Results of an Olmesartan Medoxomil–Based Treatment Regimen in Hypertensive Patients

Abstract

The efficacy and safety of an olmesartan medoxomil (OM)–based treatment algorithm was tested in a double-blind, randomized, placebo-controlled titration study in 276 patients with stage 1 or 2 hypertension. After placebo run-in, patients were randomized to placebo (12 weeks) or OM 20 mg/d (weeks 1–3). OM was up-titrated to 40 mg/d (weeks 4–6), then OM/hydrochlorothiazide (HCTZ) 40/12.5 mg/d (weeks 7–9) and OM/HCTZ 40/25 mg/d (weeks 10–12) were started if blood pressure (BP) remained ≥120/80 mm Hg at each time interval. End points were change from baseline in mean systolic BP (primary) and mean diastolic BP (secondary). OM-based treatment was well tolerated and changed BP by −22.3/−12.1 mm Hg from baseline vs −0.1/+0.8 mm Hg for placebo (P<.0001). Cumulative goal BP (<140/90 mm Hg) was achieved in 74.1% and 30.7% of OM- compared with placebo-treated patients, respectively (P<.0001). BP normalized (<120/80 mm Hg) in 44.8% of OM- vs 1.4% of placebo-treated patients with stage 1 hypertension (P<.0001).

High blood pressure (BP) is a global health issue responsible for a substantial proportion of deaths worldwide.¹ The Framingham Heart Study² reported that the risk of major cardiovascular events increases with increasing severity of hypertension in every age group. In addition, Lewington and associates demonstrated that death from ischemic heart disease and stroke increases progressively starting from a systolic BP (SBP) of 115 mm Hg and a diastolic BP (DBP) of 75 mm Hg.³ Hypertension, defined as BP levels >140/90 mm Hg, is associated with an increased risk of chronic kidney disease (CKD).⁴ Even BP values in the range of 130 to 139/85 to 89 mm Hg have been shown to be associated with a greater than 2-fold increase in relative risk from cardiovascular disease when compared with BP values <120/80 mm Hg.⁵ Reducing BP has been associated with decreases in cardiovascular disease complications.⁶

Despite the well-established correlation between BP lowering and a reduction in the risk of cardiovascular events,⁷ BP control rates remain suboptimal worldwide. The US National Health and Nutrition Examination Survey (NHANES) indicated that only 37% of adult patients with hypertension receive treatment to a BP goal of <140/90 mm Hg or <130/80 mm Hg for those with diabetes or CKD.⁸ Recent survey data do suggest, however, that treatment and response rates have increased since the 1999–2004 report.⁹ Approximately 90% of patients with hypertension report taking medication, and about 50% state that their BP values have been <140/90 mm Hg. Clinical or “therapeutic” inertia contributes to the lack of BP control in patients with hypertension as reflected by physician reluctance to intensify antihypertensive therapy through increased drug doses or changes in medication.^10–14 The Harris Survey reports that about 30% of patients did not have medication changed despite having BP levels above goals.⁹ Achieving target BP often requires >1 antihypertensive medication, a fact that should be recognized by physicians early in a patient’s treatment since up-titration of monotherapy frequently fails to achieve BP goal.^15,16

The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends selection of antihypertensive agents with different mechanisms of action to enhance BP-lowering effects.¹⁵ For stage 1 hypertension (SBP 140–159 mm Hg or DBP 90–99 mm Hg), the recommended initial drug is a thiazide-type diuretic in most patients, although angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs), or a combination of these may also be considered for specific indications.¹⁵ For stage 2 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg), JNC 7 suggests initiating treatment with 2 drugs from different classes of antihypertensive agents.¹⁵

ARBs such as olmesartan medoxomil (OM), telmisartan, and losartan effectively reduce BP and are generally well tolerated.¹⁷ The BP-lowering efficacy of ARBs is enhanced by combining them with a diuretic (eg, hydrochlorothiazide [HCTZ]).^18–21 It has previously been reported that the use of an ARB in combination with HCTZ results in dose-dependent BP reductions in patients with stage 2 diastolic²² or systolic²³ hypertension. In these studies, the addition of another agent to an ARB allowed recommended BP goals to be achieved in a majority of patients with no clinically significant increases in adverse events.

