Antihypertensive Efficacy of Olmesartan Medoxomil, a New Angiotensin II Receptor Antagonist, as Assessed by Ambulatory Blood Pressure Measurements

Abstract

Olmesartan medoxomil is a new angiotensin II receptor blocker. In this randomized, double‐blind, placebo‐controlled study, the efficacy and safety of olmesartan medoxomil was assessed in 334 patients with moderate to severe essential hypertension. Patients were randomized to receive placebo; 5, 20, or 80 mg olmesartan medoxomil q.d.; or 2.5, 10, or 40 mg olmesartan medoxomil b.i.d. Ambulatory and cuff blood pressure were measured prior to and after 8 weeks of treatment. Treatment with olmesartan medoxomil resulted in a significant placebo‐adjusted reduction of mean 24‐hour ambulatory diastolic blood pressure of 9.6 mm Hg, 12.2 mm Hg, and 10.6 mm Hg in the 5‐, 20‐, and 80‐mg q.d. groups, respectively. Corresponding reductions in mean ambulatory systolic blood pressure were 14.5 mm Hg, 16.5 mm Hg, and 15.4 mm Hg. Similar reductions of diastolic and systolic blood pressure were seen with b.i.d. dosing. The diastolic trough‐to‐peak ratios of the q.d. doses of olmesartan medoxomil ranged from 57%–70%, indicating 24‐hour effectiveness. The safety profile of olmesartan medoxomil was similar to that of placebo. Olmesartan medoxomil appears to be a safe and effective once‐a‐day treatment for hypertension.

The angiotensin II receptor blockers are a class of antihypertensive agents that inhibit the renin‐angiotensin system by selectively binding to the type 1 (AT₁) subpopulation of angiotensin II receptors. ¹ Olmesartan medoxomil is a new angiotensin II receptor blocker that was developed as part of a systematic survey of the AT₁‐binding properties of substituted imidazole‐5‐carboxylic acids. ² Olmesartan medoxomil is a prodrug antagonist that is de‐esterified in vivo to the active acid metabolite, olmesartan. ³ It is a highly selective antagonist of angiotensin II, binding to the AT₁ receptor. ⁴ In conscious, normotensive rats, oral administration of this agent reduced the pressor response to intravenous angiotensin II in a dose‐dependent fashion. ⁴ Subsequent testing of the ambulatory blood pressure (BP) response of eight salt‐restricted, hypertensive patients to single oral doses of olmesartan medoxomil showed that doses of 10 mg/day or higher significantly reduced mean 24‐hour BP. ⁵

The present randomized, double‐blind, placebo‐controlled study evaluated the antihypertensive properties of olmesartan medoxomil in a population of patients with moderate to severe essential hypertension. The purpose of this study was to assess the dose‐response relationship, duration of action, and safety of this new angiotensin II receptor blocker. In order to avoid the potential errors associated with periodic measurement of cuff BP, 24‐hour ambulatory BP monitoring was used to assess effectiveness.

METHODS

Patient Selection

Male and female outpatients 18 years of age or older with moderate to severe essential hypertension (cuff diastolic BP [DBP] ≥100 mm Hg and ≤115 mm Hg and mean daytime DBP ≥90 mm Hg by ambulatory BP monitoring) were eligible for enrollment in this study. All patients were required to have a body weight within 30% of ideal body weight for height and frame size. All women in the study had been surgically sterilized, were postmenopausal, or were using an adequate method of birth control. All patients were taken off of antihypertensive medications for at least 7 full days prior to beginning the study. Exclusion criteria included serious concomitant diseases that would limit the participation of the patient in the study or a recent history of myocardial infarction, cerebrovascular accident, or transient ischemic attack. A requirement for concomitant medication that could directly or indirectly act on BP was also considered grounds for exclusion. An institutional review board of each of the participating sites approved the study. Written informed consent was obtained from all patients prior to enrollment.

