2) evaluation of which combinations were more effective in reducing BP compared with the respective placebo treatments; and 3) determination of the responder rate, defined as SeDBP <90 mm Hg or a decrease in SeDBP from baseline of ≥10 mm Hg. Changes in BP and heart rate from baseline to week 8 were compared within each dose combination group by paired t test.

The hypothesis to be tested was that none of the dose combinations were more effective than the associated component doses. The first step of the efficacy evaluation was the AVE test,30 a test procedure based on the average of the maximum differences in response (change from baseline in SeDBP at week 8) of each combination and their corresponding components. This test was used to determine whether at least one combination existed that was more efficacious than its corresponding components. Once this was confirmed, a quadratic dose-response model was fitted to calculate the predicted dose response. A 95% CI was calculated for the treatment effect of each of the 12 groups to identify which combination was better than its individual components. Based on the fitted model, a response surface graph was generated to facilitate visual inspection of the treatment effects. Statistical analyses comparing the BP reductions obtained with different combination doses were not performed.

Safety and tolerability were assessed through the recording of clinical AEs and evaluation of clinical laboratory parameters. Summary statistics, patient listings, or both were provided for each treatment group for all safety parameters. Reasons for early withdrawal from the study were tabulated for each treatment group.

Results

A total of 863 patients were screened; of these, 750 were found eligible for enrollment, 502 were randomized, and 451 completed the study. Of the 502 patients who were randomly assigned to one of 12 treatment groups (35 to 47 patients per group), 55.6% were male and 74.1% were of white ethnicity. Mean age was 53 years, and mean baseline SeDBP and SeSBP in the 12 treatment groups ranged from 102.6 to 104.4 mm Hg and from 151.9 to 156.6 mm Hg, respectively. There were no statistically significant differences in baseline characteristics among the 12 treatment groups (Tables 1 and 2).

Table 1

Baseline patient demographics (all randomized)