Here we report the efficacy and safety of an ARB-based titration regimen. The Benicar Efficacy: New Investigative Findings Show Olmesartan Medoxomil Safely and Effectively Reduces Blood Pressure Compared With placebo in a Clinical Evaluation of Patients With Stage 1 and Stage 2 Hypertension (BENIFORCE) study compared OM, alone and in combination with HCTZ, with placebo in patients with stage 1 or stage 2 hypertension. The primary end point was the change from baseline in mean SBP after 12 weeks of therapy. Secondary end points included the change from baseline in mean DBP after 12 weeks, the change from baseline in mean SBP and DBP at each titration step, and the proportion of patients in whom BP goals (<140/90, <130/85, <130/80, and <120/80 mm Hg) were reached at each titration step and at the end of the study. Some of the primary and secondary end point data from this study were presented at the American Society of Hypertension (ASH) 23rd Annual Scientific Meeting and Exposition and published in abstract form.²⁴ One of the important features of this study is the titration of BP to <120/80 mm Hg, a level considered to be optimal or “normal,” but one not targeted in most of the clinical trials to date.

Materials and Methods

Study Design

This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, titrate-to-goal study. Patients were screened within 14 days of entry into placebo run-in, during which time they were weaned from antihypertensive medications. Patients received single-blind placebo tablets once daily for 3 to 4 weeks and were randomized into 2 groups to receive active treatment or placebo for 12 weeks if they met study inclusion criteria (Figure 1). Active treatment patients received OM 20 mg/d and were up-titrated as necessary at 3-week intervals to OM 40 mg/d followed by the addition of HCTZ 12.5 and 25 mg to achieve a target BP of <120/80 mm Hg. Responders (patients in whom target BP was achieved) were not further up-titrated but remained on the study medication dose that achieved target BP unless BP elevation above target level occurred at the next titration point. Patients with a mean SBP ≥120 mm Hg or a mean DBP ≥80 mm Hg at subsequent visits were considered to have uncontrolled BP and were up-titrated to the next dose level according to the titration scheme. At the end of weeks 3, 6, and 9, patients with BP values >179/109, >169/105, and 160/100 mm Hg, respectively, were considered nonresponders and exited the study. Study protocol and consent forms for the 29 participating centers were reviewed and approved by an institutional review board prior to initiation of the study. Each participant provided written informed consent at the screening visit. The study was conducted in accordance with the institutional review board committee at each study center and Declaration of Helsinki principles.

Figure 1.  Treatment algorithm. Patients meeting the screening inclusion criteria entered the placebo run-in phase and received placebo medication at the first visit 3 weeks prior to randomization. Patients were assessed at 1-week intervals during the placebo run-in period, and then those meeting inclusion criteria at visit 4 underwent ambulatory blood pressure monitoring (ABPM) to confirm the presence of hypertension. Those who met the ABPM criteria received the randomized medication and the 12-week double-blind phase began. Titration to the next level of the regimen could occur at any of the titration steps at weeks 3, 6, and 9. HCTZ indicates hydrochlorothiazide; OM, olmesartan medoxomil.

Patients

Patients eligible for randomization were aged 18 years or older with a seated cuff SBP (SeSBP) ≥140 mm Hg and ≤179 mm Hg and seated cuff DBP (SeDBP) ≤109 mm Hg confirmed at weekly intervals during the placebo run-in period. Differences in SeSBP of ≤10 mm Hg were required between qualifying visits. Patients were randomized if they met cuff BP inclusion criteria at the end of the placebo run-in and also displayed a mean SBP value ≥135 mm Hg and ≤179 mm Hg and DBP ≤109 mm Hg during 8-hour daytime ambulatory BP monitoring (ABPM). Randomization was stratified to ensure that proportions of stage 1 (SBP, 140–159 mm Hg or DBP 90–99 mm Hg) and stage 2 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg) patients were similar.

