Journal of Human Hypertension (2008) 22, 266274

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ORIGINAL ARTICLE

A comparison of the efficacy and safety of

irbesartan/HCTZ combination therapy with
irbesartan and HCTZ monotherapy in the
treatment of moderate hypertension
JM Neutel1, SS Franklin2, P Lapuerta3, A Bhaumik3, A Ptaszynska3
1
3

Orange County Research Center, Tustin, CA, USA; 2University of California, Irvine, CA, USA and
Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ, USA

This prospective, double-blind, parallel-group study

randomized patients with moderate hypertension (seated
systolic blood pressure (SeSBP) 160179 mm Hg when
seated diastolic blood pressure (SeDBP) o110 mm Hg; or
SeDBP 100109 mm Hg when SeSBP o180 mm Hg) 3:1:1
to treatment with irbesartan 300 mg/hydrochlorothiazide
(HCTZ) 25 mg combination therapy (n 328), irbesartan
300 mg monotherapy (n 106) or HCTZ monotherapy
25 mg (n 104). Treatment was initiated at half dose, with
forced titration to full dose after two weeks followed by
ten further weeks treatment. The primary efficacy variable was the mean reduction in SeSBP from baseline to
week 8. Baseline characteristics were similar between
groups, with mean baseline blood pressure approximately 162/98 mm Hg; the mean age was 55 years. At
week 8 there was a reduction in SeSBP of 27.1 mm Hg
with irbesartan/HCTZ, compared with 22.1 mm Hg with

irbesartan monotherapy (P 0.0016) and 15.7 mm Hg with

HCTZ (Po0.0001). Both the rate of decline and the total
degree of decline achieved were greatest with irbesartan/
HCTZ and least with HCTZ. A significantly greater
percentage of patients reached a treatment goal of
SeSBP o140 mm Hg and SeDBP o90 mm Hg by week 8
with irbesartan/HCTZ (53.4%), compared with irbesartan
(40.6%; P 0.0254) and HCTZ (20.2%; Po0.0001) alone.
Treatment was well tolerated in all three-treatment groups
with a slight increase in adverse events in the combination therapy group. In conclusion, irbesartan/HCTZ
(300/25 mg) is well tolerated and achieves rapid and
sustained reductions in both systolic blood pressure and
diastolic blood pressure in patients with moderate
hypertension.
Journal of Human Hypertension (2008) 22, 266274;
doi:10.1038/sj.jhh.1002293; published online 11 October 2007

Keywords: irbesartan; irbesartan/HCTZ; angiotensin receptor blocker; moderate hypertension; combination therapy

Introduction
The reported prevalence of hypertension varies
widely between countries, but is increasing globally
as populations age and the dietary and lifestyle
preferences typical of industrialized countries become more widespread.1,2 The number of adults with
hypertension was recently predicted to exceed 1.5
billion worldwide by 2025.3 Alongside this failure of
prevention, blood pressure is also poorly controlled
in most countries. Studies in both Europe and the
United States have reported that only around 25% of
all hypertensives and 50% of treated patients have
controlled blood pressure,47 while further European
studies have suggested that true rates of control may
be significantly lower.810
Correspondence: Professor Dr JM Neutel, Orange County Heart
Institute and Research Center, 14351 Myford Road, Tustin, CA
92780, USA.
E-mail: jmneutel@aol.com
Received 3 July 2007; accepted 13 August 2007; published online
11 October 2007

The reasons for poor blood pressure control rates

are complex. In part, they reflect the impact of
structural and economic factors on access to health
care, but local clinical, prescriber and patient factors
that undermine the adequacy of treatment are also
significant. These include patient non-adherence
with therapy and physician inertia, particularly with
regard to the need to increase the dose of antihypertensive treatment until goals are achieved.5,11 To
address the problem of persistently poor control rates,
a working party representing nine international
hypertension, cardiology and healthcare societies
recently called for renewed emphasis on the basic
principles of hypertension management. One of their
key recommendations was to restate the need for a
clear and unambiguous commitment to the aggressive,
early and well-tolerated treatment of hypertension
to goal.12
The majority of patients with hypertension require
two or more antihypertensive medications to achieve
blood pressure targets.13 Indeed, by combining two
agents with different modes of action, it is possible to

Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
267

obtain additive or synergistic blood pressure lowering.14 There is thus a clear rationale for treating
patients with moderate or severe hypertension with
a combination of drugs from the outset of treatment,
provided that such therapy is well tolerated. Current
JNC-7 and European Society of Hypertension guidelines both recommend initial combination therapy
for patients with moderate or severe hypertension, in
whom blood pressure exceeds the goal by 20/
10 mm Hg or greater.15,16 When combination therapy
is administered, fixed-dose combinations are more
convenient to patients and may improve treatment
adherence.17 A fixed-dose combination of an angiotensin receptor blocker (ARB) with a thiazide,
typically hydrochlorothiazide (HCTZ), is a widely
used strategy in hypertension management. However, there is a need for further data for ARB/thiazide
fixed-dose combination therapy in patients with
moderate hypertension, including in the context of
initial therapy.
Irbesartan is a potent and well-tolerated ARB that
is widely used in fixed-dose combination form with
HCTZ. Clinical studies of irbesartan/HCTZ suggest
that this combination is not only clinically effective,
but also has a favourable safety profile,18 producing
significantly greater dose-dependent reductions in
blood pressure compared with monotherapy1921
while attenuating some of the side effects (for
example, hypokalaemia) associated with HCTZ.21
Here, we investigate the efficacy, safety and tolerability of high-dose irbesartan/HCTZ in patients
with moderate hypertension, a high proportion of
whom were overweight, with dyslipidaemia and/or
diabetes.

Materials and methods

The study was conducted in adult patients aged 18
years or older with moderate hypertension that at
enrolment was either untreated for at least 4 weeks
or uncontrolled by monotherapy. Monotherapy was
defined as treatment with a single antihypertensive
drug for at least 4 weeks; fixed-dose combination
therapy was not considered monotherapy. Untreated
patients were enrolled if they had moderate hypertension (seated systolic blood pressure (SeSBP) 160
179 mm* Hg or seated diastolic blood pressure
(SeDBP) 100109 mm Hg). Patients on monotherapy
could be enrolled if they had SeSBP 150179 mm Hg
or SeDBP 95109 mm Hg.
Patients with severe hypertension (SeSBPX
180 mm Hg or SeDBPX110 mm Hg) were excluded,
as well as those with SeSBPo130 mm Hg. Patients
were also excluded if they had malignant, accelerated or secondary hypertension, or were in need
of immediate blood pressure-lowering therapy.
Patients with hypertensive encephalopathy, stroke
or transient ischaemic attack within the past 12
months, or unstable angina, myocardial infarction or
coronary grafting or revascularization within the

past 6 months, were excluded. Among the other

exclusion criteria were significant chronic renal
impairment or renovascular disease, hepatic disease, systemic lupus erythematosus, malignancy,
gastrointestinal disease or gastrointestinal surgery
that might interfere with drug absorption. Patients
could not participate if they had a history of drug or
alcohol abuse, or had any medical or psychiatric
condition that might confound assessment of study
medication or jeopardize the patients safety.
Women of childbearing potential were eligible to
participate, provided they had a negative pregnancy
test within 72 h of the start of study medication and
used an adequate method of contraception, both
during the study and for up to 1 week after study
completion. Pregnant or lactating women were not
eligible to participate.
The study was conducted at 135 centres in the
USA, Canada, France and Germany. Ethics Committee and/or Institutional Review Board approval was
granted at all participating centres, and all patients
gave written informed consent prior to enrolment.
The study was conducted in accordance with the
ethical principles of the current Declaration of
Helsinki and consistent with the International Conference on Harmonization Good Clinical Practice.
Study design

This was a randomized, double-blind, active-controlled, parallel-group study of 12 weeks duration.

Eligible patients entered a 21-day single-blind,
placebo wash-out period before randomization in a
3:1:1 ratio to 12 weeks of active treatment. Patients
randomized to combination therapy received fixeddose irbesartan 150 mg/HCTZ 12.5 mg for 2 weeks
followed by forced titration to irbesartan 300 mg/
HCTZ 25 mg for the remaining 10 weeks, while those
on irbesartan monotherapy received 2 weeks of
irbesartan 150 mg followed by 10 weeks of irbesartan
300 mg. Patients in the HCTZ treatment group
received HCTZ 12.5 mg for 2 weeks, increased to
HCTZ 25 mg for the remaining 10 weeks. Study drugs
together with matching placebo were taken once
daily between 0600 and 1100 hours except on the
morning of a study visit so that blood pressure could
be measured at trough (that is, 2473 h following the
last dose of study medication). Concomitant administration of vasoactive drugs, any drug or herbal
preparation likely to affect blood pressure, as well as
those likely to interact with study medication, was
prohibited throughout the study.
Efficacy assessments

Blood pressure and heart rate were measured using a

sponsor-provided automatic blood pressure monitor.
In the USA and Canada, an OMRON HEM-712CN
(Omron Healthcare Inc., Bannockburn, IL, USA) was
provided, whereas in Europe, an OMRON MX3
(Omron Healthcare Europe BV, Hoofddorp, The
Journal of Human Hypertension

Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
268

Netherlands) was employed. Both models were

tested and recommended against two protocols,
those from the Association for the Advancement of
Medical Instruments and the International Protocol
of the European Society of Hypertension, for accuracy.22 Patients rested for a minimum of 10 min in
a seated position before any measurements were
taken. An average of 35 replicate SeBP measurements were obtained at least 1 min apart followed by
an average of three replicate measures of standing
blood pressure. Measurements were taken from both
arms and the arm with the higher reading used in
those cases where blood pressure readings differed
between arms. This same arm was used to obtain
trough blood pressure readings at all subsequent
study visits, which included day 14 of the singleblind, placebo wash-out period, before randomization to double-blind treatment on day 21 and at
weeks 2, 4, 8 and 12 of double-blind treatment.
An IMMULITE 2000 high-sensitivity CRP analyzer (Diagnostic Products Corporation, Los Angeles,
CA, USA) was used to measure high-sensitivity
C-reactive protein (hs-CRP) levels in blood samples
obtained at baseline and at weeks 8 and 12.
The primary efficacy end point was change in
SeSBP after week 8. Secondary efficacy end points
included change from baseline in SeDBP at weeks 8
and 12, change from baseline in SeSBP at week 12
and the proportion of subjects who met JNC-7 criteria
of blood pressure control, that is with simultaneous
SeSBPo140 mm Hg and SeDBP o90 mm Hg at
weeks 8 and 12.

with combination therapy than with either irbesartan or HCTZ monotherapy alone.
A sample size of 298 patients in the combination
treatment arm and 99 patients in each of the two
monotherapy arms was chosen to provide at least
90% power at a one-sided significance level of 0.025
to detect a 6.0 mm Hg difference between combination therapy and monotherapy in change from
baseline in SeSBP at week 8. This sample size would
also give 90% power to detect an overall difference
of 3.2 mm Hg between combination therapy and
monotherapy in change from baseline in SeDBP at
week 8. The sample size calculation assumed a
standard deviation of 14 and 7.5 mm Hg for change in
SeSBP and SeDBP, respectively, and also allowed for
a 5% dropout rate.
All efficacy analyses were made on an intent-totreat basis, using the data set of all randomized
subjects. Changes in SeSBP and SeDBP from baseline to week 8 were compared between treatment
groups using one-way analysis of covariance, with
baseline blood pressure (seated systolic and seated
diastolic) as the covariate. Combination therapy was
considered statistically significantly superior if the
larger of the two one-sided P-values obtained by
testing combination therapy separately against the
two monotherapy groups was o0.025; the min test
of Laska and Meisner23 is inherently one-sided.
Analysis of covariance was also used for secondary
efficacy end points, in which treatment was the main
effect and baseline value the covariate. The covariate-adjusted mean difference between the combination treatment group and each monotherapy regimen
was tested at the two-sided 5% significance level.

Safety assessments

On enrolment to the study, all patients gave a detailed

medical history and underwent a complete physical
examination, including a 12-lead electrocardiogram.
Blood and urine samples for laboratory analyses were
collected at baseline, before randomization to doubleblind treatment on day 21 and at weeks 2, 4, 8 and 12
of the double-blind active treatment period.
Safety was assessed in all randomized patients
who took at least 1 dose of study medication. The
frequency and severity of adverse events (AEs) as
well as their relationship to study medication were
summarized. Adverse events related to aggressive
blood pressure-lowering therapy, including hypotension, dizziness, syncope and headaches, as well
as the frequency of hypokalaemia and hyperkalaemia at week 12, were prespecified as secondary
outcome measures in this study. The incidences of
clinical laboratory test abnormalities during doubleblind treatment were also summarized.

Results
Patient disposition

In total, 769 patients were enrolled, of whom 538

were randomized to study medication and began
double-blind treatment. Of the 231 patients who
were enrolled but not randomized, the large majority
(187) were excluded because they no longer met
study criteria. The number of patients receiving
irbesartan/HCTZ combination therapy, irbesartan
monotherapy and HCTZ monotherapy was 328, 106
and 104, respectively. A total of 472 patients (87.7%
of randomized patients) completed double-blind
treatment, while similar numbers discontinued prematurely in all three groups41 patients (12.5%), 12
patients (11.3%) and 13 patients (12.5%) in the
irbesartan/HCTZ, irbesartan and HCTZ groups, respectively. The single most common reason for
premature withdrawal was AEs. One patient in each
group withdrew due to lack of efficacy.

