Efficacy in angiotensin receptor blockade: a comparative review of data with olmesartan.

Abstract

A range of angiotensin II receptor blockers (ARB) is available, and analyses suggest there are differences between agents in terms of antihypertensive efficacy and 24-hour blood pressure control.This review assesses the data comparing olmesartan with other ARBs in terms of blood pressure reductions, goal achievement, 24-hour control and speed of onset. Olmesartan seems to have a more favourable efficacy profile relative to standard doses of the ARBs used in comparative studies; results consistent with the high degree of blockade of the angiotensin II type 1 receptor for olmesartan.Taken together, there might be differences between ARBs regarding their blood pressure lowering efficacy, and these results may provide further support of the benefits of olmesartan therapy since choice of an effective agent is crucial in antihypertensive therapy.

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DOI: 10.1177/1470320309342735
2009 10: 147 originally published online 3 August 2009 Journal of Renin-Angiotensin-Aldosterone System
Josep Redon and Maria Jose Fabia
Efficacy in angiotensin receptor blockade: a comparative review of data with olmesartan


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Paper
147
SAGE Publications 2009 Los Angeles, London, New Delhi and Singapore
© The Authors, 2009. Reprints and Permissions: http://www.sagepub.co.uk/journalspermissions.nav
Journal of
the Renin-
Angiotensin-
Aldosterone
System
(Including other
Peptidergic systems)
September 2009
Volume 10
Number 3
10.1177/1470320309342735
Hypertension Clinic,
Hospital Clínico
Universitario, University
of Valencia, Valencia,
Spain and CIBER 03/06
Physiopathology of
Obesity and Nutrition,
Institute of Health
Carlos III, Minister of
Health, Spain.
Correspondence to:
Professor Josep Redon
Hypertension Clinic,
Internal Medicine,
Hospital Clinico,
University of Valencia,
Avda Blasco Ibañez, 17,
E-46010 Valencia, Spain.
Tel: +34 96 3862647
Fax: +34 96 3862647
Email: josep.redon@
uv.es
Abstract
A range of angiotensin II receptor blockers (ARB)
is available, and analyses suggest there are
differences between agents in terms of
antihypertensive efficacy and 24-hour blood
pressure control. This review assesses the data
comparing olmesartan with other ARBs in terms
of blood pressure reductions, goal achievement,
24-hour control and speed of onset. Olmesartan
seems to have a more favourable efficacy profile
relative to standard doses of the ARBs used in
comparative studies; results consistent with
the high degree of blockade of the angiotensin II
type 1 receptor for olmesartan. Taken together,
there might be differences between ARBs
regarding their blood pressure lowering efficacy,
and these results may provide further support
of the benefits of olmesartan therapy since
choice of an effective agent is crucial in
antihypertensive therapy.
Introduction
Current guidelines issued by the European Society
of Hypertension (ESH) and European Society of
Cardiology emphasise the importance of manag-
ing hypertension in order to reduce the substan-
tial morbidity and mortality associated with
cardiovascular events.1 When initiating therapy in
hypertensive patients, the guidelines recommend
monotherapy, or combination therapy using low
doses of each agent.1
Two classes of agents that are well suited to com-
bination therapy are the angiotensin-converting
enzyme inhibitors (ACE-I) and the angiotensin II
receptor blockers (ARB). This is related to their
favourable tolerability profile, which allows these
agents to be used in combination with other
agents without increasing the incidence of adverse
events.2 Treatment guidelines provide clear recom-
mendations on the patient types and conditions
for which treatment with ACE-Is and ARBs is
suited.1 Although ACE-Is and ARBs are well toler-
ated, certain undesirable effects, notably cough
and angioedoema, are associated with the use of
ACE-Is. Indeed, the incidence of each of these
events was significantly higher with ramipril com-
pared with telmisartan in the recent ONTARGET
study.3 Furthermore, the ONTARGET study spe-