 Olmesartan Medoxomil Dosage 
 0 mg/day 10 mg/day 20 mg/day 40 mg/day 
HCTZ dosage     
 0 mg/day     
  n 42 39 41 45 
  Mean age (y) 54.0 49.9 54.1 54.4 
  SD (y) 9.9 10.9 9.9 11.2 
  Ethnicity 34 (81.0%) 30 (76.9%) 28 (68.3%) 34 (75.6%) 
   White 3 (7.1%) 4 (10.3%) 8 (19.5%) 4 (8.9%) 
 5 (11.9%) 4 (10.3%) 3 (7.3%) 6 (13.3%) 
   African American 0 (0%) 1 (2.6%) 2 (4.9%) 1 (2.2%) 
 0 (0%) 0 (0%) 0 (0%) 0 (0%) 
   Hispanic     
   Asian     
   Other     
  Sex     
   Male 27 (64.3%) 24 (61.5%) 21 (51.2%) 28 (62.2%) 
   Female 15 (35.7%) 15 (38.5%) 20 (48.8%) 17 (37.8%) 
  Antihypertensive therapy     
   Yes 31 (73.8%) 29 (74.4%) 34 (82.9%) 32 (71.1%) 
   No 11 (26.2%) 10 (25.6%) 7 (17.1%) 13 (28.9%) 
 12.5 mg/day     
  n 45 35 44 42 
  Mean age (y) 54.1 52.4 52.3 52.0 
  SD (y) 10.8 10.7 10.2 10.5 
  Race:     
   White 36 (80.0%) 27 (77.1%) 32 (72.7%) 28 (66.7%) 
   African American 4 (8.9%) 2 (5.7%) 4 (9.1%) 6 (14.3%) 
   Hispanic 4 (8.9%) 4 (11.4%) 4 (9.1%) 6 (14.3%) 
   Asian 1 (2.2%) 2 (5.7%) 1 (2.3%) 1 (2.4%) 
   Other 0 (0%) 0 (0%) 3 (6.8%) 1 (2.4%) 
  Sex     
   Male 25 (55.6%) 18 (51.4%) 29 (65.9%) 21 (50.0%) 
   Female 20 (44.4%) 17 (48.6%) 15 (34.1%) 21 (50.0%) 
  Antihypertensive therapy     
   Yes 36 (80.0%) 27 (77.1%) 35 (79.5%) 31 (73.8%) 
   No 9 (20.0%) 8 (22.9%) 9 (20.5%) 11 (26.2%) 
 25 mg/day     
  n 43 39 47 40 
  Mean age (y) 54.7 54.4 51.6 51.7 
  SD (y) 10.5 11.7 14.0 11.6 
  Ethnicity     
   White 25 (58.1%) 32 (82.1%) 34 (72.3%) 32 (80.0%) 
   African American 12 (27.9%) 4 (10.3%) 6 (12.8%) 4 (10.0%) 
   Hispanic 5 (11.6%) 3 (7.7%) 4 (8.5%) 3 (7.5%) 
   Asian 0 (0%) 0 (0%) 2 (4.3%) 1 (2.5%) 
   Other 1 (2.3%) 0 (0%) 1 (2.1%) 0 (0%) 
  Sex     
   Male 21 (48.8%) 19 (48.7%) 26 (55.3%) 20 (50.0%) 
   Female 22 (51.2%) 20 (51.3%) 21 (44.7%) 20 (50.0%) 
  Antihypertensive therapy     
   Yes 32 (74.4%) 31 (79.5%) 37 (78.7%) 33 (82.5%) 
   No 11 (25.6%) 8 (20.5%) 10 (21.3%) 7 (17.5%) 
 Olmesartan Medoxomil Dosage 
 0 mg/day 10 mg/day 20 mg/day 40 mg/day 
HCTZ dosage     
 0 mg/day     
  n 42 39 41 45 
  Mean age (y) 54.0 49.9 54.1 54.4 
  SD (y) 9.9 10.9 9.9 11.2 
  Ethnicity 34 (81.0%) 30 (76.9%) 28 (68.3%) 34 (75.6%) 
   White 3 (7.1%) 4 (10.3%) 8 (19.5%) 4 (8.9%) 
 5 (11.9%) 4 (10.3%) 3 (7.3%) 6 (13.3%) 
   African American 0 (0%) 1 (2.6%) 2 (4.9%) 1 (2.2%) 
 0 (0%) 0 (0%) 0 (0%) 0 (0%) 
   Hispanic     
   Asian     
   Other     
  Sex     
   Male 27 (64.3%) 24 (61.5%) 21 (51.2%) 28 (62.2%) 
   Female 15 (35.7%) 15 (38.5%) 20 (48.8%) 17 (37.8%) 
  Antihypertensive therapy     
   Yes 31 (73.8%) 29 (74.4%) 34 (82.9%) 32 (71.1%) 
   No 11 (26.2%) 10 (25.6%) 7 (17.1%) 13 (28.9%) 
 12.5 mg/day     
  n 45 35 44 42 
  Mean age (y) 54.1 52.4 52.3 52.0 
  SD (y) 10.8 10.7 10.2 10.5 
  Race:     
   White 36 (80.0%) 27 (77.1%) 32 (72.7%) 28 (66.7%) 
   African American 4 (8.9%) 2 (5.7%) 4 (9.1%) 6 (14.3%) 
   Hispanic 4 (8.9%) 4 (11.4%) 4 (9.1%) 6 (14.3%) 
   Asian 1 (2.2%) 2 (5.7%) 1 (2.3%) 1 (2.4%) 
   Other 0 (0%) 0 (0%) 3 (6.8%) 1 (2.4%) 
  Sex     
   Male 25 (55.6%) 18 (51.4%) 29 (65.9%) 21 (50.0%) 
   Female 20 (44.4%) 17 (48.6%) 15 (34.1%) 21 (50.0%) 
  Antihypertensive therapy     
   Yes 36 (80.0%) 27 (77.1%) 35 (79.5%) 31 (73.8%) 
   No 9 (20.0%) 8 (22.9%) 9 (20.5%) 11 (26.2%) 
 25 mg/day     
  n 43 39 47 40 
  Mean age (y) 54.7 54.4 51.6 51.7 
  SD (y) 10.5 11.7 14.0 11.6 
  Ethnicity     
   White 25 (58.1%) 32 (82.1%) 34 (72.3%) 32 (80.0%) 
   African American 12 (27.9%) 4 (10.3%) 6 (12.8%) 4 (10.0%) 
   Hispanic 5 (11.6%) 3 (7.7%) 4 (8.5%) 3 (7.5%) 
   Asian 0 (0%) 0 (0%) 2 (4.3%) 1 (2.5%) 
   Other 1 (2.3%) 0 (0%) 1 (2.1%) 0 (0%) 
  Sex     
   Male 21 (48.8%) 19 (48.7%) 26 (55.3%) 20 (50.0%) 
   Female 22 (51.2%) 20 (51.3%) 21 (44.7%) 20 (50.0%) 
  Antihypertensive therapy     
   Yes 32 (74.4%) 31 (79.5%) 37 (78.7%) 33 (82.5%) 
   No 11 (25.6%) 8 (20.5%) 10 (21.3%) 7 (17.5%) 

