AJH 1999;12:797– 805

Matrix Study of Irbesartan With

Hydrochlorothiazide in Mild-to-Moderate
Hypertension
M. Kochar, R. Guthrie, J. Triscari, K. Kassler-Taub, and R.A. Reeves

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The purpose of this study was to assess the safety groups, and ⴚ8.1 to ⴚ15.0 for the combination
and antihypertensive dose-response effects of groups. Irbesartan plus HCTZ produced additive
irbesartan and hydrochlorothiazide (HCTZ) in reductions in both SeDBP and seated systolic BP,
patients with mild-to-moderate hypertension. After with at least one combination producing greater BP
a 4- to 5-week single-blind placebo lead-in period, reduction than either drug alone (P < .001). All
683 patients with seated diastolic blood pressure treatments were well tolerated; there were no
(SeDBP) between 95 and110 mm Hg were treatment-related serious adverse events. Irbesartan
randomized to receive once-daily dosing with one tended to ameliorate the dose-related biochemical
of 16 different double-blind, fixed combinations of abnormalities associated with HCTZ alone. In
irbesartan (0, 37.5, 100, and 300 mg irbesartan) and conclusion, the combination of HCTZ in doses up
HCTZ (0, 6.25, 12.5, and 25 mg HCTZ) for 8 weeks. to 25 mg with irbesartan, in doses up to 300 mg, is
The primary efficacy variable was the change from safe and produces dose-dependent reductions in
baseline in trough SeDBP after 8 weeks of therapy. BP. Am J Hypertens 1999;12:797– 805 © 1999
Data were analyzed by response surface modeling. American Journal of Hypertension, Ltd.
At Week 8, mean changes from baseline in trough
SeDBP (mm Hg) ranged from ⴚ3.5 for placebo, KEY WORDS:Irbesartan, hydrochlorothiazide,
ⴚ7.1 to ⴚ10.2 for the irbesartan monotherapy randomized controlled trial, hypertension,
groups, ⴚ5.1 to ⴚ8.3 for the HCTZ monotherapy combination therapy.

I
rbesartan is a long-acting angiotensin II receptor irbesartan may offer potential advantages in safety
blocker (ARB) that is highly selective for the AT1 and tolerability over other classes of antihypertensive
receptor subtype.1 Once-daily administration of agents.
irbesartan has dose-dependent antihypertensive Irbesartan in combination with hydrochlorothiazide
effects.2– 6 Because of its specific mechanism of action, (HCTZ)7,8 is safe and effective in reducing blood pres-
sure (BP) in patients with hypertension. The combina-
tion of the two drugs significantly reduces BP in pa-
Received April 17, 1998. Accepted December 30, 1998. tients not controlled by irbesartan5 or HCTZ alone.8
From the Clement J. Zablocki VA Medical Center, Milwaukee,
Wisconsin (MK); Ohio State University, Columbus, Ohio (RG); and Hydrochlorothiazide is a commonly used diuretic
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, in the treatment of hypertension.9 However, long-term
New Jersey (JT, KK-T, RAR). diuretic use is associated with dose-related hypokale-
This study was sponsored by Bristol-Myers Squibb Pharmaceuti-
cal Research Institute, Princeton, New Jersey. mia, glucose intolerance, and increases in serum low-
Address correspondence and reprint requests to Mahendr S. Ko- density-lipoprotein cholesterol and uric acid levels.9,10
char, MD, Clement J. Zablocki VA Medical Center, The Medical
College of Wisconsin, 5000 West National Avenue (14A), Milwau- Combination with another antihypertensive agent,
kee, WI 53295; e-mail: [email protected] however, allows lower doses of HCTZ to be used, and

© 1999 by the American Journal of Hypertension, Ltd. 0895-7061/99/$20.00

Published by Elsevier Science, Inc. PII S0895-7061(99)00053-9
798 KOCHAR ET AL AJH–AUGUST 1999 –VOL. 12, NO. 8, PART 1