Study Design

This randomized, double‐blind, placebo‐controlled, parallel‐group study was conducted at 36 centers in the United States. All patients underwent a 14–21 day single‐blind placebo run‐in prior to randomization into the double‐blind active treatment phase of the trial. Patients who met the eligibility criteria for admission into the trial were randomized in blocks of seven into one of seven treatment groups: 5, 20, or 80 mg olmesartan medoxomil q.d.; 2.5,10, or 40 mg olmesartan medoxomil b.i.d.; or placebo. All drugs were administered orally. Patients were instructed to take the first dose of the study drug with breakfast and the second dose approximately 12 hours later. Patients receiving q.d. dosing were given active drug for the morning dose and matched placebo for the evening dose.

The trial was designed to continue for 8 weeks. During this double‐blind, active treatment period, patients were scheduled to complete six office visits. In addition to the baseline visit (day 1), there was an additional visit during the first week (day 8) and one visit each during weeks 2 (day 15), 4 (day 29), 6 (day 43), and 8 (day 57). On each visit day, patients reported to the study center prior to taking their morning medication. At this time, sitting cuff BP and heart rate were measured, samples were taken for clinical laboratory tests, and adverse events and compliance with medication were assessed. Cuff measurements were taken in duplicate by the same observer at each visit. At any visit, if the daily average sitting cuff DBP was ≥120 mm Hg or daily average sitting cuff systolic BP (SBP) was ≥200 mm Hg, the patient was removed from the study and treated with appropriate antihypertensive therapy at the discretion of the investigator. Ambulatory BP was measured for 24 hours on days 1 and 58 with a Spacelabs 90207, 3000‐series monitoring device (Spacelabs, Redmond, WA). All 24‐hour BP measurements were recorded automatically by Medicom computer software (Medifacts, Ltd., Rockville, MD).

Efficacy and Safety Variables

The primary efficacy variable in this trial was the change in mean 24‐hour DBP during treatment in the placebo and olmesartan medoxomil q.d. dose groups. This change was calculated as the difference between mean baseline 24‐hour DBP, as measured by ambulatory BP monitoring, and the same measurement on day 58. Other variables examined include the following: change in 24‐hour DBP in the olmesartan medoxomil b.i.d. dosing group; change in 24‐hour SBP in all treatment groups; change in mean daytime (8 a.m.–7:59 p.m.) and nighttime (8 p.m.–7:59 a.m.) DBP and SBP in all treatment groups; and change in sitting cuff BP in all treatment groups. The duration and consistency of the BP reduction during treatment was assessed by measuring the trough‐to‐peak (T/P) ratio of the 24‐hour DBP and SBP records after 8 weeks of treatment.

The safety assessment included a complete medical history during screening and a complete physical examination at screening, before randomization (baseline), and at day 58. A 12‐lead supine electrocardiogram was obtained during screening and on days 1, 29, and 58 of the active treatment period. During screening, a chest x‐ray was taken of each patient who had not received one during the previous 12 months. Pill counts were performed to assess compliance with all medication protocols.

Samples for blood chemistry, hematology, and urinalysis were obtained at screening and at each visit during the active treatment period. All samples were taken after a minimum fast of 8 hours. At each visit, all adverse events reported spontaneously by the subjects or observed or elicited by the investigator were recorded. The intensity of the adverse event and the possible relationship of the adverse event to the study medication were assessed by the investigator who recorded the event. An adverse event was classified as severe if it was incapacitating and resulted in loss of ability to perform work or usual activities.

Statistical Analyses

All statistical analyses presented were performed on the intent‐to‐treat population. Two intent‐to‐treat populations were defined: one for ambulatory BP measurement and one for cuff BP measurement. These populations were defined as those patients who received at least one dose of randomized study drug and had a follow‐up measurement of ambulatory BP and/or cuff BP. If a subject dropped out of the experiment prior to day 58, data from the last observation were carried forward for purposes of analysis.

