Download A randomised, double-blind comparison of the angiotensin

Journal of Human Hypertension (1998) 12, 203–208
 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00
ORIGINAL ARTICLE
A randomised, double-blind comparison of
the angiotensin II receptor antagonist,
irbesartan, with the full dose range of
enalapril for the treatment of mild-tomoderate hypertension
A Mimran1, L Ruilope2, L Kerwin3, M Nys4, D Owens3, K Kassler-Taub3 and
M Osbakken3
1
Lapeyronie Hospital, Montpellier, Cedex 5, France; 2Unidad de Hipertension Arterial Servicio de
Nefrologia Hospital Universitario 12 de Octubre, Madrid, Spain; 3Bristol-Myers Squibb, Princeton NJ, USA
and 4Waterloo, Belgium
Objective: To compare the anti-hypertensive efficacy,
safety, and tolerability of irbesartan with those of the full
dose range of enalapril in patients with mild-to-moderate hypertension.
Design and methods: A total of 200 patients were randomised to irbesartan 75 mg or enalapril 10 mg (once
daily). Doses were doubled at Weeks 4 and/or 8 if seated
diastolic blood pressure (DBP) was ⭓90 mm Hg. Trough
blood pressure was measured after completion of a 4to 5-week placebo lead-in period and again after 2, 4, 8,
and 12 weeks of treatment.
Main outcome measures: Efficacy was evaluated by
determining the change from baseline in trough seated
blood pressure and the proportion of patients normalised (seated DBP ⬍90 mm Hg) at Week 12. Safety and
tolerability were assessed by adverse events reported
by physicians, by patients in response to a specific-
symptoms questionnaire, by open-ended questioning of
patients by physicians, and by clinical laboratory evaluations.
Results: Both treatments significantly lowered blood
pressure with no significant difference in efficacy
between treatment groups. At Week 12, the percentage
of patients titrated to either enalapril 40 mg or irbesartan
300 mg was 24% and 28%, respectively. The frequency
of overall adverse events was similar in both groups.
The incidence of cough in the enalapril and irbesartan
groups was 17% and 10%, respectively. In contrast to
other AII receptor antagonists, there was no change in
uric acid concentrations with irbesartan.
Conclusions: Irbesartan was as effective as the full dose
range of enalapril. Irbesartan also demonstrated an
excellent tolerability profile.
Keywords: angiotensin II receptor antagonist; irbesartan; angiotensin-converting enzyme inhibitor; enalapril; hypertension
Introduction
The renin-angiotensin system (RAS) plays a crucial
role in regulating blood pressure. High concentrations of angiotensin II (AII) are associated with
elevated systemic blood pressure. The pressor effect
of AII appears to be mediated by the AT1 receptor
subtype of AII.1–3 One approach to lowering systemic blood pressure is to reduce the level of AII,
for example by inhibiting angiotensin-converting
enzyme (ACE)—the enzyme responsible for AII production.4–6 However, AII is also produced through
non-ACE-dependent pathways;7 thus, treatment
with ACE inhibitors may not completely prevent AII
Correspondence: Dr Mary Osbakken, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, J4017, Princeton, NJ
08543-4000, USA
Received 15 September 1997; revised and accepted 28 November 1997
production. Moreover, because ACE is also involved
in the breakdown of bradykinin, inhibition of ACE
tends to increase circulating levels of this peptide,8–10
which may account for the increased incidence of
cough reported in up to 20% of patients treated with
ACE inhibitors.11–13 All receptor antagonists, however, inhibit the potent pressor effect of AII by blocking its binding to the receptor. Therefore, it is
expected that they will effectively lower systemic
blood pressure without inducing adverse effects,
such as cough, that are associated with ACE inhibitors.
Irbesartan (BMS-186295; SR 47436; Bristol-Myers
Squibb/Sanofi) is a potent, long-acting AII receptor
antagonist, with high selectivity for the AT1 receptor
subtype.14,15 Results of recent clinical studies show
that irbesartan safely and effectively lowers blood
pressure within 1 week in patients with mild-tomoderate hypertension.15,16
The objective of this study was to compare the
Irbesartan vs enalapril in hypertension
A Mimran et al
204
anti-hypertensive efficacy, safety, and tolerability of
irbesartan with those of the full dose range of the
ACE inhibitor enalapril, in patients with mild-tomoderate hypertension.
despite doubling of dose at Week 4, doses were
doubled again (irbesartan was increased from
150 mg to 300 mg; enalapril was increased from
20 mg to 40 mg).