TABLE 1. TREATMENT GROUPS

Irbesartan Dose

HCTZ dose 0 mg 37.5 mg 100 mg 300 mg

0 mg 0 mg/0 mg 0 mg/37.5 mg 0 mg/100 mg 0 mg/300 mg
6.25 mg 6.25 mg/0 mg 6.25 mg/37.5 mg 6.25 mg/100 mg 6.25 mg/300 mg
12.5 mg 12.5 mg/0 mg 12.5 mg/37.5 mg 12.5 mg/100 mg 12.5 mg/300 mg
25 mg 25 mg/0 mg 25 mg/37.5 mg 25 mg/100 mg 25 mg/300 mg

may blunt the adverse metabolic effects associated fying patients were then randomized to one of 16
with diuretic use.11 double-blind treatment groups (Table 1). All patients
This trial used a 4 ⫻ 4 factorial or “matrix” design. were instructed to take three capsules (irbesartan or

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The objectives of this study were to assess both the matching placebo) and one tablet (HCTZ or matching
antihypertensive efficacy of once-daily irbesartan and placebo) once daily between 6 am and 10 am for 8
HCTZ across their respective dose ranges in patients weeks. Patients were seen biweekly during the dou-
with hypertension, as well as the safety and tolerabil- ble-blind period.
ity (including the effects on serum uric acid, potas-
sium, glucose, and lipid levels) of the combination. Observation Methods At all clinic visits, trough
(24 ⫾ 2 h after the last dose), seated and standing BP,
MATERIALS AND METHODS and heart rate (HR) were measured. After resting for
Patient Selection Men and surgically sterile or post- 10 min in a seated position, BP was determined by
menopausal women aged 18 years or older with a calculating the mean of three replicate measurements
supine, seated, or standing diastolic BP ⱖ 95 mm Hg taken 1 min apart. The mean of three SeDBP readings
were enrolled into the study. All patients gave written was calculated if the readings were within 8 mm Hg of
informed consent (form approved by the local insti- each other; if not, two additional readings were ob-
tutional review board). At enrollment, a medical his- tained and the mean was calculated from the five
tory was obtained and a physical examination and readings. After 2 min of standing, three BP measure-
laboratory tests were performed. Any antihyperten- ments were obtained. Heart rate was measured by
sive agents were withdrawn after consent. counting the pulse for 30 s and multiplying by 2. At
Patients were excluded if they had known or sus- Week 8, seated and standing BP and HR were mea-
pected secondary hypertension (ie, renovascular oc- sured 1, 2, 3, 4, 5, and 6 h after dosing to determine
clusive disease, significant renal or endocrinologic dis- peak BP-lowering effects and to calculate trough:peak
ease, malignancy, use of oral contraceptives), a seated ratio for SeDBP.
diastolic BP (SeDBP) ⱖ 110 mm Hg, allergies to HCTZ Observed and volunteered adverse events were re-
or sulfa drugs, concomitant illnesses that would make corded at all clinic visits. Blood and urine samples
participation not in their best interest, or were taking were obtained for standard laboratory tests at base-
concomitant medications that would prevent accurate line, Week 3 of the single-blind period, and Weeks 2,
evaluation of safety or efficacy. Patients were with- 4, and 8 of the double-blind portion of the study. A
drawn from the study for seated systolic BP (SeSBP) physical examination and 12-lead electrocardiogram
⬎ 205 mm Hg or SeDBP ⬎ 112 mm Hg or if they (ECG) were performed at baseline and at the end of
needed a prohibited medication. the study.

Study Design This randomized, double-blind, pla- Statistical Methods All statistical tests were two-
cebo-controlled study was conducted at 46 sites in the sided and carried out at a significance level of ␣ ⫽
United States. During a 4- to 5-week lead-in period, 0.05.
patients took single-blind placebo (three capsules and Demographic and Baseline Characteristics Quanti-
one tablet) once daily. To be eligible for randomiza- tative data were analyzed using a one-way analysis of
tion, patients had to have a mean SeDBP at both variance (ANOVA) with treatment group as the factor.
Weeks 3 and 4 between 95 and 110 mm Hg (readings Qualitative data were assessed using a ␹2 test.
could not differ by ⬎ 8 mm Hg) and demonstrate
good compliance (80% to 120% of expected medica- Sample Size Determination Forty subjects in each
tion consumption). If patients did not meet the BP of the 16 treatment groups provided a 95% confidence
entry criteria at Week 4, an optional visit was permit- that for any dose combination, the mean SeDBP re-
ted at Week 5 and the mean SeDBP values at Weeks 4 duction after 8 weeks of therapy would be estimated
and 5 were then used to determine eligibility. Quali- to within 1.3 mm Hg of the true mean.
AJH–AUGUST 1999 –VOL. 12, NO. 8, PART 1 IRBESARTAN/HCTZ MATRIX STUDY 799