Descriptive statistics of all variables are presented as means and standard deviations. For baseline comparison among the treatment groups, the chi‐square test or Fisher's exact test was used for categorical variables, while analysis of variance was used for continuous variables. The primary efficacy variable was analyzed with an analysis of covariance model, with the baseline value as a covariate. The model‐adjusted (least‐squares) means were computed accordingly, and Dunnet's test was used to compare the least‐squares means for each active treatment with placebo. All subsequent references to means in the discussion of the results of the analyses of mean change from baseline refer to least‐squares means rather than unadjusted raw means. All statistical tests were two‐tailed, and a probability (p) of <0.05 was considered significant.

The T/P ratio was calculated by determining the placebo‐corrected difference in hourly BP between the baseline and last‐day measurements. The differences were then fitted with a seven‐term Fourier series, and the T/P ratio was calculated as the ratio of the BP measurement at 24 hours after treatment to the maximum value for the curve and expressed as a percentage. Application of Fourier analysis to long‐term ambulatory BP measurements identifies systematic trends by reducing the short‐term variation in the data, thus smoothing the BP curve and improving trough and peak estimates. ⁶

RESULTS

Patient Characteristics

A total of 650 patients were screened at 36 centers for entry into this study, and 535 patients were enrolled for the placebo run‐in. Of these 535, 145 failed to meet either the ambulatory BP or cuff BP criteria for randomization into the study. Another 56 patients were not randomized for various reasons. The demographic characteristics of the 334 randomized patients (48 placebo, 286 olmesartan medoxomil) are shown in Table I.

Table I.

Mean Demographic Characteristics of All Randomized Patients

		q.d. Groups			b.i.d. Groups
	Placebo	5 mg	20 mg	80 mg	2.5 mg	10 mg	40 mg
N	48	45	45	48	50	48	50
Mean age (years)	53	56	52	52	53	53	56
Male (%)	60	67	69	67	68	60	68
Black (%)	10.4	8.9	6.7	10.4	14.0	8.3	8.0
Mean weight (lb)	186	184	189	184	190	185	189
Baseline mean 24‐hr DBP (mm Hg)	94	96	96	95	94	95	95
Baseline mean 24‐hr SBP (mm Hg)	149	151	149	148	148	148	151
DBP=diastolic blood pressure; SBP=systolic blood pressure

A total of 36 patients (10.8%) (eight placebo, 28 olmesartan medoxomil) discontinued the study before completion of the 8‐week double‐blind treatment period. The most common reasons for discontinuation were patient request (10, olmesartan medoxomil); adverse events (eight; two placebo, six olmesartan medoxomil); and investigator's judgment (seven; two placebo, five olmesartan medoxomil).

Ambulatory BP and Heart Rate Measurements

A total of 317 (95%) of the randomized patients had a follow‐up ambulatory BP measurement and thus constituted the intent‐to‐treat group for this measurement. Hourly predicted values of mean DBP and SBP before and after 8 weeks of treatment with 20 mg olmesartan medoxomil q.d., as predicted from fitted Fourier series, are shown in Figure 1. Treatment with olmesartan medoxomil resulted in a significant reduction of both mean DBP and mean SBP that was sustained over 24 hours. A qualitatively similar result was noted with all other doses of the study drug.

Figure 1.

Mean fitted values of 24‐hour ambulatory diastolic blood pressure (DBP) and ambulatory systolic blood pressure (SBP), as determined by Fourier analysis at baseline and after 8 weeks of treatment with 20 mg olmesartan medoxomil q.d. (n=41)

The change in mean 24‐hour DBP, the primary efficacy variable of this study, is shown in Figure 2. Treatment of patients with a total daily dose of 5, 20, or 80 mg of olmesartan medoxomil in either q.d. or b.i.d. dosing resulted in a significant (p<0.0001) reduction in mean DBP compared to the placebo group. The placebo‐corrected reduction in mean 24‐hour DBP after treatment ranged from 8.7–12.2 mm Hg.

Figure 2.

