Olmesartan Medoxomil-Based Antihypertensive Therapy Evaluated by Ambulatory Blood Pressure Monitoring

Olmesartan Medoxomil-Based AntihypertensiveTherapy Evaluated by Ambulatory Blood PressureMonitoringEfficacy in High-Risk Patient Subgroups

Steven G. Chrysant,1 F. Wilford Germino2 and Joel M. Neutel3

1 Oklahoma Cardiovascular and Hypertension Center and the University of Oklahoma School of Medicine, Oklahoma City, OK, USA

2 Department of Internal Medicine, Orland Primary Care Specialists, Orland Park, IL, USA

3 Orange County Research Center, Tustin, CA, USA

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

1.1 Importance of Blood Pressure (BP) Goals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

1.2 Role of 24-Hour BP Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

1.3 Treatment Recommendations and Rationale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

1.4 Objective of this Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

1.5 Search Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

2. Efficacy of Olmesartan Medoxomil-Based Therapy on Ambulatory BP Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

2.1 Ambulatory BP Lowering from Baseline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

2.1.1 Olmesartan Medoxomil-Based Therapy Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

2.1.2 Impact of Time of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

2.1.3 Olmesartan Medoxomil versus Comparator Antihypertensives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

2.2 24-Hour Systolic BP/Diastolic BP Goal Attainment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

2.3 Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

3. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

Abstract Hypertension affects approximately 26% of the world’s adult population and is a recognized major risk

factor for morbidity and mortality associated with cardiovascular, cerebrovascular, and renal diseases.

However, despite the availability of a range of effective antihypertensive agents and a growing awareness of

the consequences of high blood pressure (BP), the treatment and control of hypertension remains sub-

optimal. A number of patient subgroups are categorized as ‘high risk’ and may have hypertension that is

more difficult to treat, including obese individuals, patients with stage 2 hypertension, those with type 2

diabetes mellitus (T2DM), patients with coronary artery disease or a history of stroke, and Black patients.

As the benefits of lowering BP in patients with hypertension are unequivocal, particularly in high-risk

patients, treating high-risk patients with hypertension to BP goals and maintaining 24-hour BP control is

important to help reduce cardiovascular risk and improve outcomes. Although the BP goals recommended

in current consensus guidelines for the management of patients with hypertension are based on cuff BP

measurements, ambulatory BP monitoring (ABPM) provides a valuable diagnostic tool and allows a more

accurate assessment of BP levels throughout the 24-hour dosing period. ABPM is a better predictor of

REVIEWARTICLEAm J Cardiovasc Drugs 2012; 12 (6): 375-389

1175-3277/12/0006-0375/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

prognosis than office BP measurement and is also useful for assessing whether antihypertensive therapy

remains effective in the critical last few hours of the dosing period, which usually coincides with the morning

BP surge associated with arousal and arising.

ABPM has been adopted by new evidence-based guidelines in the United Kingdom to confirm a sus-

pected diagnosis of hypertension, which is an indication of the growing importance of ABPM in the

management of hypertension. This review provides an overview of the efficacy and safety of anti-

hypertensive therapy based on olmesartan medoxomil – hydrochlorothiazide and amlodipine/olmesartan

medoxomil in high-risk patient populations enrolled in studies that reported ambulatory BP endpoints. The

studies identified in this review showed that a titrate-to-BP goal strategy using olmesartan medoxomil- or

amlodipine/olmesartan medoxomil-based antihypertensive therapy was an effective and well-tolerated ap-

proach for maintaining BP control throughout the full 24-hour dosing period in high-risk patients with

difficult-to-treat hypertension.

1. Introduction

Hypertension is highly prevalent globally and a recognized

major risk factor for morbidity and mortality associated with

cardiovascular (CV), cerebrovascular, and renal diseases.[1-3] Hy-

pertension affects approximately 26% of the world’s adult popu-

lation, ranging from 20% to 40% of adults inWestern countries,[4]

and approximately one-third of the adult US population.[5]

There is a linear correlation between blood pressure (BP)

and the risk of death from ischemic heart disease and stroke,

regardless of age, with a doubling of the risk for each 20-mmHg

increase in systolic BP (SBP) or 10-mmHg increase in diastolic

BP (DBP).[3,6] Despite the availability of a range of effective

antihypertensive agents and a growing awareness of the con-

sequences of high BP, treatment and control of hypertension

remain suboptimal.[5] As a consequence of the low rate of BP

goal achievement, current guidelines recognize that most pa-

tients will require combination therapy to achieve their BP

goal.[6-8] The need for multiple drug therapy to achieve a BP

goal of <130/80mmHg for patients with diabetes mellitus is

supported by the American Diabetes Association and American

Association of Clinical Endocrinologists guidelines.[9,10] More-

over, for Black patients, the International Society on Hyper-

tension in Blacks 2010 Consensus Statement also recommends

combination therapy if BP is >15/10mmHg over their recom-

mended target, and BP ‡135/85mmHg if no target organ

damage, preclinical CV disease (CVD), or CVD are present, or

BP <130/80mmHg if target organ damage, preclinical CVD,

and/or history of CVD are present.[11]

Specific subgroups of patients with hypertension are considered

to be high risk, including obese individuals, patients with either

more severe (stage 2) or isolated systolic hypertension, those

with type 2 diabetes mellitus (T2DM), patients with coronary

artery disease or a history of stroke, and Black patients. Such

patients are considered to be more challenging to treat and

manage because of a high incidence of co-morbidities and other

clinical issues.[6,7,12] Hypertension is highly prevalent in patients

with T2DM, occurring at a rate approximately 1.5 to 3 times

higher than in the age-matched non-diabetic population.[13]

Also, the risk of CVD (including coronary artery disease, pe-

ripheral arterial disease, myocardial infarction, heart failure,

and stroke) and renal insufficiency in patients with both dia-

betes and hypertension is greatly increased.[13] Other compli-

cations in patients with diabetes and hypertension include

diabetic nephropathy, retinopathy, and neuropathy.[14,15]

Someminority populationswith hypertension are also at higher

risk than the general population. Specifically, in the United States,

hypertension ismore common inBlacks, develops at an earlier age,

is more severe, and is associated with a higher rate of clinical

complications than in age-matched non-Hispanic Whites.[6] In

addition, higher rates of other CV risk factors, such as obesity and

diabetes, increase the risk of fatal and non-fatal stroke, congestive

heart failure, and end-stage kidney disease in Blacks.[6,12,16,17]

In addition to predisposing patients to diabetes, obesity is in

itself a major independent CV risk factor[6] and influences prog-

nosis in hypertensive patients.[7] Finally, more severe (stage 2)

hypertension is more difficult to treat[6] and is associated with a

higher risk of CVD and stroke than less severe hypertension.[3,16]

However, the clinical benefits of lowering BP in patients with

hypertension are unequivocal, particularly in high-risk patients.[6,7]

Therefore, treating high-risk patients with hypertension to BP

goals and maintaining 24-hour BP control are important fac-

tors to reduce CV risk and improve outcomes.