Materials and methods
Clinical evaluation
Patients
At enrolment a full medical history and chest X-ray
were performed, and patients were given a complete
physical examination. Blood and urine samples
were collected for routine laboratory analysis, and a
pregnancy test, if necessary, was obtained. On Days
22 or 29, blood and urine samples were again collected, a 12-lead electrocardiogram (ECG) was performed, and, if pregnancy was suspected, a pregnancy test was obtained. During each lead-in visit,
blood pressure and heart rate were measured, and
patient compliance was assessed. Blood pressure
was measured with a standard, calibrated mercury
sphygmomanometer. The mean of three readings,
taken 1 min apart, was used for analysis of efficacy.
During the double-blind treatment period, routine
visits were scheduled for Weeks 0, 2, 4, 8, and 12
(±3 days). At each visit, the patient’s weight, seated
systolic blood pressure (SBP), seated DBP, standing
SBP, standing DBP, seated heart rate (HR), and
standing HR were measured.
Patients ⭓18 years of age with mild-to-moderate
hypertension (seated diastolic blood pressure (DBP)
95–110 mm Hg) were included in this study.
Exclusion criteria were limited to concomitant diseases or medication that would present safety hazards or interfere with the assessment of the safety or
efficacy of the study medications. Women who were
pregnant, lactating, or of childbearing potential were
also excluded. This study was approved by the local
ethics committees, and all patients gave their informed consent at the time of enrolment.
Study protocol
This study was a multicentre, randomised, doubleblind trial conducted in 51 centres in France and
Spain. The first study phase consisted of a 4- to 5week, single-blind, placebo lead-in period. The
second phase consisted of a 12-week, double-blind
treatment period that began immediately after eligibility was established. All blood pressure measurements were obtained with patients in the seated position except where otherwise noted. During the leadin period, visits were scheduled for Days 1, 15, 22,
and 29 (an additional visit was scheduled for Day
36 if necessary, see below). To be eligible for randomisation into the double-blind phase of the study,
patients were to have completed all pretreatment
evaluations (described below) and met all inclusion
and exclusion criteria. At each visit during the leadin and treatment periods, enough medication was
dispensed to last until the next scheduled visit.
Investigators checked return bottles to assess patient
compliance. This method of estimating patient compliance has been used in similarly designed studies
of anti-hypertensive agents (eg, see reference 17).
Patients had to demonstrate good compliance
(expected lead-in medication consumption ⬎80%
and ⬍120%) to be eligible for randomisation. In
addition, DBP on Days 22 and 29 had to be between
95 mm Hg and 110 mm Hg inclusive, and the values
for each day must not have differed by more than 8
mm Hg. If a patient failed to meet blood pressure
criteria on Day 22, an optional visit on Day 36 was
allowed, and eligibility was determined based on
DBP values for Days 29 and 36.
Patients who qualified for the treatment phase of
the study were randomised to receive either irbesartan 75 mg (n = 98) or enalapril 10 mg (n = 102).
Patients were instructed to take one capsule once
per day between 6 am and 10 am. If DBP at trough
(ie, 24 ± 3 h after the previous dose) was ⭓90 mm Hg
at Weeks 4 or 8, the dosage of study medication was
doubled (irbesartan was increased from 75 mg to
150 mg; enalapril was increased from 10 mg to
20 mg). If DBP remained ⭓90 mm Hg at Week 8
Evaluation of safety
Safety was assessed by evaluating the incidence of
clinical and laboratory adverse events. Blood and
urine samples were collected and a brief physical
examination was performed at Weeks 4, 8, and 12.
At Week 12, a 12-lead ECG was obtained. Patients
were monitored for adverse events by examination
and by general open-ended questioning during each
lead-in and treatment-period visit. At Week 12,
patients were asked specifically whether they had
experienced any of the following events during the
treatment period: cold extremities, drowsiness/
sleepiness, fatigue/tiredness/lethargy, headache,
impotence, weakness, dizziness, cough, or rash.
Adverse events were further categorised as follows:
adverse drug experiences were those adverse events
considered by the investigator to be related, possibly
related, probably related, or of unassessable relationship to the study medication. Serious adverse events
were those adverse events that were either fatal, life
threatening, permanently disabling, resulted in inpatient or prolonged hospitalisation, a congenital
anomaly, cancer, or overdose.
Statistical analysis
For patient demographic and baseline efficacy measures, quantitative data were analysed using a oneway analysis of variance (ANOVA). Qualitative data
were assessed using a Fisher’s Exact Test. Changes
from baseline in blood pressure and heart rate
within treatment regimens were analysed using a
paired t-test. Changes from baseline in blood pressure and heart rate between treatment regimens were
analysed using an analysis of covariance
(ANCOVA). The proportion of patients whose blood
Irbesartan vs enalapril in hypertension
A Mimran et al
pressure was normalised (DBP ⬍90 mm Hg) at each
timepoint was analysed using a Cochran-MantelHaenszel chi-squared test stratified by site. All statistical tests were two-tailed, and P values ⬍0.05
were considered significant.