Statistical analysis

This study was designed to test the hypothesis that

after 8 weeks of double-blind treatment in patients
with moderate hypertension, the reduction in baseline SeSBP would be greater following treatment
Journal of Human Hypertension

Baseline characteristics

The treatment groups were similar at baseline with

respect to demographic and clinical characteristics

Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
269

(Table 1). Most patients were middle-aged: the mean

age was approximately 55 years and 71.5% were
between the ages of 40 and 64 years. Overall, 81
(15.1%) were aged 6574 years and 29 (5.4%) were
aged 75 or older. Some 292 subjects (55%) were
male; 452 (84.0%) were white and 74 (13.8%)
were black/African-American. At baseline, the mean
sitting blood pressure was 161.7/97.5 mm Hg. Overall, 228 patients (42.4%) had hyperlipidemia, while
74 (13.8%) had diabetes mellitus. Patients with a
prior history of angina pectoris, myocardial infarction or stroke/transient ischaemic attack were fewer
than 2% in all three groups. In total, 52.4, 49.1 and
45.2% of subjects in the irbesartan/HCTZ, irbesartan
and HCTZ groups, respectively, had previously
received antihypertensive therapy.
Efficacy

Irbesartan/HCTZ combination therapy reduced blood

pressure to a greater degree than either irbesartan or
HCTZ monotherapy. With regard to the primary
efficacy variable, the mean reductions in SeSBP from
baseline to week 8 were 27.1 mm Hg in the
irbesartan/HCTZ group, compared with 22.1 mm Hg
in the irbesartan group (P 0.0016) and 15.7 mm Hg
in the HCTZ group (Po0.0001; Figure 1). Similarly,
mean reductions in SeDBP from baseline to week 8
were 14.6 mm Hg in the irbesartan/HCTZ group,
compared with 11.6 mm Hg in the irbesartan group
(P 0.0013) and 7.3 mm Hg in the HCTZ group
(Po0.0001).
Similar blood pressure-lowering responses were
observed when the results were stratified according

to whether patients were previously untreated or

had been transferred from insufficiently effective
antihypertensive medications. At week 8, the mean
reductions in SeSBP with irbesartan/HCTZ were
28.2 and 26.0 mm Hg in the previously treated and
previously untreated groups, respectively. Mean
reductions in SeDBP were 14.2 and 15.0 mm Hg in
the previously treated and previously untreated
groups, respectively. Comparable data were observed
in the irbesartan and HCTZ monotherapy groups.
The magnitude of response to treatment in diabetic
and non-diabetic patients was also comparable to
that in the study population as a whole, as was that
observed in the obese and dyslipidaemic subgroups
(data not shown).
With regard to the time course of blood pressure
reduction, significantly greater reductions in both
SeSBP and SeDBP in the combination therapy group
were observed at all time points, with increasing
reductions in blood pressure throughout the course
of the study (Figure 2). Both the rate of decline and
the total degree of decline achieved were greatest
with irbesartan/HCTZ combination therapy and
least with HCTZ monotherapy.
As shown in Figure 3, similar results were
observed with regard to the proportion of patients
reaching a treatment target of SeSBP o140 mm Hg
and SeDBP o90 mm Hg. In total, 53.4% of patients
in the irbesartan/HCTZ arm were controlled by week
8, compared with 40.6% of patients in the irbesartan
monotherapy arm (P 0.0254) and 20.2% in the
HCTZ arm (Po0.0001). By week 12, 55.8% of
patients in the irbesartan/HCTZ group had controlled blood pressure as defined by JNC-7 criteria.

Table 1 Patient characteristics at baseline (all randomized patients)

Demographics
Male/female (%)
Race (%)
Caucasian
Black/African-American
Asian
Native Hawaiian/
other Pacific Islander/America-Indian/Alaska
native
Mean age (range), years
Mean weight (range), kg
Cardiovascular history
Mean SeDBP (range), mm Hg
Mean SeSBP (range), mm Hg
Mean seated heart rate (range), bpm
Diabetes mellitus, n (%)
Hyperlipidaemia, n (%)
Stable angina pectoris, n (%)
Stroke or TIA, n (%)
Myocardial infarction, n (%)

Irbesartan/HCTZ
(N 328)

Irbesartan monotherapy
(N 106)

HCTZ monotherapy
(N 104)

181 (55.2)

49 (46.2)

62 (59.6)

82.6
15.2
1.8
0.3

89.6
8.5
0
1.8

82.7
14.4
1.9
1.0

55.1 (2487)
87.6 (46.0152.0)

55.3 (2587)
88.2 (47.0146.10)

56.0 (2183)
88.4 (55.0146.1)

97.5
161.7
75.5
47
146
6
6
5

(66.0114.7)
(127.7203.3)
(48.0110.0)
(14.3)
(44.5)
(1.8)
(1.8)
(1.5)

97.9
161.4
75.3
14
45
2
0
1

(74.3109.3)
(135.7178.0)
(52.0100.0)
(13.2)
(42.5)
(1.9)
(0)
(0.9)

97.6
162
76.6
13
37
1
1
2

(74.7110.7)
(136.0180.0)
(50.0108.0)
(12.5)
(35.6)
(1.0)
(1.0)
(1.9)

Abbreviations: HCTZ, hydrochlorothiazide; SeBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure; TIA, transient ischemic
attack.
Journal of Human Hypertension

Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
270

Figure 1 Adjusted mean change in trough seated systolic blood pressure (SeSBP) and trough seated diastolic blood pressure (SeDBP)
from baseline to week 8. Error bars denote standard error. P-values refer to comparisons with combination therapy.

hs-CRP

At week 12, there was a mean increase from baseline

in hs-CRP level of 4.5% in the irbesartan/HCTZ
group (geometric means at baseline and at week 12
were 3.18 (s.e. 0.21) and 3.28 (s.e. 0.23), respectively) and mean reductions of 21.3% in the irbesartan
group (geometric means at baseline and at week 12
were 3.0 (s.e. 0.35) and 2.37 (s.e. 0.28), respectively) and 1.2% in the HCTZ monotherapy group
(geometric means at baseline and at week 12 were 2.78
(s.e. 0.32) and 2.82 (s.e. 0.31), respectively). There
was a significant divergence between the irbesartan/
HCTZ and irbesartan monotherapy groups at week 12
(P 0.0036).
Safety and tolerability

Treatment was well tolerated in all three arms of the

study. The overall frequency of AEs during doubleblind treatment period was similar in the three
treatment groups (Table 2). Treatment-related AEs
were more common in the combination arm (14.3%)
than in the irbesartan monotherapy (11.3%) and
HTCZ group (7.7%). There were six serious AEs in
the irbesartan/HCTZ combination arm, only one of
which was considered related to study medication:
this was a reported case of hypokalaemia that was
mild in severity. There were no serious AEs in the
irbesartan monotherapy group and there were three
AEs in the HCTZ group, none of which were
considered related to study therapy. The percentages of patients discontinuing treatment due to an
AE were 6.7, 3.8 and 4.8% in the irbesartan/HCTZ,
irbesartan and HCTZ groups, respectively. Withdrawals due to dizziness (four subjects) and hypotension (three subjects) were both observed in the
irbesartan/HCTZ group, but these events were
infrequent and occurred primarily following forced
Journal of Human Hypertension

titration in patients in whom blood pressure was

already controlled.
Overall, the incidence of prespecified AEs was
somewhat greater in the combination therapy group
(10.7% of patients, compared with 6.6 and 6.7% in
the irbesartan and HCTZ monotherapy groups,
respectively). Headache was the most common
prespecified AE in all three groups. There was one
reported episode of syncopethis occurred in the
HCTZ monotherapy group following upwards titration of the dose. Increases or decreases in serum
potassium were each reported in approximately 1%
of subjects in the combination therapy group; at
week 12, there was a mean decrease in serum
potassium of 0.14 mEq l1 in this group compared
with baseline, and of 0.3 mEq l1 in the HCTZ
monotherapy group. There was no change in the
irbesartan monotherapy group.
There were 10 subjects (3.1%) in the irbesartan/
HCTZ combination therapy group with a value
consistent with the criteria for a marked elevation
in creatinine, compared to 3 (2.9%) and 5 (4.9%) in
the irbesartan and HCTZ monotherapy groups,
respectively. It should be noted that the definition
of marked laboratory abnormality included relatively small changes that could still be in the normal
range, since any value 41.5 times the pretreatment
value was considered a marked abnormality. The
highest serum creatinine value reported for a subject
in whom a renal and urinary AE was reported was
1.3 mg per 100 ml, observed in a subject whose
baseline serum creatinine was 1.2 mg per 100 ml; the
highest creatinine value seen during the study in
any subject was 1.7 mg per 100 ml.
None of the other laboratory tests revealed any
findings of concern. In tests of creatine kinase, serum
glucose, uric acid and albumin, there were modest
numbers (three instances, 0.9%) of abnormalities in

Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
271

Figure 2 Mean change from baseline in (a) trough seated systolic blood pressure and (b) trough seated diastolic blood pressure during
the course of the study.

the irbesartan/HCTZ combination therapy group. The

irbesartan monotherapy group had four instances
(4.0%) and the HCTZ monotherapy group had none.
There were no instances of an abnormal change in
total cholesterol level in any study subject.

Discussion
Hypertensive patients should be treated with the
objective of attaining blood pressure goals fully and
rapidly, since significant delays or failure to achieve
goals are associated with an increased risk of cardiovascular events.24 Since patients with moderate or
severe hypertension are likely to require two or more
agents to reach goal, current JNC-7 and European

Society of Hypertension guidelines both recommend

the use of initial combination therapy to manage
their blood pressure.15,16
This large study involving 558 patients investigated the efficacy and safety of irbesartan/HCTZ 300/
25 mg in subjects with moderate hypertension, with
approximately equal numbers of previously untreated patients and those in whom prior therapy
had been inadequate. The clinical profile of the
study participants was broad and representative of
the general hypertensive population, and included
patients who were diabetic, obese and/or dyslipidaemic. Irbesartan/HCTZ combination therapy proved
highly effective in lowering blood pressure: the mean
reduction in blood pressure after 8 weeks was 27.1/
14.6 mm Hg for irbesartan 300 mg/HCTZ 25 mg, a
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Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
272

Figure 3 Proportion of patients achieving a target of o140/90 mm Hg for controlled blood pressure. *Po0.05, **Po0.01, ***Po0.0001,
compared to combination therapy.