Women could not be pregnant (practicing protocol-approved birth control), able to become pregnant (1 year postmenopausal, hysterectomy, or 6 months post–tubal ligation), or breastfeeding in order to participate. Patients with type 1 diabetes were excluded, but patients with type 2 diabetes were included if receiving stable antihyperglycemic therapy for at least 4 weeks with plasma glucose levels of <160 mg/dL at screening. Patients needed to demonstrate at least 80% compliance with the study medication regimen during the placebo run-in period, as determined by tablet counts. Additional exclusion criteria included the circumference of the nondominant arm (arm extended, upper arm midpoint circumference) <24 cm or >42 cm, and serious cardiovascular, renal, pulmonary, hepatic, gastrointestinal, endocrine, metabolic, hematologic, oncologic, neurologic, or psychiatric disease. Patients with a history of myocardial infarction, angina, angioplasty, coronary artery bypass grafting or heart failure in the previous 6 months or cerebrovascular accident or transient ischemic attack in the previous 12 months were excluded. Other exclusion criteria included clinically significant cardiac conduction defects, hemodynamically significant valvular disease, secondary hypertension, and taking excluded medications (eg, antihypertensive medications, except study drugs), specified central nervous system agents, β-agonists, and appetite suppressants.

Efficacy and Tolerability Assessments

All efficacy analyses were based on the efficacy cohort, defined as all patients who received at least one dose of study medication and had a baseline assessment and at least one postbaseline efficacy assessment. Safety analyses were performed on the safety cohort, defined as all patients who received at least one dose of randomized study medication. BP was measured at trough medication levels (prior to treatment administration) with a validated automatic BP-monitoring device (Omron Corporation, Bannockburn, IL) on the nondominant arm, after the patient had been sitting for 5 minutes. Three separate seated cuff BP measurements were taken at 2-minute intervals. The mean of 3 readings constituted the mean SeSBP and SeDBP for that visit. BP values were assessed during clinic visits at weeks 1, 2, and 3 of the placebo run-in period as well as day 1 and weeks 3, 6, 9, and 12 of the double-blind active treatment period. During the active treatment period, measurements were obtained prior to 10 am on all study days and at 8 am± 90 minutes on study day 1 to allow sufficient time for an 8-hour baseline ABPM recording.

Study baseline was defined as the average of the last 2 mean values for the last 2 weeks of the placebo run-in period (ie, visit 3 and visit 4 or visit 4 or visit 4X), where the mean value was the average of 3 consecutive readings at each visit. This baseline was used in the primary efficacy variable analysis (the change from baseline in mean SBP after 12 weeks of treatment) and the analysis of the secondary efficacy end point (the change from baseline in mean DBP after 12 weeks of treatment and the change from baseline in mean SBP and mean DBP at each titration step). Baseline for all safety assessments was the last evaluation obtained prior to administration of the first dose of study medication.

Compliance was assessed by tablet count at each clinic visit. Safety variables were evaluated throughout the placebo run-in and the active treatment periods by monitoring adverse events, changes in vital signs, routine laboratory tests, and physical findings. Complete medical histories and routine laboratory safety tests, including a complete blood count, serum chemistry profile, urinalysis, and serum pregnancy test, were performed at screening and at week 12.

The primary efficacy variable was the least-squares (LS) mean change from baseline in SeSBP after 12 weeks of randomized treatment. Secondary efficacy variables included the LS mean change from baseline in SeDBP after 12 weeks, the change from baseline, and the incremental change in BP at each titration step. Other secondary variables included a determination of the proportion of patients in whom a BP goal of <140/90, <130/85, <130/80, or <120/80 mm Hg was reached at the end of the study and at each titration step.

Statistical Methods

It was determined that a sample size of 200 was required to provide a power of at least 95% at a 2-sided significance level of 5% to demonstrate the superiority of OM-based treatment over placebo. A sample size of 250 (125 from each group) was selected to compensate for potential patient dropouts. Continuous variables were summarized using descriptive statistics, and categorical variables were summarized using the frequency and percentage of patients. The change from baseline in mean SeSBP was analyzed using an analysis of covariance (ANCOVA) model with randomized treatment and baseline hypertension stage (stage 1 or 2) as factors and study baseline BP and placebo values as covariates. LS means for treatment effect difference between OM-based treatment and placebo were estimated, and the standard error (SE) of the estimated difference was used to construct the 2-sided 95% confidence intervals (CI) for the treatment effect differences. Data concerning attainment of each of the secondary BP goals and the extent of BP reduction were summarized and presented as cumulative percentages for each treatment level. Comparisons between the treatment groups were made using Fisher’s exact test or chi-square test.