1.1 Importance of Blood Pressure (BP) Goals

Current consensus practice guidelines for the management

of hypertension are based on clinical trial evidence demon-

376 Chrysant et al.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Am J Cardiovasc Drugs 2012; 12 (6)

strating that treating patients with hypertension to defined BP

thresholds, or goals, improves long-term outcomes.[6,7,18] To

maximize CV protection, the guidelines recommend a seated

cuff BP goal of <140/90mmHg in the general hypertensive

population, with a more stringent goal of <130/80mmHg for

patients with diabetes, established CVD, or chronic kidney

disease.[6,7] There is reasonably strong clinical evidence for

this more stringent goal in patients with diabetes. However,

lower levels of evidence supporting this lower goal exist

for Black patients, patients with obesity, or those with stage 2

hypertension.[6,7]

1.2 Role of 24-Hour BP Monitoring

The limitations of traditional office BP measurement are

increasingly recognized, as measuring BP in a clinical setting

may be inadequate or misleading for the following reasons:

(i) the inherent variability of BP together with the small number

of readings typically taken in the office and ‘white coat’ or

‘masked’ effects resulting in increased or decreased BP, re-

spectively; (ii) observer bias; (iii) poor measurement technique,

including incorrect choice of cuff size, terminal digit preference,

rapid cuff deflation, and bladder size; (iv) improper sphyg-

momanometry equipment maintenance and/or calibration; and(v) varying levels of technical expertise in BP measurement

amongst the clinic staff.[18-20] Ambulatory BP monitoring

(ABPM) allows the collection of multiple BP measurements

on a regular basis. Consequently, ABPM provides a more ac-

curate assessment of mean BP levels, and thus better reflects

prevailing BP than office BP readings, and reveals masked

hypertension.[18] ABPM also provides important additional

clinical value, as clinic BP has a weak relationship with 24-hour

BP, and ambulatory BP (ABP) is relatively unaffected by ‘white

coat’ hypertension and has a better correlation with hyper-

tension-related organ damage and the effect of antihypertensive

treatment than do clinic BP readings.[6,7,18] Furthermore, com-

parison of the impact of office andABP on long-term prognosis

shows that ABP better predicts prognosis, even after adjust-

ment for associated risk factors.[19,21-23] For example, over

a 5-year follow-up period of 1963 adult patients (mean age

57 years), those with mean 24-hour SBP ‡135mmHg on anti-

hypertensive therapy were almost twice as likely to have a CV

event as patients with mean 24-hour SBP of <135mmHg, re-

gardless of office BP values.[21] In another study, ABPM was

also a more accurate predictor of CV mortality than was clinic

BP in 1144 elderly patients (mean age 73 years) with hyper-

tension.[24] After adjusting for clinic BP, night-time BP in this

study was a better predictor than daytime BP; there was an 18%

increase in the relative risk of CV death for each 10-mmHg

increase in night-time SBP, compared with a 10% mortality

increase for each 10-mmHg increase in daytime SBP. In con-

trast, for a corresponding increase in clinic SBP, there was no

significant increase in mortality.[24] Therefore, in order to re-

duce CV events and improve the CV risk profile of patients with

hypertension, optimal antihypertensive therapy should main-

tain BP control throughout the full 24-hour dosing period.

The availability of automated, non-invasive ABPM devices

that measure BP throughout the 24-hour period has demon-

strated that BP generally follows a distinct and reproducible

circadian pattern, with BPmaintained at its highest level during

the daytime and declining during the night-time to reach a

trough between approximately midnight and 03:00 hours.[25]

A slow and steady increase in BP is then observed until ap-

proximately 06:00 hours, at which point an abrupt and steep

surge in BP occurs that coincides with arousal and arising.[25,26]

This is particularly important because the end of the 24-hour

drug-dosing period usually coincides with the morning BP

surge, which is linked to an increased risk of CV events.[25,27]

Therefore, ABPM is also a useful approach for assessing the

ability of an antihypertensive agent to control BP throughout

the entire 24-hour dosing interval.

In addition to its prognostic value in predicting clinical

outcomes, ABP may provide additional predictive informa-

tion.[19,22] There is increasing evidence that BP variability

in itself is an independent predictor of clinical outcomes, and

ABPMprovides information on aspects of the circadian profile

of BP, including BP variability, the morning surge in BP noted

above, dipping status, and nocturnal BP patterns.[18,19] This

allows the identification of high-risk patients, independent of

BP measurement obtained in the office setting. False-positive

diagnoses (‘white coat’ hypertension) and false-negative diag-

noses (masked hypertension) are reduced, avoiding either un-

necessary treatment or undertreatment. ABPM is also the most

effective method of determining BP values during the sleep

cycle when nocturnal hypertension or a non-dipping pattern of

diurnal BP variation (<10% reduction from daytime to night-

time BP) are suspected.[19] This pattern is of relevance in the

treatment of high-risk patients because an increased prevalence

of non-dipper status has been reported in obese patients,

patients with sleep apnea, patients with T2DM or stage 2 hy-

pertension, and in Black patients.[28,29] Furthermore, there is

some evidence that non-dippers are at greater CV risk than

those with a normal nocturnal dipping pattern (typically SBP is

10–20mmHg lower at night-time than during the day),[22,28]

and a treatment that promotes a switch from non-dipper to

dipper status may facilitate a reduction in CV risk.

Efficacy of Olmesartan-Based Therapy in High-Risk Patients 377


Although there are currently no specific practice guideline

recommendations for ABP goals, the American Heart Associ-

ation and the European Society of Hypertension suggest target

levels of <135/85, <120/70, and <130/80mmHg as normal for

daytime, night-time, and 24-hour average ABP, respectively, and

<130/80, <115/65, and <125/75mmHg as optimal values.[22,30]

A daytimeABPof 135/85mmHg corresponds approximately to

a clinic BP of 140/90mmHg, which is the threshold abovewhich

CV risk appears to substantially increase.[23,31]

The recent evidence-based guidelines from the National In-

stitute for Health and Clinical Excellence (NICE)[18] in the

United Kingdom include ABPM guidance that is expected

to have far-reaching implications. They recommend that if

hypertension is suspected (clinic BP of ‡140/90mmHg), the

patient should be offered ABPM to confirm the diagnosis of

hypertension, and ensure that they do not have masked hy-

pertension, determine their dipping status, and check for BP

variability.[18] Although this is not currently the standard of

care in the USA, it does provide an additional rationale for the

use of ABPM. Furthermore, the NICE recommendations are

supported by robust evidence that ABPM is superior to clinic

BP measurement for the cost-effective diagnosis of hyper-

tension in patients with suspected BP of >140/90mmHg, re-

sulting in improved health outcomes for men and women with

hypertension regardless of age.[32] It should be noted that there

are currently no specific ABP target recommendations for pa-

tients with difficult-to-treat hypertension such as Black patients,

patients with diabetes, elderly patients, etc.