HCTZ = hydrochlorothiazide

Table 2

Mean SeSBP and SeDBP at baseline and at week 8 LOCF (intent-to-treat population)

 SeSBP/SeDBP mm Hg (n
 Olmesartan Medoxomil Dosage 
 0 mg/day 10 mg/day 20 mg/day 40 mg/day 
HCTZ dosage     
 0 mg/day     
  n 42 39 41 45 
  Baseline 152.1/103.4 153.6/104.1 154.6/103.2 152.9/102.6 
  Week 8 148.7/95.7 143.2/91.0 139.4/90.5 136.5/88.1 
 12.5 mg/day     
  n 45 35 44 42 
  Baseline 153.4/103.0 156.6/104.0 152.3/103.1 151.9/103.5 
  Week 8 145.2/93.9 136.3/88.7 131.4/87.6 132.6/85.6 
 25 mg/day     
  n 43 39 46 39 
  Baseline 155.9/104.4 153.7/103.8 154.7/103.8 153.6/103.4 
  Week 8 138.3/91.5 131.0/85.5 129.0/84.9 125.7/81.5 
 SeSBP/SeDBP mm Hg (n
 Olmesartan Medoxomil Dosage 
 0 mg/day 10 mg/day 20 mg/day 40 mg/day 
HCTZ dosage     
 0 mg/day     
  n 42 39 41 45 
  Baseline 152.1/103.4 153.6/104.1 154.6/103.2 152.9/102.6 
  Week 8 148.7/95.7 143.2/91.0 139.4/90.5 136.5/88.1 
 12.5 mg/day     
  n 45 35 44 42 
  Baseline 153.4/103.0 156.6/104.0 152.3/103.1 151.9/103.5 
  Week 8 145.2/93.9 136.3/88.7 131.4/87.6 132.6/85.6 
 25 mg/day     
  n 43 39 46 39 
  Baseline 155.9/104.4 153.7/103.8 154.7/103.8 153.6/103.4 
  Week 8 138.3/91.5 131.0/85.5 129.0/84.9 125.7/81.5 

HCTZ = hydrochlorothiazide; LOCF = last observation carried forward; SeDBP = seated diastolic blood pressure; SeSBP = seated systolic blood pressure.