If a patient was removed from the study during a treatment period, his/her last BP measurement taken during that period was carried forward as the end-of-period measurement if at least one dose of the study drug was administered. This last value was not carried forward in the summary of the next treatment period. The most recent BP measurement was used as the end-of-study value for any patient exiting the study as a nonresponder. Any patient who exited the study during the randomized treatment period had the last postbaseline BP value carried forward to the end of study using the last observation carried forward (LOCF) method.

Results

Patient Disposition and Baseline Characteristics

A total of 552 patients were screened, and 465 entered the run-in phase and received at least one dose of placebo medication. For the randomized study component, 278 patients met the inclusion criteria: 138 were assigned to placebo and 140 to OM-based treatment. For the efficacy cohort, the mean age of patients was approximately 56 years in both treatment groups, and the OM group had a slightly greater proportion of women (Table I). The racial composition of the OM-based treatment and placebo groups was similar. The efficacy cohort consisted of 276 patients (OM, 139; placebo, 137), and the safety cohort comprised all patients who received one dose of randomized treatment, a total of 278 patients (OM, 140; placebo, 138). Two patients in the active treatment arm received OM 40 mg/d, rather than 20 mg/d, as their first treatment dosage. This resulted in an initial OM efficacy and safety cohort of 137 and 138, respectively. Of these, 93 patients in the placebo group and 112 in the OM-based regimen group completed 12 weeks of treatment.

Table I.   Summary of Patient Baseline Characteristics and Demographics (Efficacy Cohort)

Parameter	Total Cohort		Stage 1 Hypertension		Stage 2 Hypertension
	OM-Based Regimen (n=137)	Placebo (n=137)	OM-Based Regimen (n=56)	Placebo (n=72)	OM-Based Regimen (n=81)	Placebo (n=65)
Abbreviations: DBP, diastolic blood pressure; OM, olmesartan medoxomil; SBP, systolic blood pressure. Values are No. (%) unless otherwise indicated.
Mean age, y (SD)	55.9 (10.8)	55.9 (9.5)	56.1 (10.1)	55.0 (9.4)	55.7 (11.3)	56.9 (9.6)
Male	63 (46.0)	66 (48.2)	18 (32.1)	33 (45.8)	45 (55.6)	33 (50.8)
Female	74 (54.0)	71 (51.8)	38 (67.9)	39 (54.2)	36 (44.4)	32 (49.2)
White	85 (62.0)	87 (63.5)	35 (62.5)	44 (61.1)	50 (61.7)	43 (66.2)
Black	27 (19.7)	28 (20.4)	9 (16.1)	14 (19.4)	18 (22.2)	14 (21.5)
Hispanic	18 (13.1)	17 (12.4)	7 (12.5)	10 (13.9)	11 (13.6)	7 (10.8)
Asian	1 (0.7)	1 (0.7)	1 (1.8)	0 (0.0)	0 (0.0)	1 (1.5)
Other	6 (4.4)	4 (2.9)	4 (7.1)	4 (5.6)	2 (2.5)	0 (0.0)
Mean SBP, mm Hg (SD)	156.9 (9.2)	155.3 (9.7)	150.6 (5.7)	149.6 (5.8)	161.2 (8.7)	161.5 (9.4)
Mean DBP, mm Hg (SD)	94.2 (7.7)	93.7 (7.4)	90.0 (6.5)	90.7 (6.1)	97.0 (7.2)	97.1 (7.2)
Mean heart rate, beats/min (SD)	75.1 (10.9)	73.6 (9.4)	74.2 (11.0)	73.9 (9.5)	75.6 (10.8)	73.4 (9.3)

The 2 treatment groups displayed similar demographic and disease characteristics (Table I). Mean baseline BP was 155.3/93.7 mm Hg in the placebo group and 156.9/94.2 mm Hg in the OM-based treatment group. Fifteen patients (10.7%) in the OM arm and 21 patients (15.2%) in the placebo arm had diabetes. No statistical analysis was performed to determine efficacy differences in patients with diabetes vs patients without diabetes because diabetes was not a prespecified population in this study. The efficacy cohort consisted of 130 and 146 patients with stage 1 (OM, 56; placebo, 72) and stage 2 (OM, 81; placebo, 65) hypertension, respectively. The characteristics of patients within the stage 1 and stage 2 hypertension subgroups were similar with respect to age, race, ethnicity, weight, and heart rate.