1.3 Treatment Recommendations and Rationale

A titrate-to-BP goal approach is usually used to manage

hypertension, starting with the appropriate class and com-

bination of antihypertensives according to the degree of

hypertension and other risk factors.[6] If more than one anti-

hypertensive agent is required to achieve BP control, selecting

agents with complementary mechanisms of action is a rational

and recommended treatment approach.[6-8] For example,

the antihypertensive effects of angiotensin II type I receptor

blockers (ARBs) can be enhanced by the addition of a diuret-

ic.[33] Combination therapy may be more effective than

increasing the dose of a single agent, and may also alleviate ad-

verse events[30] associated with any of the component mono-

therapies, contributing to long-term compliance.[6-8,34]

The efficacy and safety of treatment regimens based on the

ARB olmesartan medoxomil, alone or in combination with

hydrochlorothiazide (HCTZ) or the dihydropyridine calcium

channel blocker (CCB) amlodipine, has been demonstrated in a

number of clinical trials and/or subgroup analyses in a variety

of high-risk patient populations, such as those with stage 2

hypertension, obesity, T2DM, and in Black patients.[34-40] The

24-hour BP-lowering efficacy of olmesartan medoxomil anti-

hypertensive therapy has also been compared with the ARB tel-

misartan in Japanese patients with hypertension and T2DM.[41]

1.4 Objective of this Review

This article reviews the efficacy and safety of olmesartan

medoxomil –HCTZ and amlodipine/olmesartan medoxomil

combination therapy in high-risk patient populations (Blacks,

patients with obesity, stage 2 hypertension, or T2DM) enrolled

in studies that reported ABP endpoints.

1.5 Search Strategy

A search of the medical literature using MEDLINE and

EMBASE (English-language articles only) was conducted

using the keywords ‘olmesartan’ and ‘hypertension’ and ‘am-

bulatory’ for the search period of January 1995–December

2011. The full articles were retrieved and the results were then

manually filtered to identify studies in which the efficacy of

olmesartan medoxomil-based antihypertensive therapies in

high-risk patients was assessed using ABPM. Additional ref-

erences were identified from the reference list of published ar-

ticles. Searches were last updated on 20 December 2011. It

should be noted that, although the search results did include

a phase III trial against azilsartan wherein some patients

had stage 2 hypertension, no subgroup results were provided,

and thus those findings could not be included in the present

review.[42]

2. Efficacy of Olmesartan Medoxomil-Based Therapy

on Ambulatory BP Parameters

Table I summarizes the study design, patients, interventions,

and endpoints of studies of olmesartan medoxomil-based

therapy in which changes in ABP parameters were reported in

the high-risk patient subgroups included in this review (Blacks,

stage 2 hypertension, T2DM, and obesity). Although not a

specific focus of this review, studies of elderly patient cohorts

were included if they reported ABP data and included analysis

of data from high-risk patient subgroups of interest. In cases

where reported data for a high-risk subgroup or groups was

part of a subgroup analysis, results for the total study popu-

lation are not included but only data for the high-risk sub-

group(s) in order to keep within the scope of the review.

378 Chrysant et al.


Table I. Clinical trials with ABP endpoints that assessed OM-based antihypertensive therapy in high-risk patient subgroups of interest

Study Pts (no.) Study design Patient details Treatment groups Primary efficacy endpoint

AZTEC[43,44] HTN (185) 16-wk, OL, MC, SA titration study in

adult pts with mean SeSBP ‡140and £199mmHg or mean SeDBP

‡90 and £109mmHg

Female= 43%White = 78%Black= 14%Mean age=57 yStage 2 HTN= 56%T2DM =25%Obese= 52%Mean SeSBP/SeDBP = 158.2/92.8mmHg

Mean 24-h ABP=144.8/85.7mmHg

1) PLA run-in for 3–4wk

2) AML 5mg od for 3wk

3) Step-wise titration to successive

3-wk courses of AML/OM 5mg/20mg,

AML/OM 5mg/40mg, and AML/OM

10mg/40mg od if SeBP remained

‡120/80mmHg

Change from BL in mean

24-h ambulatory SBP at

12wk

BP-CRUSH[45,46] HTN (999) 20-wk OL, MC, SA titration study in

adults with HTN uncontrolled on

‡1mo of antihypertensive

monotherapywith anACEI, ARB, b-

blocker, CCB, or diuretic

Female= 49%White = 63%Black= 23%Hispanic = 11%Mean age=56 yT2DM =19%Obese= 51%Mean SeSBP/SeDBP = 153.7/91.9mmHg


1) AML/OM 5mg/20mg od for 4wk



AML/OM 10mg/40mg, AML/OM

10mg/40mg + HCTZ 12.5mg, and

AML/OM 10mg/40mg + HCTZ 25mg if

mean BP remained ‡120 and

<200mmHg or a mean DBP ‡70 and

<115mmHg

Cumulative percentage of

pts attaining SeSBP goal of

<140mmHg (<130mmHg in

pts with T2DM) at any time

during first 12wk

BeniSILVER[35,47,48] Elderly [‡65 y](176)

12-wk, OL, MC, blinded-endpoint

study in pts aged ‡65 y with stage 1

or 2 HTN and SeSBP/SeDBP‡140/90mmHg

Female= 48%White = 83%Black= 16%Age ‡65 y= 100%Mean age=72 yBMI ‡30 kg/m2 = 37%Stage 2 HTN= 66%T2DM =11%Mean SeSBP/SeDBP = 165.5/87.7mmHg


ISH= 56%


2) OM 20mg od for 3wk


3-wk courses of OM 40mg, OM/HCTZ40mg/12.5mg, and OM/HCTZ40mg/25mg od if SeBP remained

‡120/70mmHg



12wk

Continued next page

Efficacy

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Table I. Contd

Study Pts (no.) Study design Patient details Treatment groups Primary efficacy endpoint

BENIFICIARY[36,49,50] T2DM (192) 12-wk, OL, MC study in pts with

T2DM and SeSBP ‡140 to

£199mmHg and mean SeDBP

£114mmHg

Female= 44%White = 76%Black= 22%Mean age=58 yT2DM =100%Stage 2 HTN= 47%Mean SeSBP/SeDBP = 158.1/90.0mmHg