Changes in trough seated and standing blood pressure

The raw mean SeSBP and SeDBP reductions from baseline for olmesartan medoxomil combined with HCTZ ranged from −20.5/−16.0 mm Hg to −28.3/−22.3 mm Hg. The AVE test was used to confirm the existence of at least one combination that was superior to its components. The P value corresponding to the AVE test for the week 8 SeDBP (P < .01) was smaller than the .05 critical value. Thus, at least one dose combination was more effective than its components in lowering SeDBP from baseline to week 8. Dose-related reductions in SeDBP at week 8, fitted by the quadratic model, were observed with increasing doses of olmesartan medoxomil monotherapy, HCTZ monotherapy, and olmesartan medoxomil/HCTZ combination therapy. All six olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP compared with placebo (there was no overlap in the 95% CI computed from the quadratic model for each of the olmesartan medoxomil/HCTZ combination therapies and the 95% CI for placebo, ie, 0 mg olmesartan medoxomil/0 mg HCTZ; Fig. 1 and Table 2). The greatest reduction in SeDBP (∼22 mm Hg) occurred with the combination of olmesartan medoxomil/HCTZ 40/25 mg/day. Evidence of efficacy for all active treatments was observed as early as week 1 and increased throughout the course of the study.

Reduction (model fitted) in seated diastolic blood pressure (SeDBP) for 12 groups in the factorial design by olmesartan medoxomil and hydrochlorothiazide (HCTZ) dosage. All active combination therapies resulted in significantly superior reductions in SeDBP versus placebo. The 95% CIs (in mm Hg) are as follows: (−10.3, −6.0) for placebo/placebo; (−13.0, −9.6) for olmesartan medoxomil 10 mg/placebo; (−15.5, −12.1) for olmesartan medoxomil 20 mg/placebo; (−16.8, −12.3) for olmesartan medoxomil 40 mg/placebo; (−12.0, −8.4) for placebo/HCTZ 12.5 mg; (−15.2, −11.9) for olmesartan medoxomil 10 mg/HCTZ 12.5 mg; (−8.1, −14.7) for olmesartan medoxomil 20 mg/HCTZ 12.5 mg; (−19.3, −15.4) for olmesartan medoxomil 40 mg/HCTZ 12.5 mg; (−15.1, −10.7) for placebo/HCTZ 25 mg; (−18.8, −15.5) for olmesartan medoxomil 10 mg/HCTZ 25 mg; (−21.7, −18.2) for olmesartan medoxomil 20 mg/HCTZ 25 mg; (−24.3, −19.5) for olmesartan medoxomil 40 mg/HCTZ 25 mg.

The AVE test confirmed that at least one combination treatment produced significantly larger reductions in SeSBP than either component from baseline to week 8 (P < .01). All six olmesartan medoxomil/HCTZ combinations resulted in statistically significant reductions in SeSBP, compared with placebo, with a dose-response related to both drug components (Fig. 2 and Table 2). Model fitted mean reductions in StDBP and StSBP followed patterns similar to those observed for seated BP (Table 3).

Table 3

Change from baseline (model fitted) in mean trough StSBP/StDBP (mm Hg) at week 8 LOCF