Efficacy Analyses of efficacy assessments included (Figure 1). The response surface model of predicted
data for all patients who had a baseline evaluation and change from baseline to Week 8 in SeDBP shows an
at least one on-therapy evaluation. The primary effi- additive relationship with irbesartan and HCTZ (Fig-
cacy variable was the mean change from baseline in ure 2). For irbesartan doses up to 300 mg, the pre-
trough SeDBP at Week 8. Changes in SeDBP and dicted reductions increased linearly with increasing
SeSBP were analyzed using both a response surface doses of HCTZ. For doses of HCTZ up to 25 mg,
model and analysis of covariance (ANCOVA). A inclusion of a quadratic term characterized the reduc-
global test procedure12 was performed to determine tion in SeDBP with increasing doses of irbesartan such
whether at least one combination of irbesartan/HCTZ that, at doses approaching 300 mg, the effects of irbe-
was more effective than each of its components. No sartan appeared to reach a plateau. The global test
tests were performed to compare specific pairs of procedure12 showed that there was at least one com-
treatment, as it was not an objective of the study. bination treatment that produced significantly larger
reductions in trough SeDBP than either component

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Safety Results from safety assessments were sum- alone (P ⬍ .001).
marized for all patients who received at least one dose Similar results were seen for trough SeSBP (Figure
of randomized therapy. Mean changes from baseline 3 and Table 2), ie, additive effects of HCTZ and irbe-
were calculated for selected laboratory tests. sartan characterized by a linear relationship with the
RESULTS HCTZ dose and a curvilinear relationship with the
irbesartan dose. There was also at least one combina-
Patient Disposition A total of 1126 patients were tion treatment that produced significantly larger re-
enrolled into the study. Of these, 443 patients were not ductions in SeSBP than either component alone (P ⬍
randomized for various reasons, including failure to .001). From these models, a combination of 300 mg
qualify per protocol criteria, patient request, reported irbesartan/12.5 mg HCTZ is estimated to yield a pla-
adverse events during placebo lead-in period, BP cebo-subtracted decrease in trough BP of about 14/9
greater than the limit allowed for randomization, and mm Hg.
loss to follow-up. Of the 683 patients randomized to Mean reductions in standing diastolic and systolic
double-blind therapy, 52 patients were discontinued BP followed patterns similar to those observed for
(adverse events [n ⫽ 22], patient request [n ⫽ 9], poor seated BP (data not shown). Seated and standing HR
BP control [n ⫽ 10], loss to follow-up [n ⫽ 4], and did not change by more than 4 beats/min in any
other reasons including poor compliance, use of pro- treatment group, and there was no dose-related pat-
hibited medications, and administrative issues [n ⫽ tern to the HR changes.
7]). Of the randomized patients, 82% had received
antihypertensive treatment within 1 month of enroll- Therapeutic Response The proportion of patients
ment. normalized (trough SeDBP ⬍ 90 mm Hg) at Week 8
Of the patients who completed the study, six were increased with increasing doses of irbesartan or HCTZ
not included in the efficacy analyses because of incom- (Figure 4). The proportion of total responders (normal-
plete source documentation at one investigator’s site. ized or trough SeDBP decreased by ⱖ 10 mm Hg) was
In addition, five discontinued patients had data col- 24% in the placebo group, 36% to 53% in the HCTZ
lected at Week 8 and so were included in the efficacy monotherapy groups, 35% to 58% in the irbesartan
analysis. Thus, 630 patients were included in the effi- monotherapy groups, and 44% to 80% in the irbesar-
cacy analysis. tan/HCTZ combination treatment groups.