2) OM 20mg od for 3wk


3-wk courses of OM 40mg, OM/HCTZ40mg/12.5mg, and OM/HCTZ40mg/25mg od if SeBP remained

‡120/70mmHg



12wk

APEX[51] T2DM (207) 18-wk OL, MC, SA titration study

in adult pts with T2DM and mean

SBP >130mmHg and/or DBP>80mmHg

Female= 41%White = 79%Black= 17%Hispanic = 26%Mean age=59 yT2DM =100%Mean BMI= 32.8 kg/m2

Obese= 24%Mean SeSBP/SeDBP = 158.8/89.1mmHg



2) AML 5mg od for 3wk



AML/OM 5mg/40mg, and AML/OM

10mg/40mg od, followed by the

addition of HCTZ 12.5mg and 25mg

od, if SeBP remained ‡120/70mmHg



12wk

Tofe Povedano and

Garcia De La Villa[52]T2DM (38) 16-wk, randomized, C/O study in

antihypertensive-naıve pts with

T2DM, SeSBP >130mmHg,

and/or SeDBP >80mmHg,

confirmed by ABPM

Female= 58%Mean age=54 yT2DM =100%Mean T2DM duration= 5.4 yMean BMI= 27.9 kg/m2


Nocturnal BP fall =11%Dippers = 70%

1) OM 40mg od at awakening

(07:00–09:00) for 8wk

2) OM 40mg od at bedtime

(22:00–24:00) for 8wk

OM 40mg could be reduced to OM

20mg in cases of hypotension



wk 8 and 16

Nakayama et al.[41] Early stage

T2DM (20)

16-wk, OL, C/O study in pts with

early stage T2DM and HTN

treated with VAL 80mg od for

‡8wk

Female= 30%Mean age=64 yEarly stage T2DM= 100%Mean T2DM duration= 8.1 yMetabolic syndrome = 65%Mean BMI= 25.6 kg/m2


1) VAL 80mg od run-in for ‡8wk2) OM 20mg or TEL 40mg od for 8wk

3) Pts C/O to TEL 40mg or OM 20mg

od for 8wk

Concomitant antihypertensive

medication (calcium antagonist n = 9;diuretic n =3) was continued

unchanged



wk 8 and 16

ABP =ambulatory BP;ABPM =ambulatory BPmonitoring;ACEI= angiotensin-converting enzyme inhibitor;AML= amlodipine;ARB=angiotensin II type 1 receptor blocker;BL = baseline;BMI =body mass index; BP = blood pressure; C/O= crossover; h = hour(s); HCTZ = hydrochlorothiazide; HTN= hypertension; ISH= isolated systolic hypertension; MC=multicenter;

mo=month(s); no.= number; od = once-daily; OL= open-label; OM= olmesartan medoxomil; PLA= placebo; pt(s)= patient(s); SA = single-arm; SeDBP = seated cuff diastolic BP;

SeSBP = seated cuff systolic BP; T2DM = type 2 diabetes mellitus; TEL = telmisartan; VAL= valsartan; wk =week(s); y = year(s).

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2.1 Ambulatory BP Lowering from Baseline

2.1.1 Olmesartan Medoxomil-Based Therapy Regimens

The ABP-lowering efficacy of olmesartan medoxomil-based

therapy from studies with subgroup analyses of Blacks or pa-

tients with stage 2 hypertension, T2DM, or obesity are shown in

tables II, III, and IV. Five of the studies that used ABP param-

eters to evaluate the efficacy of olmesartan medoxomil-based

dose-titration antihypertensive regimens in high-risk patient

subgroups were identified and summarized below.

AZTEC

TheAZORTrial Evaluating Blood Pressure Reductions and

Control (AZTEC) (ClinicalTrials.gov identifier: NCT00527514)

was conducted in 185 patients with hypertension who were

treated with a fixed-dose combination of amlodipine and ol-

mesartanmedoxomil, using step-wise dose titration to achieve a

seated cuff BP goal of <120/80mmHg (table I).[43,44] ABP re-

sults stratified by obesity and T2DM are presented in table II.

After treatment for 12 weeks, the results of the subgroup anal-

ysis paralleled those shown in the primary study of patients

with stage 1 or 2 hypertension. Amlodipine/olmesartan me-

doxomil combination therapy reduced 24-hour mean ABP by

-21.4/-12.7mmHg in the overall study population, compared

with -21.6/-13.4mmHg in obese patients and -21.5/-12.6mmHg

in patients with T2DM. Changes from baseline in mean day-

time and night-time BP were also similar in the overall study

population, obese patients, and patients with T2DM (table II).

ABP changes from baseline during the last hours of the

dosing interval were also comparable (table II). For example,

mean BP changes during the last 6 hours were -18.8/-11.1mmHg

overall, and -18.0/-11.1 and -18.7/-10.3mmHg in obese patients

and patients with T2DM, respectively.

BP-CRUSH

The Blood Pressure Control in All Subgroups With Hy-

pertension (BP-CRUSH) study (ClinicalTrials.gov identifier:

NCT00791258) enrolled 999 patients with hypertension uncon-

trolled on one or more antihypertensive monotherapies with an

angiotensin-converting enzyme inhibitor, ARB, b-adrenoceptorblocker (b-blocker), CCB, or diuretic. This was a dose-titration

study wherein patients were treated with amlodipine/olmesartan

medoxomil–HCTZ for 12 weeks, and uptitrated to achieve BP

goals of <120/70mmHg (table I).[45] A subgroup analysis was

conducted in patients stratified by obesity (table II).[46]

Treatment with amlodipine/olmesartanmedoxomil –HCTZ

reduced 24-hour mean ABP by 14.8/9.4mmHg in non-obese

patients and by 13.6/8.8mmHg in obese patients. In both non-

obese and obese patients, there were also significant changes

from baseline in mean daytime and night-time BP (table II).