Least‐squares mean change in ambulatory diastolic blood pressure (DBP) in intent‐to‐treat patients receiving placebo (PL) or olmesartan medoxomil. All values are means±SD. The total daily dose of olmesartan medoxomil was given q.d. (filled bar) or b.i.d. (open bar). *Significant (p<0.0001) difference from placebo

The placebo‐corrected changes in mean 24‐hour DBP and SBP and in daytime and nighttime ambulatory DBP and ambulatory SBP are presented in Table II. All doses of olmesartan medoxomil resulted in highly statistically significant (p<0.0001) reductions in all BP measurements, regardless of whether dosing was q.d. or b.i.d. The placebo‐corrected reduction in mean 24‐hour SBP ranged from 12.4–16.5 mm Hg. Reductions in both mean DBP and mean SBP tended to be somewhat larger during the day than during the night. There was minimal change from baseline BP in the patients given placebo.

Table II.

Placebo‐Adjusted Mean Change in 24‐Hour, Daytime, and Nighttime Blood Pressure for the Intent‐to‐Treat Population Treated With Olmesartan Medoxomil or Placebo

	q.d. Groups			b.i.d. Groups
	5 mg	20 mg	80 mg	2.5 mg	10 mg	40 mg
	n=43	n=41	n=45	n=49	n=45	n=48
Δ 24‐hour DBP	−9.6	−12.2	−10.6	−8.7	−11.0	−11.1
	± 1.7	± 1.7	± 1.7	± 1.3	± 1.4	± 1.4
Δ 24‐hour SBP	−14.5	−16.5	−15.4	−12.4	−15.8	−16.3
	± 2.4	± 2.4	± 2.3	± 2.0	± 2.1	± 2.1
Δ Daytime DBP	−10.2	−12.8	−10.5	−8.3	−10.5	−12.0
	± 1.9	± 1.9	± 1.8	± 1.4	± 1.5	± 1.5
Δ Daytime SBP	−15.7	−17.9	−16.2	−12.4	−15.6	−18.1
	± 2.5	± 2.5	± 2.5	± 2.1	± 2.2	± 2.1
Δ Nighttime DBP	−8.5	−11.5	−10.6	−9.1	−11.3	−10.0
	± 1.8	± 1.8	± 1.8	± 1.5	± 1.6	± 1.5
Δ Nighttime SBP	−13.1	−15.2	−14.8	−12.4	−16.0	−14.2
	± 2.6	± 2.6	± 2.5	± 2.3	± 2.4	± 2.3
DBP=diastolic blood pressure; SBP=systolic blood pressure							All values are means±SD (mm Hg). All changes in blood pressure were statistically significant (p<0.0001) compared to placebo.

The change in 24‐hour heart rate in all groups treated with olmesartan medoxomil was small and nonsignificant. The magnitude of the change in 24‐hour heart rate was less than one beat per minute in all treatment groups except those on the largest doses (80 mg q.d. group), where a nonsignificant increase of 2.1 beats per minute was noted.

T/P Ratio

Placebo‐adjusted T/P ratios of DBP and SBP in patients are shown in Table III. For all q.d. and b.i.d. doses, the T/P ratios were greater than 50% on the last day of treatment. T/P diastolic ratios ranged from 57%–73%, and systolic ratios from 58%–63%.

Table III.

Mean Trough‐to‐Peak Ratios (%) of DBP and SBP Measurements in Patients Treated With Olmesartan Medoxomil

	q.d. Groups			b.i.d. Groups
	5 mg	20 mg	80 mg	2.5 mg	10 mg	40 mg
Diastolic T/P	57.2	70.1	64.9	69.5	73.0	68.2
Systolic T/P	62.6	57.7	60.9	59.2	63.0	60.1
T/P=trough‐to‐peak; DBP=diastolic blood pressure; SBP=systolic blood pressure

Comparability of Once‐ and Twice‐Daily Dosing

Comparability of q.d. and b.i.d. dosing was assessed by comparing mean reductions of ambulatory BP during the last hour of the 24‐hour dosing period with comparable amounts of olmesartan medoxomil given either q.d. or b.i.d. on day 57 of treatment. The results of this comparison are shown in Table IV. At all comparable doses, reductions of mean DBP and SBP following q.d. and b.i.d. dosing were not significantly different.