 Placebo Olmesartan Medoxomil10 mg/day Olmesartan Medoxomil20 mg/day Olmesartan Medoxomil40 mg/day 
Placebo     
 Change in StSBP/StDBP −5.0/−6.3 −11.0/−9.8 −14.3/−11.8 −14.7/−12.0 
 95% CI (StSBP) (−8.5, −1.5) (−13.6, −8.4) (−17.0, −11.6) (−18.3, −11.1) 
 95% CI (StDBP) (−8.5, −4.2) (−11.5, −8.1) (−13.6, −10.1) (−14.3, −9.8) 
HCTZ 12.5 mg/day     
 Change in StSBP/StDBP (mm Hg) −10.3/−8.8 −16.8/−12.7 −19.6/−15.2 −21.4/−16.4 
 95% CI (StSBP) (−13.2, −7.3) (−19.4, −14.2) (−22.5, −16.7) (−24.5, −18.3) 
 95% CI (StDBP) (−10.7, −6.9) (−14.3, −11.1) (−17.0, −13.4) (−18.4, −14.5) 
HCTZ 25 mg/day     
 Change in StSBP/StDBP (mm Hg) −15.4/−10.3 −20.8/−14.5 −25.4/−17.4 −27.7/−19.7 
 95% CI (StSBP) (−18.8, −12.0) (−23.4, −18.3) (−28.2, −22.6) (−31.5, −23.9) 
 95% CI (StDBP) (−12.5, −8.1) (−16.1, −12.9) (−19.2, −15.7) (−22.1, −17.2) 
 Placebo Olmesartan Medoxomil10 mg/day Olmesartan Medoxomil20 mg/day Olmesartan Medoxomil40 mg/day 
Placebo     
 Change in StSBP/StDBP −5.0/−6.3 −11.0/−9.8 −14.3/−11.8 −14.7/−12.0 
 95% CI (StSBP) (−8.5, −1.5) (−13.6, −8.4) (−17.0, −11.6) (−18.3, −11.1) 
 95% CI (StDBP) (−8.5, −4.2) (−11.5, −8.1) (−13.6, −10.1) (−14.3, −9.8) 
HCTZ 12.5 mg/day     
 Change in StSBP/StDBP (mm Hg) −10.3/−8.8 −16.8/−12.7 −19.6/−15.2 −21.4/−16.4 
 95% CI (StSBP) (−13.2, −7.3) (−19.4, −14.2) (−22.5, −16.7) (−24.5, −18.3) 
 95% CI (StDBP) (−10.7, −6.9) (−14.3, −11.1) (−17.0, −13.4) (−18.4, −14.5) 
HCTZ 25 mg/day     
 Change in StSBP/StDBP (mm Hg) −15.4/−10.3 −20.8/−14.5 −25.4/−17.4 −27.7/−19.7 
 95% CI (StSBP) (−18.8, −12.0) (−23.4, −18.3) (−28.2, −22.6) (−31.5, −23.9) 
 95% CI (StDBP) (−12.5, −8.1) (−16.1, −12.9) (−19.2, −15.7) (−22.1, −17.2) 

Abbreviations as in Table 2.

Reduction (model fitted) in seated systolic blood pressure (SeSBP) for 12 groups in the factorial design by olmesartan medoxomil and hydrochlorothiazide (HCTZ) dosage. All active combination therapies resulted in significantly superior reductions in SeSBP versus placebo. The 95% CIs (in mm Hg) were as follows: (−6.8, −0.3) for placebo/placebo; (−3.4, −8.1) for olmesartan medoxomil 10 mg/placebo; (−18.3, −12.7) for olmesartan medoxomil 20 mg/placebo; (−19.7, −12.2) for olmesartan medoxomil 40 mg/placebo; (−12.7, −6.6) for placebo/HCTZ 12.5 mg; (−20.1, −14.7) for olmesartan medoxomil 10 mg/HCTZ 12.5 mg; (−23.0, −17.1) for olmesartan medoxomil 20 mg/HCTZ 12.5 mg; (−23.8, −17.4) for olmesartan medoxomil 40 mg/HCTZ 12.5 mg; (−20.6, −13.6) for placebo/HCTZ 25 mg; (−25.6, −20.3) for olmesartan medoxomil 10 mg/HCTZ 25 mg; (−30.0, −24.2) for olmesartan medoxomil 20 mg/HCTZ 25 mg; (−30.8, −22.8) for olmesartan medoxomil 40 mg/HCTZ 25 mg.

Responder and control rates

The proportion of patients with BP response (trough SeDBP <90 mm Hg, or a reduction from baseline ≥10 mm Hg) for each of the 12 treatment groups at week 8 LOCF is shown in Table 4. The highest responder rate was observed in the group assigned to olmesartan medoxomil/HCTZ 40/25 mg/day. The proportion of patients with diastolic control (trough SeDBP <90 mm Hg) and systolic control (trough SeSBP <140 mm Hg) at week 8 LOCF is also shown in Table 4. Although statistical analyses comparing the responder and control rates of different combinations were not performed, the highest rates were observed in the olmesartan medoxomil/HCTZ 40/25 mg/day group.