This treatment regimen produced significant changes from

baseline in ABP during the last hours of the dosing inter-

val (table II). During the last 6 hours, mean changes were

Table II. ABP-lowering efficacy of olmesartan medoxomil-based antihyper-

tensive therapy stratified by obesity and/or T2DM in studies of patients with

HTN that included high-risk subgroups at week 12

AZTEC study in 185 adult pts with HTN[43,44]

Results at wk 12 Overall

(N= 172)Obese pts

(n= 89)T2DM

(n= 43)

Pts achieving mean ABP targets, %

24-h (<130/80mmHg) 70.9 75.3 79.1

24-h ABP, mean (mmHg)

BL 144.8/85.7 143.7/84.9 145.6/83.1

Wk 12 123.5/73.0 122.1/71.5 124.1/70.5

Change from BL -21.4/-12.7* -21.6/-13.4* -21.5/-12.6*

Daytime BP, mean (mmHg)

Change from BL -23.1/-14.0* -23.6/-14.8* -23.7/-14.2*

Night-time BP, mean (mmHg)

Change from BL -18.5/-10.9* -18.5/-11.3* -19.9/-10.4*

Change from BL in last h of dosing interval, mean BP (mmHg)

6 h -18.8/-11.1* -18.0/-11.1* -18.7/-10.3*

4 h -19.5/-11.8* -18.7/-11.7* -19.1/-11.5*

2 h -20.6/-12.4* -18.9/-12.1* -19.3/-12.5*

BP-CRUSH study in 999 pts with uncontrolled HTN[45,46]


(N=243)Obese pts

(n= 118)


24-h (<130/80mmHg) 73.4 77.1

Daytime (<135/85mmHg) 72.9 78.0

Night-time (<120/70mmHg) 62.0 64.4


BL 136.2/81.6 134.3/79.8

Wk 12 121.4/72.2 121.2/71.0

Change from BL -14.8/-9.4* -13.6/-8.8*


Change from BL -16.3/-10.6* -15.6/-10.4*


Change from BL -12.5/-7.6* -10.7/-6.5*


6 h -12.6/-7.7* -11.4/-7.1*

4 h -13.0/-8.0* -12.0/-7.6*

2 h -13.6/-8.6* -12.5/-7.9*

ABP= ambulatory BP; BL= baseline; BP =blood pressure; h= hour(s);HTN= hypertension; pts= patients; T2DM= type 2 diabetes mellitus; wk =week(s). * p< 0.0001 vs BL.



-12.6/-7.7mmHg overall and -11.4/-7.1mmHg in obese

patients.

BeniSILVER

The Benicar Efficacy: New Investigation Shows Olmesartan

Medoxomil Treatment Increasingly Leads Various Elderly

Populations to Safe BP Reductions (BeniSILVER) study

(ClinicalTrials.gov identifier: NCT00412932) treated 176 elder-

ly hypertensive patients (aged ‡65 years) with olmesartan me-

doxomil –HCTZ, and uptitrated in a step-wise manner to

achieve BP goals of <120/70mmHg (table I). Patients were

stratified by race and hypertension severity (table III).[35,47,48]

At week 12, changes from baseline in 24-hour mean ABP

were -25.7/-12.3mmHg overall, -26.7/-11.8mmHg in Black

patients, and -26.5/-12.6mmHg in the stage 2 hypertension

subgroup (table III). ABP was significantly reduced from

baseline in the daytime and night-time intervals and in the last

hours of the dosing interval. Changes from baseline in mean

daytime and night-time ABP were similar across patient sub-

groups (table III), and similar significant changes in ABP

during the last hours of the dosing interval were also achieved.

During the last 6 hours, mean changes were -24.1/-11.6mmHg

overall, and -25.6/-11.4 and -24.6/-11.6mmHg in Black

patients and patients with stage 2 hypertension, respectively.

Table III. ABPgoal attainment rate andABP-lowering efficacy of olmesartan

medoxomil-based antihypertensive therapy stratified by race and HTN se-

verity (Black and stage 2 HTN subgroups) in studies of high-risk patients with

HTN at week 12

BeniSILVER study in 176 pts aged ‡65 y[35,47,48]


(N= 150)Black pts

(n= 22)Stage 2 HTN

(n= 99)


24-h (130/80mmHg) 73.3 72.7 64.6

Daytime (<135/85mmHg) 66.7 NS NS

Night-time (<120/80mmHg) 66.0 NS NS


BL 148.8/80.9 152.2/81.7 152.0/82.0

Wk 12 123.1/68.6 125.4/69.9 125.5/69.4

Change from BL -25.7/-12.3* -26.7/-11.8* -26.5/-12.6*


Change from BL -26.5/-13.0* -28.0/-13.4* -26.9/-13.1*


Change from BL -24.4/-11.5* -24.9/-10.1* -25.3/-11.6

Last h of dosing interval, mean BP (mmHg)

6h

Change from BL -24.1/-11.6* -25.6/-11.4* -24.6/-11.6*

4h

Change from BL -24.4/-11.8* -26.4/-11.9* -25.1/-12.0*

2h

Change from BL -24.2/-11.4* -26.5/-11.6* -25.2/-11.9*

BENIFICIARY study in 192 adult pts with T2DM[36,49,50]

Results at wk 12 Overall (T2DM)

(N= 172)Black pts

(n= 39)Stage 2 HTN

(n= 80)


24-h (<130/80mmHg) 61.6 64.1 46.3

Daytime (<130/80mmHg) 51.7 59.0 36.3

Night-time (<120/80mmHg) 50.6 46.2 37.5


BL 146.4/83.3 146.6/86.0 152.0/85.6

Wk 12 126.0/72.2 123.6/73.0 131.7/74.6

Change from BL -20.4/-11.1* -23.0/-13.0* -20.4/-10.9*


Change from BL -22.3/-12.0* -24.4/-13.4* -22.3/-11.6*


Change from BL -18.8/-10.2* -21.6/-12.2* -18.6/-10.3*


6 h -18.6/-10.8* -23.0/-14.2* -19.2/-11.2*

4 h -18.2/-10.7* -22.4/-14.0* -18.6/-11.3*

2 h -18.6/-10.6* -21.6/-13.6* -18.6/-10.5*

Continued

APEX study in 207 adult pts with T2DM[51]

Results at wk 12 T2DM (n= 165)


24-h (<130/80mmHg) 70.0

Daytime (<130/80mmHg) 50.0

Night-time (<120/80mmHg) 68.0


BL 144.3/81.6

Wk 12 124.3/70.4

Change from BL -19.9/-11.2*






6 h -18.9/-10.9*

4 h -19.1/-11.1*

2 h -19.5/-11.5*

ABP= ambulatory BP; BL= baseline; BP = blood pressure; h= hour(s); HTN= hypertension; NS = not stated; pts =patients; T2DM= type 2 diabetes

mellitus; wk =week(s). * p < 0.0001 vs BL.

Table III. Contd

382 Chrysant et al.


In BeniSILVER, 36.4% of Black patients were non-dippers

and 63.6%were dippers at baseline, while at the end of the study

37.5% of the non-dippers became dippers. For non-Black

patients, 31.3% were non-dippers at baseline and 68.8% were

dippers, with 52.5% of the non-dippers becoming dippers after

12 weeks of treatment.[47]

BENIFICIARY

In the Benicar Safety and Efficacy Evaluation (BENIFI-

CIARY) study (ClinicalTrials.gov identifier: NCT00403481),

192 patients with T2DM and hypertension were treated with

olmesartan medoxomil –HCTZ, titrated to achieve a BP

goal of <120/70mmHg (table I). Patients were stratified by race

and hypertension severity (table III).[36,49,50] At week 12, the

changes from baseline in 24-hour mean ABP for the total,

Black, and stage 2 hypertension cohorts were -20.4/-11.1,-23.0/-13.0, and -20.4/-10.9mmHg, respectively (table III).