Table 2 Incidence of AEs, prespecified AEs, treatment-related AEs, serious AEs and deaths (all randomized patients)

Patients with at least one AE, n (%)

Patients with at least one prespecified AEs, n
(%)
Prespecified AE, n (%)
Dizziness
Headache
Hyperkalaemia/increased potassium
Hypokalaemia/decreased potassium
Hypotension
Serum potassium o3.0 mmol l1
Serum potassium 46.0 mmol l1
Treatment-related AEs, n (%)
Serious AEs, n (%)
Deaths, n (%)
Discontinuations due to AEs, n (%)

Irbesartan/HCTZ
(N 328)

Irbesartan monotherapy
(N 106)

HCTZ monotherapy
(N 104)

154 (47.0)
35 (10.7)

48 (45.3)
7 (6.6)

41 (39.4)
7 (6.7)

4 (3.8)
4 (3.8)
0
0
0
0
0
12 (11.3)
0
0
4 (3.8)

1 (1.0)
5 (4.8)
1 (1.0)
0
0
0
0
8 (7.7)
3 (2.9)
0
5 (4.8)

10
18
4
3
3
4
47
6
22

(3.0)
(5.5)
(1.2)
(0.9)
(0.9)
0
(1.2)
(14.3)
(1.8)
0
(6.7)

Abbreviations: AEs, adverse events; HCTZ, hydrochlorothiazide.

significantly greater reduction than with irbesartan or

HCTZ monotherapy, thereby confirming the primary
hypothesis of the study that the combination would
deliver superior control in this high-risk, difficult-totreat patient population. The response to treatment
was rapid and sustained, with increasing reductions
in blood pressure throughout the course of the trial.
Moreover, patients who had previously responded
inadequately to treatment were found to have the
same reductions in blood pressure as previously
untreated patients, emphasizing the blood pressurelowering effectiveness of the irbesartan/HCTZ combination. The response in diabetic and non-diabetic
subgroups was also comparable to that observed in the
study population as a whole, although in this study
the diabetic subgroup was quite small, at around
13.8% of the total.
Journal of Human Hypertension

The proportion of patients achieving blood pressure goals was also greater in the combination
therapy arm, with over 55% of patients reaching a
target of below 140/90 mm Hg, compared with 40.6
and 20.2% in the irbesartan and HCTZ monotherapy
groups, respectively. This rate of goal attainment
indicates that this two-drug combination is effective
in this patient group, many of whom had been
unsuccessfully treated by prior antihypertensives.
Of note, irbesartan monotherapy was also more
effective than HCTZ monotherapy during the course
of the trial, with mean reductions in SeDBP from
baseline to week 8 of 11.6 and 7.3 mm Hg in the
irbesartan and HCTZ monotherapy groups, respectively (difference 4.4 mm Hg, 95% CI 6.62.1). The
observation that HCTZ-treated patients responded
so poorly is not surprising, as HCTZ 12.5 mg is not

Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
273

generally considered to be a very effective antihypertensiveparticularly in patients who have not

responded to monotherapy.
Irbesartan monotherapy significantly reduced hsCRP at week 12, although the variability was high
and no significant changes were observed at earlier
time points. No significant changes were observed
in the HCTZ monotherapy and irbesartan/HCTZ
combination groups. Similar findings were reported
in a recent study of valsartan/HCTZ combination
therapy, in which there was a slight increase in hsCRP levels with the HCTZ combination, compared
with a significant reduction when valsartan was
given in monotherapy.25 In the valsartan study, this
difference was reported to be unrelated to the greater
reduction of blood pressure in the combination
therapy group. The effects of thiazide combination
on the anti-inflammatory effects of ARBs require
further investigation. A larger sample size or longer
observation period may be required to characterize
these effects better.
Safety and tolerability is a critical consideration
in aggressive hypertensive therapy, which can be
associated with hypotension, syncope, headache
and hypokalaemia. In this study, the three treatment
arms were well tolerated. There was a numerically
greater incidence of some treatment-related effects,
including headache, hypotension and hypokalaemia
with irbesartan/HCTZ combination therapy, but the
treatment was well tolerated and there was no
excess of withdrawals. There were no episodes of
syncope in the study, with the exception of a single
case in the HCTZ monotherapy group following
titration. These findings vindicate the approach of
the JNC-7 and European Society of Hypertension in
recommending aggressive, two-drug therapy as
initial treatment for patients with moderate hypertension, and indicate that this strategy can be
pursued without compromising patient safety.
These results are also consistent with two other
irbesartan/HCTZ studies, which also found that
combination therapyeven in patients with severe
hypertensionwas well tolerated with no major AEs
reported.21,26
Fixed-dose combinations are likely to become an
increasingly important option in the management of
hypertension as the drive to improve the simplicity
and convenience of treatment continues. The results
of this study demonstrate that an irbesartan/HCTZ
combination was effective in a population of
patients with moderate hypertension, a significant
proportion of whom had not received prior antihypertensive treatment. It should be noted, however, that differences in blood pressure-lowering
efficacy demonstrated between ARBs when these
agents are used in monotherapy have been found to
be replicated in the setting of HCTZ combination
therapy. For instance, irbesartan 150 mg has been
found to reduce blood pressure to a significantly
greater degree than valsartan 80 mg at equivalent
doses both in monotherapy27 and, more recently,