cifically preselected ACE-I-tolerant patients by
assigning ACE-I intolerant patients to the parallel
TRANSCEND study.4 The lower incidence of
cough with ARBs may therefore explain the
higher levels of persistence seen with ARB ther-
apy relative to ACE-Is.5
The efficacy and tolerability of ARBs, as well as
other ancillary benefits, have led to their rapid
uptake and widespread use. Results from clinical
studies have demonstrated the efficacy of ARBs
as antihypertensive agents, and large-scale clini-
cal investigations have shown that their efficacy
is paralleled by reductions in the risk of cardio-
vascular and renal events such as stroke, isch-
aemic heart disease and diabetic nephropathy.6-11
The link between lower blood pressure (BP) and
reduction in cardiovascular risk is well estab-
lished. Moreover, this causal link is so strong that
even a reduction in systolic BP (SBP) of as little
as 2 mmHg can reduce the risk of death from
stroke by 10% and of death from vascular disease
by 7% in patients aged 40 to 69 years.12 This high-
lights the importance of antihypertensive efficacy,
and since several ARBs are currently available it
raises the question of whether differences in
efficacy exist among the members of this class.
Numerous studies have been conducted that
have assessed the antihypertensive efficacy of
ARBs. Although some ARBs have been directly
compared in head-to-head trials, no single study
has directly assessed the efficacy of all seven of
Efficacy in angiotensin receptor blockade:
a comparative review of data with olmesartan
Josep Redon, Maria Jose Fabia
Key words:
angiotensin
receptor
blocker, blood
pressure,
hypertension,
olmesartan,
renin-
angiotensin-
aldosterone
system
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SAGE Publications 2009 Los Angeles, London, New Delhi and Singapore
Journal of
the Renin-
Angiotensin-
Aldosterone
System
(Including other
Peptidergic systems)
September 2009
Volume 10
Number 3
the available ARBs. Two recent reviews, which
looked at the potential differences among the
ARBs based on office BP, did not demonstrate
significant differences.13,14 However, a review
which was performed with the aim of analysing
the antihypertensive activity of ARBs based upon
ambulatory blood pressure monitoring (ABPM)
and the factors that affect this has been pub-
lished.15 This emphasises the dose-dependence
of not only the efficacy but also duration of
action among the ARBs.
Compared with BP measurements made in the
clinic or office, ABPM reduces measurement
technique error, avoids ‘white coat’ hypertension,
provides temporal information about daily BP
fluctuations,16 and has been shown to be a better
predictor of cardiovascular mortality.17 Since
treatments like ARBs are dosed once daily, infor-
mation about their antihypertensive efficacy over
24 hours is important in order to ensure that the
antihypertensive effect is maintained throughout
the dosing interval. In addition, ABPM measure-
ments made during the night-time have been
shown to more accurately predict cardiovascular
events than measurements made over 24 hours.
This may relate to subjects’ general lack of phys-
ical activities during the night-time, which means
that BP measurements made during this period
are more reflective of the state of the vascular
tree than those made at other times. Beyond
these clinical benefits, ABPM is also useful
because it allows the efficacy of different antihy-
pertensive agents to be assessed.
An independent systematic review looked at
published, peer-reviewed studies that had mea-
sured BP using ABPM. Meta-regression analysis
was used to calculate the relationship between
initial BP values and BP reductions, and analysis
of variance to analyse the influence of drug and
dosage on the size of clinic BP measurements
and ABPM measurements made over 24 hours,
daytime, night-time and the last 4–6 hours of the
dosing interval. It was shown that there are sub-
stantial differences between the degree of BP
reduction achieved with the different ARBs, and
that this difference is significant when assessing
clinic diastolic BP (DBP) and 24-hour DBP and
SBP.15 Comparing individual members of the ARB