There were statistically significant daytime and night-time ABP

reductions from baseline overall, in Black patients, and in

patients who entered the study with stage 1 or 2 hypertension.

ABP changes from baseline during the last hours of the

dosing interval were similar in the overall study population and

in patients with stage 2 hypertension (table III). However,

changes in ABP during the final hours of the dosing periodwere

numerically greater in Black patients than in other patient

groups. During the last 6 hours, mean ABP changes were

-18.6/-10.8mmHg overall, -19.2/-11.2 in patients with stage 2

hypertension, and -23.0/-14.2mmHg in Black patients.

At baseline in the BENIFICIARY study, 44.8% of patients

overall, 56.4% of Black patients, and 47.5% of patients with

stage 2 hypertension were non-dippers. After 12 weeks of treat-

ment, 36.4% of all non-dippers at baseline had converted to

dippers, as had 31.8% of Black non-dippers and 31.6% of

patients with stage 2 hypertension who were non-dippers at

baseline.[49]

APEX

APEX was A Prospective, open-label, ABPM study (Clin-

icalTrials.gov identifier: NCT00654745) to evaluate the safety

and Efficacy of an olmesartan medoXomil- and amlodipine-

based treatment titration regimen in patients with T2DM and

hypertension (table I). In this study, 207 patients with T2DM

and hypertension were treated with amlodipine/olmesartan

medoxomil –HCTZ to achieve a BP goal of <120/70mmHg

(table III).[51]

At 12 weeks, the change from baseline in 24-hour mean ABP

was -19.9/-11.2mmHg, and ABP was significantly reduced in

the daytime, night-time, and last hours of the dosing interval

(table III). During the last 6 hours of the dosing interval, mean

ABP changes were -18.9/-10.9mmHg.

2.1.2 Impact of Time of Administration

The impact of morning versus night-time dosing on ABP

lowering with olmesartan medoxomil monotherapy was

studied in patients with T2DM and hypertension (table I).

The results are presented in table IV.[52] Significant changes

from baseline in 24-hour, daytime, and night-time mean ABP

were achieved regardless of the time of dosing. For 24-hour

mean ABP, there was a change of -13.7/-8.6mmHg with

morning dosing and -14.4/-10.1mmHg with night-time dosing

(table IV). However, although there was no statistically sig-

nificant difference between dosing regimens in daytime mean

ABP, night-time administration of olmesartan medoxomil

produced a significantly larger decrease in night-time mean

ambulatory SBP (-16.2 vs -11.9mmHg) compared with morn-

ing administration.

At baseline, 68% of patients were dippers; morning admin-

istration of olmesartan medoxomil increased the proportion of

dipper patients to 74%, while 82% of patients had dipper status

with nocturnal administration (p = 0.012).[52]

2.1.3OlmesartanMedoxomil versusComparator Antihypertensives

Only one study was found that treated patients with olme-

sartan medoxomil-based therapy versus an active comparator

Table IV. Effects on ABP of morning vs evening dosing of olmesartan

medoxomil in patients with T2DM at week 8

Study in 38 hypertensive patients with T2DM[52]

Results after 8wk Morning dose

(n= 38)Night-time dose

(n= 38)


BL 138.5/87.5 138.5/87.5

Wk 8 124.8/78.9* 124.1/77.4*

Change from BL -13.7/-8.6 -14.4/-10.1


BL 142.2/89.5 142.2/89.6

Wk 8 128.7/81.4* 129.5/81.1*

Change from BL -13.5/-8.1 -12.7/-8.5


BL 124.3/80.8 124.3/80.8

Wk 8 112.4/74.0* 108.1-/71.0*--

Change from BL -11.9/-6.8 -16.2/-9.8

ABP= ambulatory BP; BL =baseline; BP =blood pressure; h = hour(s);T2DM= type 2 diabetes mellitus; wk=week(s). * p <0.0001 vs BL;

- p =0.007 vs morning dose; -- p = 0.069 vs morning dose.



and gave ABP data for at least one of the subgroups of interest:

this was a 16-week crossover study of olmesartan medoxomil

and telmisartan in 20 Japanese patients with hypertension

and early stage T2DMwho had been receiving valsartan 80mg

once daily for at least 8 weeks (table I). Patients were ran-

domized to once-daily administration of olmesartan medox-

omil 20mg or telmisartan 40mg after completing the valsartan

80mg run-in period. The patients were relatively obese for a

Japanese population (mean body mass index of 25.6 kg/m2),

and 65% of patients had metabolic syndrome. The changes

from baseline in 24-hour ABP were -4.2/-0.9mmHg after

olmesartan medoxomil treatment, and -0.9/+1.8mmHg after

telmisartan (table V).

Olmesartan medoxomil significantly reduced daytime

DBP by 3.2mmHg and night-time SBP and DBP by 5.4 and

3.3mmHg, respectively, more than telmisartan (table V).[41]

2.2 24-Hour Systolic BP/Diastolic BP Goal Attainment

The proportion of patients achieving 24-hour ABP goal

rates of <130/80mmHg were broadly similar across T2DM

and obese subgroups in patients receiving treatment based on

amlodipine in combination with olmesartan medoxomil –

HCTZ, ranging from 70% to 79.1% (tables II, III, and V;

figure 1).[44-46,51] In those receiving olmesartan medoxomil –HCTZ, goal rates varied. Black patients had similar rates to the

overall population (64.1% vs 61.6% and 72.7% vs 73.3%, re-

spectively, in hypertensive patients with T2DM[49,50] and in

elderly hypertensive patients[47]), while lower rates were seen in

patients with stage 2 hypertension[36,49,50] (tables II, III, and V;

figure 1). Olmesartan medoxomil-based antihypertensive

therapy also allowed a substantial proportion of high-risk

patients to reach daytime and night-time ABP goals (tables II

and III).

In the BP-CRUSH study in patients with hypertension un-

controlled on antihypertensive monotherapy, 73.4% of patients

who switched to amlodipine/olmesartan medoxomil –HCTZ

achieved a 24-hour ABP goal of <130/80mmHg at 12 weeks,

including 77.1% of obese and 69.4% of non-obese patients

(table II; figure 1).[45,46]

2.3 Adverse Events

Although not the focus of this review, some observations on

the tolerability of olmesartan medoxomil-based therapy in

high-risk therapy should be made. Overall, treatment with ol-

mesartan medoxomil-based regimens was well tolerated. The

proportion of patients experiencing AEs is shown in table VI.