Table 4

Responder* and control rates for 12 groups at Week 8 LOCF

 Rate % (n/N) 
 Placebo Olmesartan Medoxomil 10 mg/day Olmesartan Medoxomil 20 mg/day Olmesartan Medoxomil 40 mg/day 
Placebo     
 Responder rate 38.1 (16/42) 66.7 (26/39) 68.3 (28/41) 68.9 (31/45) 
 Diastolic control rate 21.4 (9/42) 41.0 (16/39) 53.7 (22/41) 51.1 (23/45) 
 Systolic control rate 33.3 (14/42) 35.9 (14/39) 46.3 (19/41) 60.0 (27/45) 
HCTZ 12.5 mg/day     
 Responder rate 57.8 (26/45) 77.1 (27/35) 78.6 (33/42) 81.0 (34/42) 
 Diastolic control rate 35.6 (16/45) 57.1 (20/35) 64.3 (27/42) 73.8 (31/42) 
 Systolic control rate 37.8 (17/45) 60.0 (21/35) 73.8 (31/42) 61.9 (26/42) 
HCTZ 25 mg/day     
 Responder rate 65.1 (28/43) 89.5 (34/38) 89.1 (41/46) 92.3 (36/39) 
 Diastolic control rate 37.2 (16/43) 76.3 (29/38) 67.4 (31/46) 79.5 (31/39) 
 Systolic control rate 67.4 (29/43) 78.9 (30/38) 73.9 (34/46) 87.2 (34/39) 
 Rate % (n/N) 
 Placebo Olmesartan Medoxomil 10 mg/day Olmesartan Medoxomil 20 mg/day Olmesartan Medoxomil 40 mg/day 
Placebo     
 Responder rate 38.1 (16/42) 66.7 (26/39) 68.3 (28/41) 68.9 (31/45) 
 Diastolic control rate 21.4 (9/42) 41.0 (16/39) 53.7 (22/41) 51.1 (23/45) 
 Systolic control rate 33.3 (14/42) 35.9 (14/39) 46.3 (19/41) 60.0 (27/45) 
HCTZ 12.5 mg/day     
 Responder rate 57.8 (26/45) 77.1 (27/35) 78.6 (33/42) 81.0 (34/42) 
 Diastolic control rate 35.6 (16/45) 57.1 (20/35) 64.3 (27/42) 73.8 (31/42) 
 Systolic control rate 37.8 (17/45) 60.0 (21/35) 73.8 (31/42) 61.9 (26/42) 
HCTZ 25 mg/day     
 Responder rate 65.1 (28/43) 89.5 (34/38) 89.1 (41/46) 92.3 (36/39) 
 Diastolic control rate 37.2 (16/43) 76.3 (29/38) 67.4 (31/46) 79.5 (31/39) 
 Systolic control rate 67.4 (29/43) 78.9 (30/38) 73.9 (34/46) 87.2 (34/39) 
*

Trough seated diastolic blood pressure <90 mm Hg, or a reduction from baseline ≥10 mm Hg.

Diastolic control = trough seated diastolic blood pressure <90 mm Hg; systolic control = trough seated systolic blood pressure <140 mm Hg.

Abbreviations as in Table 2.

Safety

All dosages of olmesartan medoxomil monotherapy and combination therapy with HCTZ were safe and well tolerated, with no significant or clinically relevant differences in the incidence of treatment-emergent AEs noted by dosage. The percentage of patients who experienced at least one treatment-emergent AE was 57.1% in the placebo group, 51.1% in the HCTZ monotherapy groups, 49.6% in the olmesartan medoxomil monotherapy groups, and 57.1% in the olmesartan medoxomil/HCTZ groups. Most AEs were judged to be remotely or definitely not drug related, and mild or moderate in intensity. Only one patient, who received placebo, experienced a serious AE (unstable angina).

The overall discontinuation rate due to AEs of patients who received one or both of the active study drugs was low (2.0%), and there was no apparent association between discontinuation due to an AE and dosage of any study medication, used alone or in combination. Of the three most common AEs, the incidence of dizziness tended to increase with increasing dosage of HCTZ and olmesartan medoxomil/HCTZ combination. None of the episodes of dizziness were judged by the investigator to be severe. Although upper respiratory tract infection was among the most frequently reported AE, it was not dose related and did not result in any discontinuations of therapy.