Table IV.

Mean Reduction of DBP and SBP During the Last Hour of Daily q.d. or b.i.d. Dosing of Olmesartan Medoxomil

		DBP			SBP
Daily Dose (mg)	q.d.	b.i.d.	p Value	q.d.	b.i.d.	p Value
5	−6.2	−4.6	0.57	−13.8	−7.2	0.06
20	−9.2	−9.2	0.99	−12.0	−10.5	0.63
80	−8.1	−11.0	0.30	−13.6	−14.6	0.79
DBP=ambulatory diastolic blood pressure; SBP=ambulatory systolic blood pressure

Cuff BP

Changes in sitting cuff DBP in the intent‐to‐treat patients after treatment are shown in Figure 3. All doses of olmesartan medoxomil significantly decreased sitting cuff DBP (p<0.0001), regardless of whether they were given q.d. or b.i.d. Sitting cuff SBP was also reduced by treatment. SBP fell by 11.7,15.8, and 16.0 mm Hg in patients treated with 2.5, 10, and 40 mg olmesartan medoxomil b.i.d., respectively. Treatment with 5, 20, and 80 mg q.d. resulted in reductions of SBP of 9.8,12.9, and 12.6 mm Hg, respectively.

Figure 3.

Least‐squares mean change in cuff diastolic blood pressure (DBP) in intent‐to‐treat patients receiving placebo (PL) or olmesartan medoxomil. All values are means±SD. The total daily dose of olmesartan medoxomil was given q.d. (filled bar) or b.i.d. (open bar). *Significant (p<0.0001) difference from placebo

Analysis of the interim measurements of cuff BP indicated that a statistically significant response relative to placebo was present after 2 weeks of treatment. At this time, mean diastolic sitting cuff BP was reduced by 2.4, 6.8, 8.5 mm Hg, and 7.4 mm Hg in patients receiving placebo, 5, 20, or 80 mg of olmesartan medoxomil q.d., respectively.

Safety

Fifty‐six percent of the patients given placebo had at least one adverse event. A similar percentage (60%) of patients treated with 20 mg olmesartan medoxomil q.d. also had at least one adverse event. In all other dosing groups of the study drug, the incidence of adverse events was lower than in placebo‐treated patients (44%–50%). Clinical adverse events occurring in more than 2% of the patients treated with olmesartan medoxomil are shown in Table V. The most common clinical adverse events reported during treatment were headache, dizziness, and pain, but of these three, only dizziness and pain had a higher rate of occurrence than in placebo‐treated patients. None of the adverse events seen during treatment was dose‐dependent. Similarly, no trends or clinically significant dose relationships were observed for laboratory adverse events.

Table V.

Treatment‐Emergent Adverse Events Occurring in More Than 2% of Patients Treated With Olmesartan Medoxomil

Event	Olmesartan Medoxomil (n=286) %	Placebo (n=48) %
Total	49.6	56.0
Headache	16.4	20.8
Dizziness	5.2	0
Pain	5.6	0
Infection	3.8	8.3
Asthenia	3.5	4.2
Myalgia	3.1	4.2
Dyspepsia	2.4	0
Rhinitis	2.1	6.2

The overall incidence of serious adverse events was low in both olmesartan medoxomil and placebo groups (1.4% and 8.3%, respectively). Adverse events leading to withdrawal from the study were seen in six patients (2%) receiving olmesartan medoxomil and two patients (4%) receiving placebo. Only one withdrawal for nausea was considered related to treatment with olmesartan medoxomil.

DISCUSSION

In this study, we have shown that treatment with olmesartan medoxomil, an angiotensin II receptor blocker, results in significant reductions in both mean 24‐hour DBP and SBP at all evaluated dosages, when compared to placebo. In addition, the side effect profile at all dosages tested was similar to that seen with placebo.