family with each other and identifying the agent
with the greatest antihypertensive efficacy was
beyond the scope of this review. However, from
the data presented it appears that the newest
member of the ARB class, olmesartan medox-
omil, was consistently associated with a high
level of antihypertensive efficacy, both in terms
of BP reductions assessed using standard clinic
measurements and using ABPM measurements
(figure 1).
Another recent review, based upon a pharmaco-
logical approach, appears to support this observa-
tion.18 Randomised, placebo-controlled studies
with comparable designs and dose ranges were
used to extract dose-response data for several
ARBs which were then fitted to a simplified Emax
model. The Emax model was based on a calculation
of expected maximal antihypertensive efficacy by
using placebo-subtracted mean BP reductions
fitted for DBP and SBP. The BP-lowering efficacy
of olmesartan (defined as maximal effect) was
found to be larger than that seen with irbesartan,
valsartan and losartan, and larger than candesartan
for DBP reductions.
Such findings raise the possibility that olmesartan
might possess a greater degree of antihypertensive
Figure 1
Mean changes in systolic and diastolic blood pressure (SBP;
DBP) assessed by ambulatory blood pressure monitoring over
(a) 24 hours (b) the last four hours of the dosing interval.
Values are adjusted by initial dose, age, number of patients,
clinic blood pressure. Error bars denote standard error. Figure
reproduced with permission adapted from Fabia et al.15
Change in BP (mmHg)
0
−2
−4
−6
−8
−10
−12
−14
0
−2
−4
−6
−8
−10
−12
−14
Change in BP (mmHg)
Olmesartan
Eprosartan
Telmisartan
Candesartan
Irbesartan
Valsartan
Losartan
Placebo
Olmesartan
Eprosartan
Telmisartan
Irbesartan
Valsartan
Losartan
Placebo
Plain bars = SBP
Hatched bars = DBP
Plain bars = SBP
Hatched bars = DBP
(b)
(a)
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Journal of
the Renin-
Angiotensin-
Aldosterone
System
(Including other
Peptidergic systems)
September 2009
Volume 10
Number 3
SAGE Publications 2009 Los Angeles, London, New Delhi and Singapore
activity than other ARBs at standard doses. The
aim of the present review is to assess available
data relating to the efficacy and tolerability of
olmesartan in relation to other ARBs.
Olmesartan versus other ARBs
The most robust data relating to the comparative
effects of ARBs come from head-to-head studies
in which the efficacy and/or safety endpoints
have been prospectively defined.
BP reduction – monotherapy
Several head-to-head studies have been performed
in which the antihypertensive efficacy of olmesar-
tan has been compared with that of other ARBs.19-25
The majority of these studies involved hyper -
tensive patients without other significant cardiovas-
cular disease. Two studies have been performed,
however, in hypertensive patients with mild-
to-moderate renal impairment,24 and with early-
stage type 2 diabetes.25 It should be noted that the
majority of the published studies was supported by
the respective manufacturers.
The designs of the double-blind head-to-head
studies are summarised in table 1. Most studies
assessed the standard dose of olmesartan (20 mg).
However, one study was initiated with the lower
dose (10 mg)20 and one with a forced dose-titra-
tion step, so that the effects of the higher (40 mg)
dose could be assessed.23 The majority of the
studies had primary efficacy variables related
to reductions in DBP, assessed using cuff BP
measurements or 24-hour ABPM.
All the studies utilised parallel-group designs
with a placebo run-in phase, with the exception
of the study by Nakayama et al.,25 which used
ABPM and a crossover design in which all
patients received valsartan 80 mg prior to taking
study medication.
Reductions in DBP after 8 or 12 weeks of treat-
ment are shown for the double-blind head-
to-head studies in figure 2a. The results of the
study starting with low-dose olmesartan (10 mg)
demonstrated significantly greater reductions in
Table 1
Head-to-head double-blind studies comparing the antihypertensive efficacy of olmesartan with other angiotensin receptor
blockers when administered as monotherapy
Study