Demographic and Baseline Characteristics There Trough:Peak Ratios Peak reductions in SeDBP oc-
were no significant differences between the treatment curred between 2 and 5 h postdose for all treatment
groups in baseline BP or demographic characteristics groups. For the 100 mg and 300 mg irbesartan mono-
(all P ⬎ .3). Sixty-five percent of the patients were therapy groups, the placebo-adjusted trough:peak
male, 85% were white, and the mean (⫾ SD) age was ratios for SeDBP at Week 8 were 63% and 55%, re-
55 ⫾10.5 years. Mean seated BP at baseline was 151/ spectively. For the 12.5 mg and 25 mg HCTZ mono-
100 ⫾ 14.7/4.2 mm Hg. therapy groups, the trough:peak ratios were 60% and
92%, respectively. Trough:peak ratios for the irbesar-
Changes in Trough Seated and Standing Blood Pres- tan/HCTZ combination treatment groups ranged
sures and Heart Rate At Week 8, dose-related reduc- from 55% for the 37.5 mg irbesartan/6.25 mg HCTZ
tions in trough SeDBP were observed with increasing group to 81% for the 300 mg irbesartan/6.25 mg
doses of irbesartan alone, with increasing doses of HCTZ group.
HCTZ alone, and with increasing doses of the combi-
nation of irbesartan with HCTZ (Figure 1 and Table 2). Subgroup Analyses Except for a larger placebo BP
This pattern was also observed at Weeks 2, 4, and 6 response in elderly patients (ⱖ 65 years old) and
800 KOCHAR ET AL AJH–AUGUST 1999 –VOL. 12, NO. 8, PART 1

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FIGURE 1. Mean changes from baseline in trough seated diastolic blood pressure with irbesartan (Irbe) and hydrochlorothiazide
(HCTZ) at Weeks 2, 4, 6, and 8.
AJH–AUGUST 1999 –VOL. 12, NO. 8, PART 1 IRBESARTAN/HCTZ MATRIX STUDY 801

TABLE 2. MEAN CHANGES FROM BASELINE IN TROUGH BLOOD PRESSURE AT WEEK 8

Placebo Irbesartan 37.5 mg Irbesartan 100 mg Irbesartan 300 mg

Placebo N ⫽ 38 N ⫽ 40 N ⫽ 36 N ⫽ 43
⫺2.3 (10.3)/⫺3.5 (6.3) ⫺7.5 (10.5)/⫺7.1 (6.7) ⫺11.1 (12.5)/⫺9.1 (8.9) ⫺14.9 (9.5)/⫺10.2 (5.8)
HCTZ
6.25 mg N ⫽ 39 N ⫽ 39 N ⫽ 41 N ⫽ 38
⫺4.6 (10.1)/⫺5.1 (6.9) ⫺10.2 (10.7)/⫺8.1 (7.7) ⫺11.9 (10.4)/⫺10.0 (6.7) ⫺17.2 (12.6)/⫺13.2 (6.2)
12.5 mg N ⫽ 39 N ⫽ 39 N ⫽ 38 N ⫽ 43
⫺8.9 (11.2)/⫺6.2 (5.5) ⫺14.7 (11.9)/⫺9.0 (5.7) ⫺14.9 (14.6)/⫺11.9 (7.7) ⫺15.9 (13.3)/⫺15.0 (7.8)
25 mg N ⫽ 36 N ⫽ 40 N ⫽ 40 N ⫽ 41
⫺11.5 (14.9)/⫺8.3 (6.7) ⫺16.8 (12.2)/⫺11.7 (6.8) ⫺21.5 (11.5)/⫺13.8 (7.0) ⫺23.1 (15.0)/⫺14.4 (8.0)
Values are mean (standard deviation) for change from baseline trough seated systolic/diastolic blood pressure.