Rates and causes of patient discontinuation were similar in both study arms, with the exception of uncontrolled BP. In the placebo arm, 28 patients (20.3% of the placebo safety cohort) discontinued the study due to uncontrolled BP (6 patients with stage 1 hypertension and 22 patients with stage 2 hypertension). In the OM-based treatment group, 7 patients (5.0% of the OM safety cohort) discontinued the study due to uncontrolled BP (1 patient with stage 1 hypertension and 6 patients with stage 2 hypertension). The other most common reasons for discontinuation were adverse events (8 in each group). More than 99% of the study patients were compliant with the study medication regimen; only 1 patient in each group was removed from the study due to noncompliance.

More patients with stage 2 than stage 1 hypertension at baseline discontinued treatment (54 vs 19, respectively). During the randomized treatment period, nearly twice as many placebo-treated patients with stage 2 hypertension (35 of 66; 53.0%) discontinued compared with OM-treated patients (19 of 82; 23.2%). Patients with stage 1 hypertension had lower discontinuation rates in both treatment arms (10 in the placebo group and 9 in the active treatment group).

It is important to note in the efficacy cohort that none of the patients completed the study while receiving OM 20 mg monotherapy. Five patients completed the study having been up-titrated from OM 20 mg to 40 mg but with no addition of HCTZ, and 21 patients completed the study with OM/HCTZ 40/12.5 mg in order to achieve BP goals. The greatest proportion of patients who completed the study, 60.4% (84 of 139), had been up-titrated to OM/HCTZ 40/25 mg. A similar distribution was observed regardless of the severity of hypertension (stage 1 or stage 2). Thus, the addition of HCTZ to OM was required in a large majority of patients to achieve target BP levels.

Efficacy

BP Changes From Baseline

The OM-based treatment regimen significantly reduced the LS mean BP compared with placebo at week 12/LOCF (Figure 2). In the total cohort, the LS mean change from baseline in SeSBP was −22.3 mm Hg compared with −0.1 mm Hg with placebo, for a treatment difference of −22.1 mm Hg (P<.0001). The LS mean change in SeDBP from baseline at week 12/LOCF was −12.1 mm Hg compared with +0.8 mm Hg with placebo, for a treatment difference of −12.8 mm Hg (P<.0001). In the stage 1 subgroup, the LS mean difference in BP reduction between active treatment and placebo for SeSBP and SeDBP was −22.1 and −12.2 mm Hg, respectively (P<.0001). In the stage 2 subgroup, the LS mean difference in BP reduction between active treatment and placebo for SeSBP and SeDBP was −22.5 and −13.2 mm Hg, respectively (P<.0001) (Figure 2). There were no clinically meaningful differences in change from baseline at week 12 with respect to baseline stage of hypertension. Within treatments, baseline stage of hypertension was not a determinant of efficacy.

Figure 2.  Least-squares (LS) mean difference in blood pressure (BP) reduction from baseline between active treatment and placebo at week 12/last observation carried forward. Bars represent standard error. The patient numbers are the same as those listed in Table I. OM indicates olmesartan medoxomil; SeDBP, seated cuff diastolic blood pressure; SeSBP, seated cuff systolic blood pressure. *P<.0001 vs placebo.

In the OM-based treatment group, as expected, SeSBP and SeDBP were both significantly reduced from baseline at each titration step (P<.0001 for all comparisons). As shown in Figure 3, mean BP reductions in patients who received active treatment were dose-dependent, ranging from −10.6 to −23.2 mm Hg for SeSBP and from −4.9 to −12.3 mm Hg for SeDBP. In patients with stage 1 hypertension, reductions in BP ranged from −8.9 to −20.5 mm Hg (SeSBP) and from −2.7 to −9.9 mm Hg (SeDBP) and with stage 2 hypertension from −11.7 to −24.6 mm Hg (SeSBP) and from −6.5 to −13.5 mm Hg (SeDBP). In the placebo group (total cohort), smaller reductions from baseline were observed, some of which were statistically significant (SeSBP at weeks 1–3, −2.4 mm Hg; 4–6, −3.1 mm Hg; and 7–9, −4.6 mm Hg; SeDBP at weeks 4–6, −1.5 mm Hg and 7–9, −2.5 mm Hg) (Figure 3).