Duration

Study
population
Mean baseline BP
(SBP/DBP mmHg)
Daily dose and
comparator
Primary out-
come variable
Oparil
et al.19


Stumpe
and
Ludwig20

Brunner
et al.21

Liau
et al.22
Giles
et al.23




Agabiti-
Rosei24



Nakayama
et al.25


8 wks



24 wks



8 wks


12 wks

12 wks





52 wks




16 wks†



Hypertensive
patients (n=588)


Hypertensive
patients (n=316)


Hypertensive
patients (n=643)

Chinese hypertensive
patients (n=126)
Hypertensive
patients (n=696)




Hypertensive patients
with renal impairment
(n=393)


Japanese hypertensive
patients with early-
stage type-2
diabetes (n=20)
157/104



DBP: 102 mmHg



146/92*


149/103

155/103





157/97




134/76* (with
valsartan
therapy)
Olmesartan 20 mg;
losartan 50 mg;
valsartan 80 mg;
irbesartan 150 mg
Olmesartan 10 mg;
losartan 50 mg; dose
doubled at week 4 in
non-responders
Olmesartan 20 mg;
candesartan 8 mg

Olmesartan 20 mg;
losartan 50 mg
Cuff DBP at wk 8
Cuff DBP at
wk 12
DBP assessed by
ABPM at wks 1,
2 and 8
Cuff BP at
wk 12
Forced titration study:
olmesartan 20 mg to
40 mg; valsartan 80 mg
to 320 mg; losartan 50 mg
to 100 mg; placebo
Olmesartan 20 mg;
losartan 50 mg
(both in combination
with furosemide 20
or 40 mg)
Olmesartan 20 mg;
telmisartan 40 mg
Cuff DBP at
wk 8
Cuff DBP at
wk 12
Not stated
Key: †Crossover study (each study period: 8 wks); *assessed using 24-hour ABPM. ABPM = ambulatory blood pressure
monitoring; BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure.
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Journal of
the Renin-
Angiotensin-
Aldosterone
System
(Including other
Peptidergic systems)
September 2009
Volume 10
Number 3
DBP than losartan after 12 weeks’ treatment.20
Olmesartan 20 mg was shown to provide signifi-
cantly greater DBP reductions than losartan
50 mg, valsartan 80 mg, irbesartan 150 mg and
candesartan 8 mg after 8 weeks’ treatment.19,21
Olmesartan 20 mg was also associated with
significantly greater DBP reductions than losartan
50 mg after 12 weeks’ treatment in hypertensive
patients with and without renal impairment.22,24
Results from the up-titration study showed that,
−11.5
−10.6
−9.3
−15.4
−12.9
-15.3
−8.2
**
−8.5
*
−11.6
*
−9.4
**
−13.4
*
−7.9
***
−11.6
−9.9
*
0
–2
–4
–6
–8
–10
–12
–14
–16
−7.8
*
–18
Reduction in DBP (mmHg)
−11.3
−14.9
−13.0
−18.9
−15.2
−9.5
−11.6
*
−13.9
−10.9
**
−8.4
−13.0
−11.0
0
–2
–4
–6
–8
–10
–12
–14
–16
–18
−11.1
*
–20
Reduction in SBP (mmHg)
Agabiti-Rosei‡
12 wks
Giles
8 wks†
Liau
12 wks
Brunner
8 wks
Stumpe
12 wks§
Oparil
8 wks
Giles
8 wks†
Liau
12 wks
Brunner
8 wks
Stumpe
12 wks§
Oparil
8 wks
LOS
50
OLM
20
LOS
50
OLM
20
LOS
50
OLM
10
LOS
50
VAL
80
IRB
150
OLM
20
CAN
8
OLM
20
LOS
100
LOS
160
OLM
40
LOS
50
OLM
20
LOS
50
OLM
10
LOS
50
VAL
80
IRB
150
OLM
20
CAN
8
OLM
20
LOS
100
LOS
160
OLM
40
(a)
(b)
Figure 2
Change in (a) diastolic blood pressure (DBP) and (b) systolic blood pressure (SBP) after 8 or 12 weeks’ treatment with olmesartan
and other angiotensin receptor antagonists in head-to-head double-blind comparative studies. All doses are mg/day. All values
were obtained with cuff measurements, with the exception of the study by Brunner et al.,21 where the data relate to daytime
ambulatory blood pressure monitoring. *p<0.05, **p<0.001, ***p<0.0001 vs. olmesartan. †Doses were up-titrated from half the
amount shown after the first 4 weeks. ‡Results obtained in patients with renal impairment (no corresponding SBP data given).
§Doses were doubled at 4 weeks in non-responders. CAN = candesartan; IRB = irbesartan; LOS = losartan; OLM = olmesartan; VAL
= valsartan (Oparil et al.19; Stumpe and Ludwig20; Brunner et al.21; Liau et al.22; Giles et al.23; Agabiti-Rosei24).
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