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women, reductions in trough SeDBP and SeSBP were the HCTZ only group, no patients (0%) in the irbesar-
generally consistent between older (n ⫽ 110) and tan only group, and 3.8% in the irbesartan/HCTZ
younger (n ⫽ 520) patients, and between men (n ⫽ combination group. The most common AE resulting in
408) and women (n ⫽ 222). The number of black discontinuation were dizziness (2.3% in the placebo
patients (fewer than seven in any treatment group) group, 0.8% in the HCTZ only group, 1.0% in the
was too small to draw any definitive conclusions; irbesartan/HCTZ group), chest pain (2.3% in the pla-
however, BP reductions appeared to be consistent be- cebo group, 1.6% in the HCTZ only group, 0.3% in the
tween black and white patients. irbesartan/HCTZ group), anxiety/nervousness (0.8%
in the irbesartan/HCTZ group), and headache (1.6%
Safety To evaluate adverse events (AE), treatment in the HCTZ only group, 0.3% in the irbesartan/HCTZ
groups were combined to compare AE in patients who group). Discontinuations because of AE in the irbesar-
received placebo only, HCTZ only, irbesartan only, or tan/HCTZ combination group were approximately
irbesartan/HCTZ combination therapy. Adverse events equally distributed among the groups, with no sug-
occurred less frequently in the irbesartan monotherapy gestion of a dose relationship.
and irbesartan/HCTZ combination groups than in the A total of 11 serious AE, such as hospitalization for
placebo group (Table 3). The proportion of patients any reason, were reported in eight of 683 (1.2%) ran-
who discontinued treatment because of an AE was domized patients; none was considered related to
⬍5% in all groups: 4.5% in the placebo group, 4.1% in study medication, and there were no deaths.

FIGURE 2. Response surface model

of the predicted change from baseline in
trough seated diastolic blood pressure at
Week 8.
802 KOCHAR ET AL AJH–AUGUST 1999 –VOL. 12, NO. 8, PART 1

FIGURE 3. Response surface model

of the predicted change from baseline in
trough seated systolic blood pressure at
Week 8.

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Changes in Laboratory Parameters and Other Safety dose combination groups showed similar increases in
Assessments Analyses of mean changes from base- BUN. Serum potassium levels decreased in a dose-
line showed that increasing doses of HCTZ were as- dependent manner with HCTZ monotherapy, and in-
sociated with increases in fasting glucose, total choles- creased in a statistically but not clinically significant
terol, triglycerides, blood urea nitrogen (BUN), and manner with irbesartan monotherapy. Irbesartan
uric acid. Irbesartan alone and in combination with tended to attenuate the potassium reductions due to
HCTZ was associated in most groups with decreases HCTZ in the combination groups (Figure 5). HCTZ
in total cholesterol levels. The combination groups increased serum uric acid levels in a dose-related man-
showed similar serum triglyceride increases as the ner, whereas in the combination groups, irbesartan
HCTZ groups, whereas irbesartan monotherapy had tended to lessen these increases (Figure 6). Only one
little effect on serum triglyceride levels. The highest patient discontinued because of laboratory abnormal-

FIGURE 4. Percent of patients in

whom blood pressure was normalized
(diastolic ⬍ 90 mm Hg) at Week 8.
AJH–AUGUST 1999 –VOL. 12, NO. 8, PART 1 IRBESARTAN/HCTZ MATRIX STUDY 803

TABLE 3. MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS

Percent of Patients Reporting

HCTZ Irbesartan Irbesartan/
Placebo Monotherapy Monotherapy HCTZ
(N ⴝ 44) (N ⴝ 123) (N ⴝ 126) (N ⴝ 390)

Headache 34.1 14.6 8.7 10.5

Dizziness 6.8 6.5 5.6 9.5
Fatigue 4.5 2.4 4.8 6.9
Upper respiratory symptoms 9.1 9.8 10.3 5.4
Sinus symptoms 9.1 4.9 3.2 4.6
Musculoskeletal pain 11.4 8.9 7.1 4.1
Edema 4.5 2.4 0.8 2.6
Chest pain 2.3 4.1 1.6 2.3