Generally, the AE rate was similar between high-risk patient

subgroups and the overall population. However, slightly higher

rates of AEs (particularly those deemed drug related) were re-

corded in some studies in patients with T2DM (AZTEC and

APEX) and in those who were obese (BP-CRUSH). For ex-

ample, in the AZTEC study, which evaluated an amlodipine/olmesartan medoxomil-based treatment regimen, 7.6% of the

study population experienced ‡1 drug-related treatment-

emergent AE, compared with 9.4% and 5.6% of the obese and

non-obese subgroups, respectively, and 13.0% and 5.8% of the

diabetes and non-diabetes groups, respectively.[44] Amlodi-

pine/olmesartan medoxomil –HCTZ treatment regimens were

used in the APEX and BP-CRUSH studies. Drug-related AEs

occurred in 19.3% of diabetic patients in APEX; as in the

AZTEC study, the most common drug-related AE was pe-

ripheral edema, although this occurred at a low rate (table VI)

and did not occur in patients uptitrated to HCTZ.[51] Similarly,

although peripheral edema occurred at a slightly higher rate in

obese compared with non-obese patients in BP-CRUSH (6.7%vs 6.3%, respectively), the addition ofHCTZ lowered the rate of

peripheral edema in both obese and non-obese patients (all

amlodipine/olmesartan medoxomil doses, 5.9% vs 1.1% with

triple therapy).[46]

Table V. OM vs comparator antihypertensive agents in patients with T2DM

Crossover study of OM vs TEL in 20 Japanese hypertensive patients with

early stage T2DM[41]

Results OM 20mg

(n= 20)TEL 40mg

(n = 20)

24-h ambulatory BP, mean (mmHg)

BLa 133.6/75.5 133.6/75.5

Post-treatment 129.4*/74.6** 132.7/77.3

Change from BL -4.2/-0.9 -0.9/+1.8


BLa 139.7/78.8 139.7/78.8

Post-treatment 134.1/76.9- 136.3/80.1

Change from BL -5.6/-1.9 -3.4/+1.3


BLa 121.4/68.9 121.4/68.9

Post-treatment 119.5--/69.6y 124.9/72.9

Change from BL -1.9/-0.7 +3.5/+4.0

a At baseline, all patients had undergone a ‡8-week run-in period with

valsartan 80mg once daily.

BL= baseline; BP = blood pressure; h= hour; OM= olmesartan medoxomil;

T2DM= type 2 diabetes mellitus; TEL= telmisartan. *p=0.0305, **p= 0.0087,- p= 0.0215, -- p= 0.0281, y p= 0.0321, all vs TEL.

384 Chrysant et al.


Conversely, the rate of drug-related AEs was lower in

Black compared with non-Black patients treated in the Beni-

SILVER (0.0% vs 14.1%, respectively) and BENIFICIARY

(4.7% vs 8.7%) studies.[47,50] The comparative tolerability of

olmesartan medoxomil and telmisartan monotherapy was not

reported in the study in Japanese hypertensive patients with

T2DM.[41]

3. Discussion

It is accepted that most patients with hypertension will re-

quire treatment with more than one antihypertensive agent to

achieve BP levels necessary to reduce CV and renal morbidity

and mortality.[6,7] This is particularly true for patients in high-

risk subgroups who often have more difficult-to-treat hyper-

tension. When such combination antihypertensive therapy

is required, effective and well-tolerated agents with comple-

mentary mechanisms of action should be selected. The studies

reviewed in this article demonstrate that olmesartan medox-

omil-based antihypertensive therapy (olmesartan medoxomil

–HCTZ and amlodipine/olmesartanmedoxomil –HCTZ com-

bination therapy) effectively controlled BP throughout the

24-hour dosing interval across a range of high-risk patient

populations, and typically to a similar extent to that achieved in

the overall study populations. The majority of patients in the

high-risk subgroups of the dose-titration studies required up-

titration to combination therapy to reach the ABP goals, sug-

gesting that more aggressive treatment may be necessary

for such patients to achieve effective BP control. However,

olmesartan medoxomil-based algorithms enabled patients to

achieve significant ABP lowering (across the 24-hour dosing

interval, daytime and night-time BP, and to meet ABP targets

[24-hour BP]) in Black patients and in patients with stage 2

hypertension, T2DM, and obesity. Step-wise treat-to-goal ol-

mesartan medoxomil-based treatment algorithms produced

statistically and clinically significant reductions in ABP for

each subgroup and, in most cases, the attainment of pre-

specified ABP study targets in the majority of patients. In the

100

70.9

73.473.3

61.6

70.0

Overall Obese T2DM Blacks Stage 2 HTNPatient subgroup

a Total cohort in this study had T2DM.b Black elderly patients.c Black patients with T2DM.d Elderly patients with stage 2 HTN.e T2DM and stage 2 HTN. f Total cohort was aged ≥65 years.

75.377.179.1

a61.6

a70.0

b72.7

c64.1

d64.6

e46.3

24-h

our

AB

P g

oal r

ate

(%)

80

60

40

20

0

AZTEC (AML/OM)BP-CRUSH (AML/OM±HCTZ)BeniSILVER (OM±HCTZ)f

BENIFICIARY (OM±HCTZ)APEX (AML/OM±HCTZ)

Fig. 1. The proportion of patients with hypertension (HTN) achieving 24-hour ambulatory blood pressure (ABP) target (<130/80mmHg) with OM-based

antihypertensive therapy in the overall study populations and in high-risk subgroups (Black patients and patients with stage 2 HTN, T2DM, or obesity) treated in

the AZTEC,[43,44] BP-CRUSH,[45,46] BeniSILVER,[35,47,48] BENIFICIARY,[36,49,50] and APEX[51] clinical trials. AML= amlodipine; HCTZ= hydrochlorothiazide;OM=olmesartan medoxomil; T2DM= type 2 diabetes mellitus.



BP-CRUSH study, this was also achieved in high-risk pa-

tients previously uncontrolled on antihypertensive mono-

therapy.[45,46]

Furthermore, BP reductions persisted during the critical last

6, 4, and 2 hours of the dosing interval, which corresponds with

the morning BP surge, indicating that olmesartan medoxomil-

based therapy provided antihypertensive effect throughout the

full dosing interval in high-risk populations.