Figure 3.  Mean change from study baseline to end of treatment period (week 12/last observation carried forward) in seated blood pressure (BP) by titration step in the (A) total efficacy cohort, (B) stage 1 hypertension subgroup, and (C) stage 2 hypertension subgroup. At each titration step, BP reductions were significantly greater in the OM-based treatment regimen compared with placebo. HCTZ indicates hydrochlorothiazide; OM, olmesartan medoxomil; SeDBP, seated cuff diastolic blood pressure; SeSBP, seated cuff systolic blood pressure. *P<.05, ^†P<.01, ^‡P<.001, ^§P<.0001 for within-group comparisons between study baseline and end of treatment using paired t-test.

Attainment of BP Goal

Attainment of BP goals (<140/90, <130/85, <130/80, and <120/80 mm Hg) at week 12 were secondary study end points (Figure 4). The cumulative number (percentage) at the end of a titration step is the number (percentage) of patients in whom each BP goal was achieved at the end of at least one titration step up to and including the last titration step. More patients receiving OM-based treatment achieved these goals at the end of the study compared with placebo; the differences between groups were more marked with increasing stringency of the goals. The cumulative proportion of patients in the total cohort in whom the BP goal of <140/90 mm Hg was reached at study end was 74.1% in the OM arm compared with 30.7% in the placebo arm (P<.0001). In the stage 1 subgroup, the cumulative proportion of patients in whom the BP goal of <140/90 mm Hg was reached at study end was 81.0% in the OM arm compared with 43.1% in the placebo group (P<.0001). In the stage 2 subgroup, it was 69.1% in the OM arm compared with 16.9% in the placebo group (P<.0001). The proportion of patients in the total cohort in whom BP normalization (<120/80 mm Hg) was achieved at study end was 27.3% in the OM group compared with 1.5% in the placebo group (P<.0001). Similar trends were observed for the stage 1 and stage 2 hypertension subgroups (Figure 4). In the stage 1 hypertension subgroup, the normotensive target (<120/80 mm Hg) was achieved in 44.8% of patients compared with 1.4% receiving placebo.

Figure 4.  Cumulative proportions of patients in whom blood pressure (BP) goals were achieved in the (A) total efficacy cohort, (B) stage 1 hypertension subgroup, and (C) stage 2 hypertension subgroup. Cumulative percentages were calculated using the total number of patients in the treatment cohort as the denominator. OM indicates olmesartan medoxomil. *P<.01, ^†P<.0001 for comparison with placebo using chi-square tests.

Safety

The OM-based treatment regimen was generally well tolerated at all dose levels, with rates of adverse events (AEs) similar to those arising in the placebo group. The overall proportion of patients in the OM treatment arm reporting at least one AE ranged from 15.9% to 28.4% across titration steps and 15.9% to 26.2% in the 3-week placebo time periods. AEs occurring in ≥2% of patients, by treatment and titration step, are summarized in Table II. Most AEs were mild to moderate in severity and had resolved or were resolving by the end of the study. Dizziness was more prevalent in patients in the OM-based treatment group compared with the placebo group (n=3, n=3, n=4, and n=3 for the OM 20 mg, OM 40 mg, OM/HCTZ 40/12.5 mg, and OM/HCTZ 40/25 mg treatment groups, respectively; and n=0 for placebo during weeks 1–3, 7–9, and 10–12; and n=1 during weeks 4–6). The majority of discontinuations occurred in the OM/HCTZ-40/12.5 mg/d and 40/25-mg/d group (3 discontinuations each) and week 4–6 placebo group (4 discontinuations). AEs resulting in the discontinuation of >1 patient were dizziness (OM, 3; placebo, 2), headache (OM, 1; placebo, 3), blurred vision (OM, 1; placebo, 1), and hypertension (OM, 1; placebo, 1).

Table II.   Clinical Adverse Events (AEs)^a Occurring in ≥2% of Patients (Safety Cohort)