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Cough 2.3 4.1 1.6 2.3
Urinary tract infection 0 3.3 0.8 2.1

ity (ie, elevated liver enzymes, on 37.5 mg irbesartan/ Irbesartan alone and in combination with HCTZ
12.5 mg HCTZ), which resolved after withdrawal. was safe and well tolerated. No dose-related AE were
There were no clinically significant changes noted in observed, and the incidence of AE and rates of dis-
physical examinations or electrocardiograms. continuation were comparable between treatment
groups. The addition of irbesartan had positive effects
DISCUSSION
on HCTZ-associated biochemical abnormalities. Irbe-
This study demonstrates that irbesartan in combina- sartan appeared to blunt the hypokalemia associated
tion with HCTZ produces clinically and statistically with HCTZ, and uric acid and total cholesterol levels
significant antihypertensive effects. After 8 weeks of were lower with the combination therapy than with
therapy, the proportion of patients normalized in- HCTZ monotherapy. The HCTZ-associated increases
creased in a dose-dependent manner with irbesartan in serum triglycerides were not exacerbated by irbe-
monotherapy, with HCTZ monotherapy, and with sartan. The combination of the ARB losartan with
combination therapy. A maximal response to irbesar- HCTZ has also been shown to blunt the hypokale-
tan alone or in combination with HCTZ was generally mia13,14 and increases in serum uric acid13–15 and cho-
observed by Weeks 4 to 6. Trough:peak ratios ranged lesterol13 levels associated with HCTZ monotherapy.
from 55% to 81% with once-daily irbesartan/HCTZ, This study did not show any new or unexpected
consistent with 24-h efficacy. safety issues with the combination therapy. Irbesartan

FIGURE 5. Change from baseline in se-

rum potassium levels at Week 8.
804 KOCHAR ET AL AJH–AUGUST 1999 –VOL. 12, NO. 8, PART 1

FIGURE 6. Change from baseline in

serum uric acid levels at Week 8.

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monotherapy and irbesartan/HCTZ combination berg, DO, Fleetwood, PA; James Gray, MD, Houston, TX;
therapy were associated with less AE than placebo, Theodore Herman, MD, Buffalo, NY; John Holmes, MD,
Mission, KS; Lawrence Horwitz, MD, Denver, CO; James
consistent with what has previously been reported for Lewis, MD, Sunnyvale, CA; Thomas Littlejohn, MD, Win-
irbesartan.5,16 –18 In particular, headache was reported ston-Salem, NC; Thomas Marbury, MD, Orlando, FL; John
much more often by the placebo-treated patients Milas, MD, Greer, SC; William Miller, MD, Wilmington, DE;
(34.1%) than by patients receiving irbesartan mono- Alan Neiderman, MD, Fort Lauderdale, FL; Paul Ogden,
therapy (8.7%) or irbesartan/HCTZ (10.5%). MD, Greenbrae, CA; Harry Phillips, MD, Columbiana, AL;
Daniel Pietro, MD, Brockton, MA; Philip Raskin, MD, Dal-
The combination of another group of antihyperten- las, TX; Sidney Rosenblatt, MD, Irvine, CA; Dennis Ruff,
sive agents that interrupt the RAS, angiotensin con- MD, San Antonio, TX; Harry Serfer, DO, Hollywood, FL;
verting enzyme (ACE) inhibitors, with a diuretic has Satish Sharma, MD, Providence, RI; Harold Silberman, MD,
also been shown to effectively lower blood pres- Coral Gables, FL; William Smith, MD, New Orleans, LA;
sure.19 –21 However, the development of ACE-inhibitor James Thompson, MD, Boulder, CO; Phillip Toth, MD, In-
dianapolis, IN; Fong Wei, MD, Princeton, NJ; Marc Wein-
related cough, which may occur in as many as 25% of berg, MD, Providence, RI; Stuart Weiss, MD, San Diego, CA;
patients,22 and, rarely, angioedema,23 can limit com- Frederick Whittier, MD, Canton, OH; Stephen Yarnall, MD,
pliance and reduce efficacy. A more favorable tolera- Edmonds, WA; Edward Zawada, MD, Sioux Falls, SD.
bility profile may occur with the combination of an
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