Although mean values for renal function tests (blood urea nitrogen [BUN] and serum creatinine) remained stable from baseline to the end of treatment, minor increases occurred more frequently in olmesartan medoxomil/HCTZ combination–treated patients than in those who received placebo or olmesartan medoxomil monotherapy. Because of the small number of patients in each treatment group, however, it is difficult to determine whether the increases in BUN or creatinine were due to study treatment. Increased BUN occurred in four subjects (two patients in each of the two highest olmesartan medoxomil dose groups in combination with HCTZ). Of these events, study investigators judged one to be possibly related to the study drug, one to be remotely related, and two as definitely not related. Only one patient (40 mg olmesartan medoxomil/25 mg HCTZ group) had a marked BUN abnormality (57 mg/dL), but this event was resolved with increased water intake and was judged by the investigator to be not clinically significant and definitely not related to the study drug. A similar pattern was observed for serum creatinine. Markedly abnormal creatinine levels occurred in two patients. One subject in the 20 mg olmesartan medoxomil/25 HCTZ group had a serum creatinine level of 2.1 mg/dL, which was considered clinically significant by the investigator. The other subject, in the 40 mg olmesartan medoxomil/25 mg HCTZ group, had a serum creatinine level of 2.2 mg/dL, which was judged to be not clinically significant. Uric acid levels increased in both the HCTZ 12.5 and 25 mg groups from baseline to week 8, but mean values remained below the upper level of normal (7.5 mg/dL).

No adverse trends in liver enzyme levels were noted for any olmesartan medoxomil/HCTZ combination group, and no patient in an olmesartan medoxomil/HCTZ combination group discontinued the study because of elevation in aspartate aminotransferase or alanine aminotransferase. Electrolyte (sodium, potassium, bicarbonate, chloride, calcium, and phosphorus) mean values generally did not change during the study, although there was a slight decrease in the mean values of potassium in the olmesartan medoxomil/HCTZ combination groups. No cases of marked hypokalemia were observed, although a markedly elevated serum potassium of 5.9 mEq/L occurred in one patient in the 40 mg olmesartan medoxomil/25 mg HCTZ group, which was considered not to be clinically significant by the investigator.

Discussion

This study demonstrates that combination therapy with olmesartan medoxomil and HCTZ provides clinically meaningful antihypertensive effects. The greater antihypertensive efficacy of the olmesartan medoxomil/HCTZ combinations compared with that of the individual drugs was evident in a dose-dependent manner. All doses of olmesartan medoxomil/HCTZ combination therapy significantly decreased SeDBP and SeSBP compared with placebo. Evidence of efficacy for all active treatments was observed after 1 week of treatment, with further increases in efficacy reported throughout the course of the study. After 8 weeks of therapy, the proportion of patients with a BP response increased in a dose-dependent manner with olmesartan medoxomil alone, with HCTZ alone, and with combination therapy.

Olmesartan medoxomil, both alone and in combination with HCTZ, was safe and well tolerated. The incidences of AEs, serious AEs, and discontinuations related to AEs were comparable among treatment groups and similar to the rates observed with placebo. The safety profile for olmesartan medoxomil/HCTZ was qualitatively similar to that reported for other ARB/HCTZ combinations.29,31 As with the safety and tolerability profile of olmesartan medoxomil monotherapy, there was no dose-response relationship between the overall rates of AEs, serious AEs, and discontinuations because of AEs and increasing doses of olmesartan medoxomil/HCTZ combination therapy. The progressively declining incidence of headache observed with increasing dosages of combination therapy in this analysis is consistent with previous reports, which note that headache may be a feature of uncontrolled hypertension, and that safe and well tolerated antihypertensive therapies may result in a reduced incidence of headache.32 Changes in laboratory values (BUN, creatinine, and uric acid) were not of clinical significance and were similar to the changes noted with other ARB/HCTZ combinations.29,31