One of the principal objectives of this study was to determine the ability of olmesartan medoxomil to maintain effective BP control over the entire dosing interval when given once a day. Once‐per‐day dosing is important because it increases patient compliance with medication, one of the most important determinants of effective BP control. ⁷ It is also important that the 24‐hour effectiveness of once‐per‐day BP medications be evaluated. If a patient takes a drug that does not have a true 24‐hour efficacy in the morning, loss of effective BP control will occur during the last 4–6 hours of the dosing period. This is the time of day that corresponds to the post‐arousal period of rapid BP rise that occurs between 6 a.m. and noon of the day following dosing, ⁸ and also coincides with the period of peak incidence of nonembolic stroke and myocardial infarction. Loss of BP control in the morning may substantially increase the risk of cardiovascular events during this period. Thus, it is important that the effectiveness of once‐daily antihypertensive treatments be evaluated during this early‐morning period.

Ambulatory BP monitoring is the most reliable way to test the 24‐hour efficacy of an antihypertensive agent. Use of ambulatory BP monitoring permits elimination of patients with white‐coat hypertension from the study and provides a continuous record of BP during the normal daily activities of the patient. ⁹ As shown in Figure 2, when ambulatory BP criteria are used for patient selection, there is virtually no BP response to placebo treatment. Minimizing the placebo effect allows a more accurate assessment of drug efficacy.

In this study, we have compared the mean reductions in BP achieved during the final hour of the 24‐hour dosing interval, as measured with an ambulatory BP monitor following comparable doses of olmesartan medoxomil given either q.d. or b.i.d. As shown in Table IV, there were no significant differences in mean DBP and SBP during the final hour following comparable q.d. or b.i.d. dosing. This is perhaps the most stringent method of assessing 24‐hour drug efficacy with once‐daily dosing, since it compares BP reductions during the final hour following a single daily dose with reductions obtained with the same agent at a time much closer to the period of peak drug availability following a second daily dose. These results clearly indicate that olmesartan medoxomil is effective in a once‐a‐day dosing schedule.

The duration of action of olmesartan medoxomil was also assessed by calculating the placebo‐corrected T/P ratio of the 24‐hour DBP and SBP records of patients receiving the drug at the end of the 8‐week treatment period. Use of the T/P ratio to evaluate the efficacy of antihypertensive drugs has been recommended by the Food and Drug Administration. ¹⁰ The principal concern addressed by the use of the T/P ratio is the need for adequate BP control late in the dosing interval without an excessive reduction in BP at the time of peak drug response. An optimal antihypertensive formulation should provide 24‐hour efficacy with a once‐daily dose, with at least 50% of the peak effect remaining at the end of 24 hours. ¹¹ For both DBP and SBP, the T/P ratios for olmesartan medoxomil ranged from 57.2% to 70.1% across the q.d. dose range. At all q.d. doses, the T/P ratio was greater than 50%, indicating continued 24‐hour antihypertensive efficacy after 8 weeks of treatment. This observation provides further evidence of the long duration of action of this agent, with maintenance of antihypertensive efficacy at the end of the dosing period.

The adverse events noted during treatment of patients with olmesartan medoxomil were similar to those reported for other drugs of this class. ¹² The observation that the incidence of headache may be slightly lower in patients treated with olmesartan medoxomil than in patients receiving placebo is consistent with recent data suggesting that effective treatment of mild to moderate hypertension may actually reduce the occurrence of headache. ¹³ The incidence of withdrawal due to adverse events (2%) was less than in placebo‐treated patients (4%) and comparable to rates reported with other angiotensin receptor blockers. ¹⁴ , ¹⁵ In general, olmesartan medoxomil appeared to be well tolerated and to have an overall adverse event profile similar to that of placebo.

In summary, the results of the present study indicate that olmesartan medoxomil is an effective and safe drug for the treatment of hypertension. A single daily dose of results in effective control of BP for the full 24‐hour treatment period as assessed by ambulatory BP measurements and T/P ratio. The full antihypertensive response is achieved within 2 weeks of initiating therapy. Olmesartan medoxomil has a safety and tolerability profile similar to that of placebo.

Acknowledgment: This study was supported by Sankyo Pharma Inc., manufacturer of olmesartan medoxomil.