In the BENIFICIARY study in patients with T2DM, ABP

goal rates achieved with olmesartan medoxomil –HCTZ ther-

apy in patients with stage 2 hypertension were 46.3%, compared

with 64.1% in Black patients and 61.6% in the overall patient

population with T2DM.[36,49,50] This suggests that T2DM in

conjunction with more severe hypertension is a condition that

may particularly benefit from amore intensive antihypertensive

strategy. The use of a more intensive olmesartan medoxomil-

based strategy (amlodipine/olmesartan medoxomil –HCTZ)

achieved better goal rates in the T2DM population in the

APEX study (in which a greater proportion of patients with

T2DM achieved the prespecified ABP targets of <130/80mmHg than patients without T2DM)[51] than in patients with

T2DM in the BENIFICIARY study who received olmesartan

medoxomil –HCTZ.[49,50] This suggests that the lower goal

achievement rate in patients with stage 2 hypertension and

T2DM in the BENIFICIARY study may possibly be increased

with the use of amlodipine/olmesartan medoxomil –HCTZ.

However, there are differences in study design, patients, and

treatments, so no extrapolation can be drawn from such an

indirect comparison. This requires further investigation in a

randomized controlled trial.

One limitation of this analysis is that the studies identified

were all of relatively short duration (8–12 weeks of active

treatment), which does not allow conclusions to be made on

long-term efficacy in these patient subgroups. Nevertheless, the

long-term efficacy of the component antihypertensive agents

has been established in a number of studies.[53-57] A second

limitation is that, although nocturnal BP has been shown to be

a predictor of CV outcomes, the use of ABPM to determine

dipping patterns must be interpreted with caution as dipping

patterns can demonstrate variability and patients may spon-

taneously shift from a non-dipping pattern to a dipping pattern

and vice versa. Thirdly, all of the titrate-to-goal studies were of

an open-label design, and patient outcomes were not analyzed

to determine the statistical significance of differences between

subgroups. In addition, a few studies had a relatively small

number of patients in some subgroups. However, the studies

provide a reflection of real-world clinical practice where struc-

tured dose titration is recommended to achieve and maintain

Table VI. Proportion of patients experiencing AEs in ABPM studies of

olmesartan medoxomil-based antihypertensive therapy

Study TEAE Drug-

related

AEs

Drug-related AEs

occurring in ‡2%of pts

Discontinuations

due to TEAE

BeniSILVER study in 176 pts aged ‡65 y[35,47,48]

Overall 32.6 11.8 Dizziness: 3.4

Hypotension: 2.2

5.1

Black pts 31.0 0.0 Dizziness: 0.0

Hypotension: 0.0

3.4

Non-Black pts 32.9 14.1 Dizziness: 4.0

Hypotension: 2.7

5.4

Stage 2 disease 32.8 12.1 Dizziness: 2.6

Hypotension: 2.6

NS

Isolated systolic

HTN

32.7 15.3 Dizziness: 4.1

Hypotension: 2.3

Headache: 2.0

Nausea: 2.0

NS

BENIFICIARY study in 192 pts with T2DM[36,50]

Overall 34.9 7.8 NS NS

Black pts 39.5 4.7 NS NS

Non-Black pts 33.6 8.7 NS NS

Stage 2 disease 33.0 5.5 NS NS

AZTEC study in 185 pts with HTN[43,44]

Overall 31.4 7.6 Peripheral

edema: 2.2

1.6

Obese pts 34.4 9.4 Peripheral

edema: 4.2

1.0

T2DM 45.7 13.0 Peripheral

edema: 2.2

Dizziness: 2.2

2.2

APEX study in 207 pts with HTN and T2DM[51]

Overall 57.0 19.0 Peripheral

edema: 6.0

Dizziness: 3.0

Hypotension: 2.0

6.0

BP-CRUSH study in 999 pts with uncontrolled HTN[45,46]

Overall 53.0 25.5 Dizziness: 7.6

Peripheral

edema: 6.5

Hypotension: 2.3

Headache: 2.0

Fatigue: 2.0

8.6

Obese pts 53.9 26.1 Peripheral

edema: 6.7

Dizziness: 5.1

Hypotension: 2.4

Headache: 2.4

7.7

ABPM= ambulatory blood pressure monitoring; AE= adverse event; HTN=hypertension; NS = not stated; pts= patients; TEAE= treatment-emergent

AE; T2DM= type 2 diabetes mellitus; y= years.

386 Chrysant et al.


BP control, an approach especially relevant in high-risk

patients who may have difficult-to-treat hypertension. Apart

from the small study by Nakayama et al., which compared

olmesartanmedoxomil and telmisartanmonotherapy in Japanese

patients with T2DM,[41] no ABP studies directly comparing

olmesartanmedoxomil-based and other ARB-based antihyper-

tensive regimens were identified. Furthermore, it is beyond the

scope of this article to review the ABP efficacy in high-risk

patient subgroups of antihypertensive therapy based on other

ARBs.

4. Conclusion

A titrate-to-BP goal strategy using olmesartan medoxomil-

or amlodipine/olmesartan medoxomil-based antihypertensive

therapy has been shown to be an effective approach in man-

aging hypertension throughout the full 24-hour dosing period

in difficult-to-treat high-risk patients, including Blacks,

obese patients, patients with T2DM, and those with stage 2

hypertension. The reductions in ABP and achievement of

ABP targets may potentially translate into improvements in

the overall CV risk profile. The good tolerability of olmesartan

medoxomil, amlodipine, and HCTZ as components of

combination antihypertensive regimens may also potentially

lead to improvements in patient compliance during long-term

therapy.

Acknowledgments

This study was supported by Daiichi Sankyo, Inc. Manuscript prepa-

ration, editing, andmedical writing support were provided byRayHill and

Alan J. Klopp, PhD, of inScience Communications, Springer Healthcare,

and funded by Daiichi Sankyo, Inc.

Steven G. Chrysant, MD, has received research grants from Daiichi

Sankyo, Inc., Novartis, Boehringer Ingelheim, Merck, Bristol-Myers

Squibb, and Takeda Pharmaceuticals and serves as a consultant for

Daiichi Sankyo, Inc., Novartis, and Boehringer Ingelheim.

F. Wilford Germino, MD, has received research grants from Daiichi

Sankyo, Inc., Novartis, and Sanofi and honoraria from Bristol-Myers

Squibb, AstraZeneca, Forest Laboratories, Takeda, and Pfizer Inc.

Joel Neutel, MD, is a member of the speaker’s bureau for Novartis,

Boehringer Ingelheim, Daiichi Sankyo, Inc., the Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership, Takeda, and Pfizer Inc.

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Correspondence: Dr Steven G. Chrysant, Director, Oklahoma Cardiovascular

and Hypertension Center, 5850 West Wilshire Blvd, Oklahoma City,

OK 73132, USA. E-mail: [email protected]



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Olmesartan Medoxomil-Based Antihypertensive Therapy Evaluated by Ambulatory Blood Pressure Monitoring