Olmesartan medoxomil/HCTZ combination therapy is especially promising for patients in need of multiple agents to achieve their BP goal. Most hypertensive patients require combination therapy to attain the recommended goal BPs of <140/90 mm Hg for the general hypertensive population and <130/80 mm Hg for high-risk hypertensive patients such as those with diabetes or renal disease.3–7,33 Furthermore, the current view of effective management of hypertension relies on combining drugs with different but complementary mechanisms of action to obtain greater BP reductions.3,34,35 The antihypertensive response to ARBs is potentiated in the presence of a negative salt balance.36 By promoting salt elimination and stimulating the RAAS via intrarenal mechanisms, thiazide diuretics make BP more dependent on angiotensin II, thereby enhancing the antihypertensive efficacy of ARBs.36,37

In this study, the combination of the RAAS blocker olmesartan medoxomil with the diuretic HCTZ resulted in BP reductions of up to 26.8/21.9 mm Hg. Combinations of drugs with complementary mechanisms have the added benefit of allowing the use of lower doses of component drugs, thereby minimizing the risk of AEs and potentially enhancing patient compliance.25–28,34,35,38

In conclusion, the combination of olmesartan medoxomil/HCTZ is a safe, well tolerated, and effective option for antihypertensive therapy, demonstrating greater BP reduction than monotherapy with either of its components. Antihypertensive efficacy of the combination of olmesartan medoxomil and HCTZ improved with increasing doses.

Appendix

List of principal investigators

Alan L. Aarons, MD, Raleigh, NC; Richard Albery, MD, Phoenix, AZ; Malik Baz, MD, Fresno, CA; Emilio Berberabe, MD, Las Vegas, NV; Robert Bettis, MD, Edmonds, WA; Norman Castellano, MD, Tampa, FL; John J. Champlin, MD, Carmichael, CA; Deanna G. Cheung, MD, Long Beach, CA; Howard Chipman, MD, Clearwater, FL; Shane G. Christensen, MD, Salt Lake City, UT; Steven G. Chrysant, MD, Oklahoma City, OK; Howard Creager, MD, Clearwater, FL; Martin J. Conway, MD, Albuquerque, NM; Charles H. DeBusk, MD, New Tazwell, TN; James I. Fidelholtz, MD, Cincinnati, OH; Chester L. Fisher, MD, Newport News, VA; Charles Fogarty, MD, Spartanburg, SC; Harry Geisberg, MD, Anderson, SC; Lisa K. Gidday, MD, Littleton, CO; Larry I. Gilderman, DO, Pembroke Pines, FL; Stephen L. Green, MD, Hampton, VA; James P. Hampsey, MD, Clearwater, FL; Dan Henry, MD, Tampa, FL; Christopher Kelsey, MD, San Diego, CA; Hartmut Koelsch, MD, Longmont, CO; Burton Lazar, MD, Portland, OR; James E. Lewis, MD, Sunnyvale, CA; Thomas W. Littlejohn, III, MD, Winston-Salem, NC; Walter C. Martinez, MD, West Palm Beach, FL; Aubrey McElroy, MD, Johnson City, TN; Richard Mills, MD, Mt. Pleasant, SC; Rafael Montoro, MD, Coral Gables, FL; Joel M. Neutel, MD, Orange, CA; Warren Pleskow, MD, Encinitas, CA; Terry L. Poling, MD, Arkansas City, KS; Bruce G. Rankin, DO, DeLand, FL; John Rubino, MD, Raleigh, NC; Rupal Shah, MD, Corona, CA; G. Boyd Shaw, MD, Jackson, MS; Stephan C. Sharp, MD, Nashville, TN; William D. Shiovitz, MD, Boulder, CO; Joanna Tan, MD, Yorba Linda, CA; Edward O. Tokatlian, MD, Phoenix, AZ; Stuart Topkis, DO, Warminster, PA; David VanSickle, MD, Tualatin, OR; Paul Wagner, MD, San Diego, CA; John J. Zerbe, MD, Cincinnati, OH; and Michael Ziter, MD, Cadillac, MI.

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Author notes

*
This study was supported by a grant from Sankyo Pharma Inc., Parsippany, NJ.