when both agents were given in combination with

HCTZ.28 Therefore, caution should be exercised
when extending these results to other agents in the
ARB class, and ideally data should be obtained for
individual ARBs.
In conclusion, these results indicate that irbesartan/HCTZ is effective, has a favourable safety profile
and is well tolerated in patients with moderate
hypertension, whether used as initial therapy or in
patients not controlled on monotherapy. Treatment
achieved substantial reductions in both systolic and
diastolic blood pressure, and enables over half of
patients to reach a target blood pressure of below
140/90 mm Hg without the need for additional
medication. These results support the use of the
irbesartan/HCTZ fixed-dose combination in the
management of moderate hypertension.

What is known about the topic:

K Current JNC-7 and ESH guidelines recommend initial
combination therapyfor example a fixed-dose
combination of an ARB with a thiazide, typically HCTZ
for patients with moderate hypertension.
K Clinical studies of irbesartan/HCTZ suggest that this
combination is not only clinically effective, but also has a
favourable safety profile.
What this study adds:
K This study investigated the efficacy, safety and tolerability
of high-dose irbesartan/HCTZ in patients with moderate
hypertension, including in the context of initial therapy.
K Irbesartan/HCTZ was well tolerated and achieved rapid and
sustained reductions in both SBP and DBP in patients with
moderate hypertension.
Abbreviations: ARB, angiotensin receptor blocker; DBP, diastolic
blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood
pressure.

Acknowledgements
This study was sponsored by Bristol-Myers Squibb
and Sanofi-aventis.
Conflicts of interest
JMN: grant and research support from BoehringerIngelheim, Bristol-Myers Squibb, GlaxoSmithKline,
Pfizer, Alteon, AtheroGenics and Novartis; Speakers
Bureau for Novartis, Bristol-Myers Squibb, Sanofiaventis, Sankyo, Boehringer-Ingelheim, Biovail, Reliant and Pfizer; consultant for Bristol-Myers Squibb,
Sanofi-aventis, Novartis, Biovail, Sankyo, Mylan
Bertek and Boehringer-Ingelheim. SSF: Speakers
Bureau for Boehringer Ingelheim, Bristol-Myers
Squibb and Merck; consultant for AtCor Medical,
Bristol-Myers Squibb, Merck and Pfizer.

References
1 Kearney PM, Whelton M, Reynolds K, Muntner P,
Whelton PK, He J. Global burden of hypertension:
analysis of worldwide data. Lancet 2005; 365: 217223.
Journal of Human Hypertension