	OM-Based Regimen				Placebo
	OM 20  mg (n=138)	OM 40  mg (n=132)	OM/HCTZ 40/12.5 mg (n=118)	OM/HCTZ 40/25 mg (n=88)	Weeks 1–3 (n=138)	Weeks 4–6 (n=126)	Weeks 7–9 (n=112)	Weeks 10–12 (n=94)
Abbreviations: HCTZ, hydrochlorothiazide; OM, olmesartan medoxomil. Values are No. (%). ^aAEs were those that either first occurred on or after the first dose of randomized study medication or occurred during placebo run-in and then again in the randomization period but with worsened severity compared to the placebo run-in.
Drug-related AEs	3 (2.2)	6 (4.6)	9 (7.6)	5 (5.7)	9 (6.5)	12 (9.5)	5 (4.5)	2 (2.1)
Serious AEs	0 (0.0)	1 (0.8)	1 (0.8)	1 (1.1)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Discontinuations due to AEs	1 (0.7)	1 (0.8)	3 (2.5)	3 (3.4)	1 (0.7)	4 (3.2)	2 (1.8)	1 (1.1)
Specific AEs
Seasonal allergy	0 (0.0)	0 (0.0)	1 (0.9)	2 (2.3)	1 (0.7)	1 (0.8)	0 (0.0)	0 (0.0)
Upper respiratory  tract infection	1 (0.7)	4 (3.0)	3 (2.5)	1 (1.1)	4 (2.9)	3 (2.4)	0 (0.0)	0 (0.0)
Urinary tract infection	1 (0.7)	1 (0.8)	0 (0.0)	2 (2.3)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Viral upper respiratory  tract infection	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.1)	1 (0.7)	3 (2.4)	2 (1.8)	1 (1.1)
Back pain	1 (0.7)	2 (1.5)	3 (2.5)	2 (2.3)	0 (0.0)	1 (0.8)	1 (0.9)	2 (2.1)
Dizziness	3 (2.2)	3 (2.3)	4 (3.4)	3 (3.4)	0 (0.0)	1 (0.8)	0 (0.0)	0 (0.0)
Headache	4 (2.9)	4 (3.0)	1 (0.9)	2 (2.3)	6 (4.4)	6 (4.8)	4 (3.6)	1 (1.1)
Cough	0 (0.0)	0 (0.0)	2 (1.7)	1 (1.1)	1 (0.7)	2 (1.6)	2 (1.8)	2 (2.1)
Hypertension	0 (0.0)	1 (0.8)	0 (0.0)	2 (2.3)	0 (0.0)	0 (0.0)	1 (0.9)	0 (0.0)

Three patients receiving the OM-based treatment regimen experienced a serious adverse event (SAE; small intestinal obstruction, supraventricular tachycardia, and hypertension), all of which were considered unrelated to study medication and resolved by the end of the study. One patient in the placebo group experienced an SAE of severe cholecystitis during the placebo run-in period, which resolved following surgery and was considered unrelated to treatment.

Discussion

The major finding of this study is that OM±HCTZ produced statistically significant reductions in BP in prespecified subgroups of patients with stage 1 or stage 2 hypertension after 12 weeks of therapy compared with placebo. For the primary end point, OM-based treatment produced statistically significant LS mean treatment differences in SBP/DBP at week 12/LOCF in the efficacy cohort as a whole, with similar reductions observed in the stage 1 and stage 2 hypertension subgroups, respectively. The largest BP reductions were observed in patients up-titrated to OM/HCTZ 40/25 mg/d. With regard to the secondary end point, the BP goal of <140/90 mm Hg was achieved in a cumulative 81.0% of patients with stage 1 hypertension and a cumulative 69.1% of patients with stage 2 hypertension. As noted, a large majority of patients required the addition of HCTZ to achieve goal BP. These results are consistent with findings of previous studies in patients with stage 2 hypertension.^22,23 Unlike in some earlier studies,^23,25 patients remained in this trial until the study end even if they reached the BP goal, which in the present study was a normotensive BP level (<120/80 mm Hg). Consequently, results from the present study are more representative of antihypertensive treatment in a real-world clinical setting wherein BP in patients in whom recommended BP goals are reached are maintained on their effective dose regimen. If BP becomes uncontrolled, the patient is then up-titrated or additional antihypertensive agents added until BP control is once again achieved. The current study demonstrates that a significant number of patients can be treated to “normotensive” BP levels—levels not usually targeted in major clinical trials.

It should be noted that BP goal was also achieved in a large proportion (30.7%) of patients receiving placebo (<140/90 mm Hg), even though the LS mean change in BP from baseline was only −0.1/+0.8 mm Hg at week 12/LOCF. The explanation for this result is that BP goal achievement was measured cumulatively; thus, if patients achieved a BP goal of <140/90 mm Hg at any time during the study, they were included in the cumulative BP goal achievement regardless of whether they remained at goal for the duration of the study. However, the statistics for LS mean reduction in BP from baseline were presented only for week 12/LOCF. Consequently, patients in the placebo group in whom BP goals were achieved had reductions in BP at some time point in the study that were greater than the mean reduction shown for the group at week 12. These earlier reductions enabled the BP goal to be reached during the study and contributed to the proportion of patients cumulatively attaining BP goal with placebo as well as with the study drugs.