Irbesartan/HCTZ in moderate hypertension

JM Neutel et al
274

2 Kearney PM, Whelton M, Reynolds K, Whelton PK, He

J. Worldwide prevalence of hypertension: a systematic
review. J Hypertens 2004; 22: 1119.
3 Hajjar I, Kotchen JM, Kotchen TA. Hypertension:
trends in prevalence, incidence, and control. Annu
Rev Public Health 2006; 27: 465490.
4 Cheung BM, Ong KL, Man YB, Lam KS, Lau CP.
Prevalence, awareness, treatment, and control of hypertension: United States National Health and Nutrition
Examination Survey 20012002. J Clin Hypertens
(Greenwich) 2006; 8: 9398.
5 Berlowitz DR, Ash AS, Hickey EC, Friedman RH,
Glickman M, Kader B et al. Inadequate management of
blood pressure in a hypertensive population. N Engl J
Med 1998; 339: 19571963.
6 Waeber B, Burnier M, Brunner HR. Compliance with
antihypertensive therapy. Clin Exp Hypertens 1999; 21:
973985.
7 Clark LT. Improving compliance and increasing control
of hypertension: needs of special hypertensive populations. Am Heart J 1991; 121: 664669.
8 Mancia G, Sega R, Milesi C, Cesana G, Zanchetti A.
Blood pressure control in the hypertensive population.
Lancet 1997; 349: 454457.
9 Mancia G, Ambrosioni E, Rosei EA, Leonetti G,
Trimarco B, Volpe M, ForLife study group. Blood
pressure control and risk of stroke in untreated and
treated hypertensive patients screened from clinical
practice: results of the ForLife study. J Hypertens 2005;
23: 15751581.
10 Mancia G, Parati G, Borghi C, Ghironzi G, Andriani E,
Marinelli L, et al., SMOOTH investigators. Hypertension
prevalence, awareness, control and association with
metabolic abnormalities in the San Marino population:
the SMOOTH study. J Hypertens 2006; 24: 837843.
11 Okonofua EC, Simpson KN, Jesri A, Rehman SU,
Durkalski VL, Egan BM. Therapeutic inertia is an
impediment to achieving the Healthy People 2010 blood
pressure control goals. Hypertension 2006; 47: 345351.
12 Hypertension Call to Action 2006. Available at http://
www.eshonline.org/education/congresses/2006/esh/
call_to_action.aspaccessed on 5th February 2007.
13 Franklin SS, Jacobs MJ, Wong ND, LIalien GJ, Lapuerta P.
Predominance of isolated systolic hypertension among
middle-aged and elderly US hypertensives: analysis
based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension 2001; 37(3):
869874.
14 Skolink NS, Beck JD, Clark M. Combination antihypertensive drugs: recommendations for use. Am Fam
Physician 2000; 61: 30493056.
15 Chobanian AV, Bakris GL, Black HR, Cushman WC,
Green LA, Izzo Jr JL et al. The Seventh Report of the
Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the
JNC-7 Report. JAMA 2003; 289: 25602572.
16 The Task Force for the Management of Arterial
Hypertension of the European Society of Hypertension

Journal of Human Hypertension

17

18

19

20

21

22

23
24

25

26

27

28

(ESH) and of the European Society of Cardiology

(ESC). 2007 Guidelines for the management of arterial
hypertension. Eur Heart J 2007; 28: 14621536.
Taylor AA, Shoheiber O. Adherence to antihypertensive therapy with fixed-dose amlodipine besylate/
benazepril HCl versus comparable component-based
therapy. Congest Heart Fail 2003; 9: 324332.
Neutel JM, Saunders E, Bakris GL, Cushman WC,
Ferdinand KC, Ofili EO et al. The efficacy and safety of
low- and high-dose fixed combinations of irbesartan/
hydrochlorothiazide in patients with uncontrolled
systolic blood pressure on monotherapy: the INCLUSIVE trial. J Clin Hypertens (Greenwich) 2005; 7:
578586.
Pool JL, Guthrie RM, Littlejohn III TW, Raskin P,
Shephard AM, Weber MA et al. Dose-related antihypertensive effects of irbesartan in patients with
mild-to-moderate hypertension. Am J Hypertens 1998;
11: 462470.
Howe P, Phillips P, Saini R, Kassler-Taub K. The
antihypertensive efficacy of the combination of irbesartan and hydrochlorothiazide assessed by 24-h
ambulatory blood pressure monitoring. Clin Exp
Hypertens 1999; 21: 13731396.
Kochar M, Guthrie R, Triscari J, Kassler-Taub K, Reeves RA.
Matrix study of irbesartan with hydrochlorothiazide in
mild-to-moderate hypertension. Am J Hypertens 1999; 12:
797805.
OBrien E, Waeber B, Parati G, Staessen J, Myers MG.
Blood pressure measuring devices: recommendations
of the European Society of Hypertension. BMJ 2001;
322: 531536.
Laska EM, Meisner MJ. Testing whether an identified
treatment is best. Biometrics 1989; 45: 11391151.
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S,
Hansson L et al. Outcomes in hypertensive patients at
high cardiovascular risk treated with regimens based
on valsartan or amlodipine: the VALUE randomised
trial. Lancet 2004; 363: 20222031.
Ridker PM, Danielson E, Rifai N, Glynn RJ, Val-MARC
Investigators. Valsartan, blood pressure reduction, and
C-reactive protein: primary report of the Val-MARC
trial. Hypertension 2006; 48: 7379.
Neutel JM, Franklin SS, Oparil S, Bhaumik A,
Ptaszynska A, Lapuerta P. Efficacy and safety of
irbesartan/HCTZ combination therapy as initial treatment for rapid control of severe hypertension. J Clin
Hypertens 2006; 8: 850857.
Bobrie G, Delonca J, Moulin C, Giacomino A, PostelVinay N, Asmar R. A home blood pressure monitoring
study comparing the antihypertensive efficacy of two
angiotensin II receptor antagonist fixed combinations.
Am J Hypertens 2005; 18: 14821488.
Mancia G, Korlipara K, van Rossum P, Villa G, Silvert B.
An ambulatory blood pressure monitoring study of the
comparative antihypertensive efficacy of two angiotensin II receptor antagonists, irbesartan and valsartan.
Blood Press Monit 2002; 7: 135142.