Although a recent analysis of NHANES data suggested that BP control (<140/90 mm Hg) in individuals receiving treatment for hypertension increased from 50% in 1999–2000 to 57% in 2003–2004,⁸ considerable opportunity for improvement persists. Suboptimal rates of BP control may be due to clinical inertia, wherein physicians fail to intensify treatment by increasing medication dose or adding additional agents as required to achieve recommended BP goals (<140/90 mm Hg; <130/80 mm Hg with diabetes or CKD).^{10–12,14,26} It has consistently been shown that addition of up to 25 mg HCTZ to ARBs such as valsartan,¹⁸ irbesartan,¹⁹ or telmisartan²⁷ or to other antihypertensive agents, β-blockers, or ACE inhibitors produces greater BP reductions than monotherapy. Results from this study reaffirm the value of incorporating a diuretic in an ARB-based treatment regimen.^23,25 Intensifying treatment to OM/HCTZ 40/25 mg/d allowed the attainment of BP normalization (<120/80 mm Hg) in a cumulative 44.8% of patients with stage 1 hypertension. Physician-related clinical inertia may be reduced by using fixed-dose combinations. This may also increase patient compliance by limiting the numbers of prescriptions and pills patients are required to take.¹⁰

Although the current BP goal is <140/90 mm Hg (<130/80 mm Hg for patients with diabetes or CKD and in those with or at high risk for coronary or other atherosclerotic disease²⁸), it has been suggested but certainly not proven that decreasing the BP goal even lower may provide greater benefit.²⁹ In the current study, 74% of patients in the total cohort achieved a BP goal of <140/90 mm Hg and 27% were able to achieve the stringent BP goal of <120/80 mm Hg. The cardiovascular benefits that may be associated with decreasing SBP to <120 mm Hg are to be explored in the National Heart, Lung and Blood Institute’s Systolic Pressure Intervention Trial (SPRINT). SPRINT is a 9-year randomized multicenter clinical trial testing the effects of intensive SBP lowering (SBP goal <120 mm Hg compared to the conventional goal of <140 mm Hg) on preventing cardiovascular disease in approximately 7500 patients without diabetes and with an SBP ≥130 mm Hg and at least one additional cardiovascular disease risk factor.

A potential limitation of the current study is that the 12-week study duration may not be sufficient to assess the long-term effect or benefit of the treatment algorithm.

OM-based treatment was well tolerated in patients with stage 1 or stage 2 hypertension, with similar rates of discontinuation in active treatment and placebo groups. All SAEs occurring during the randomization period were in the active treatment group but were unrelated to the study drug. AEs were distributed evenly between treatment arms with the exception of dizziness, which was more prevalent in patients in the OM-based treatment group.

Conclusions

An OM-based treatment regimen effectively controlled BP in a large proportion of patients with stage 1 or stage 2 hypertension: 74% of patients reached the BP goal of <140/90 mm Hg and 45% of those with stage 1 hypertension had their BP normalized (<120/80 mm Hg). A large majority required the addition of HCTZ to OM to achieve goal BP levels. OM with or without HCTZ was well tolerated.

Acknowledgments and disclosures:

The authors would like to express their thanks to Kathryn Leonard, Jennifer M. Kulak, PhD, and Alan J. Klopp, PhD, for their editorial assistance in the preparation of this manuscript. This study was supported by Daiichi Sankyo, Inc. Suzanne Oparil, MD, and Steven G. Chrysant, MD, received research support, served on the speaker’s bureau, and have been consultants for Daiichi Sankyo, Inc. Dean J. Kereiakes, MD, has received research grants from Pfizer, Cordis (Johnson & Johnson), Boston Scientific, Medtronic, and Daiichi Sankyo, Inc. Jianbo Xu, MS, is a full-time consultant of Daiichi Sankyo, Inc. William Waverczak, MS, Kathleen J. Chavanu, PharmD, and Robert Dubiel, PharmD, are employees of Daiichi Sankyo, Inc.