In addition, a retrospective examination of the
effects of incremental dose increases on changes in
blood pressure at each timepoint was performed.
Patients were summarised according to those who
remained on the lowest dosage of study medication
throughout the study, those whose dosage was
doubled once at either Weeks 4 or 8, and those
whose dosage was doubled at Week 4 and again at
Week 8. No statistical tests were performed.
Results
Patient characteristics
A total of 200 patients were randomised to treatment. There were no statistically significant or clinically important differences between treatment regimens for any of the demographic or baseline efficacy
values (Table 1).
Of the patients randomised to treatment, 124
(62%) had previously received anti-hypertensive
medication within 1 months prior to the beginning
of this study (ACE inhibitors, 35%; diuretics, 17%;
␤-blockers, 13%; calcium channel blockers, 12%).
Nine patients (three in the irbesartan group; six in
the enalapril group) withdrew from the study following randomisation; four because of adverse
events (one in the irbesartan group; three in the enalapril group; see Safety and Tolerability section);
three at the patient’s request (two in the irbesartan
group; one in the enalapril group); and two patients,
both from the enalapril group, were lost to followup.
Anti-hypertensive efficacy
Blood pressure: Table 2 shows the percentage of
patients receiving different doses of study medication at Weeks 4, 8, and 12. At Week 12, 42% of
Table 1 Patient demographic and baseline characteristics*
Enalapril
(n = 102)
Irbesartan
(n = 98)
Gender (%)
Male
Female
49
51
54
46
Age (years)
58.4 ± 10.8
58.2 ± 11.8
70
30
6
72
28
9
Baseline seated DBP (mm Hg)
101.8 ± 4.2
101.0 ± 4.1
Baseline seated SBP (mm Hg)
164.9 ± 12.8
163.9 ± 12.5
72
28
76
24
73.7 ± 9.2
74.1 ± 9.6
⬍65 years (%)
⭓65 years (%)
⭓75 years (%)
DBP subgroup (%)
⬍104 mm Hg
⭓104 mm Hg
Sitting HR (beats per min)
*Data expressed as mean ± s.d.
patients in the irbesartan group were still receiving
the lowest dose (irbesartan 75 mg) compared with
36% of patients in the enalapril group (enalapril
10 mg). A total of 40 and 35 patients received irbesartan 75 mg and enalapril 10 mg, respectively, for
the entire duration of the study; 28 and 38 patients
received irbesartan titrated to 150 mg or enalapril
titrated to 20 mg, respectively; 27 and 23 patients
received irbesartan titrated to 300 mg or enalapril
titrated to 40 mg, respectively.
The mean changes from baseline in SBP and DBP
at each timepoint are shown in Figure 1. Both treatment with irbesartan and enalapril resulted in statistically significant decreases from baseline in
trough SBP and trough DBP at all measured timepoints (Weeks 2 to 12), as well as in trough standing
SBP and trough standing DBP (data not shown).
There were no statistically significant differences
between the two treatment regimens with respect to
decrease from baseline in DBP or SBP. This similarity between treatment groups extended across all
timepoints examined (Figure 1). No clinically
important changes from baseline were observed in
seated HR or standing HR at any timepoint for either
treatment regimen (data not shown). Changes from
baseline in all efficacy variables were consistent for
both genders and age groups.
Table 3 shows the baseline and on-therapy DBP
at Weeks 4, 8, and 12 for patients who were maintained on the lowest dosage of study medication,
and for those who required dosage titration because
DBP remained above 90 mm Hg at the lower dosage.
For patients who received either irbesartan 75 mg
(40/95; 42%) or enalapril 10 mg (35/96; 36%)
throughout the study, DBP decreased by approximately 15 mm Hg within 4 weeks with no further
decrease at Weeks 8 or 12.
In patients whose dosage of study medication was
doubled only once to irbesartan 150 mg (28/95;
29%) or enalapril 20 mg (38/96; 40%) mean DBP
decreased by approximately 8 mm Hg while patients
were receiving the lowest dosages, but mean DBP
was still above 90 mm Hg. Doubling the dosage to
irbesartan 150 mg or enalapril 20 mg was associated
with an additional reduction of 5 mm Hg between
Weeks 4 and 8 for both treatment groups, resulting
in a total decrease from baseline of 13 mm Hg with
little change thereafter. Mean DBP at Week 8 for
both treatment groups was ⬍90 mm Hg.
In patients whose dosage of study medication was
doubled twice to a final dosage of irbesartan 300 mg
(27/95; 28%) or enalapril 40 mg (23/96; 24%), DBP
decreased by 5 mm Hg and 1 mm Hg in the enalapril
and irbesartan groups, respectively, while patients
were receiving the lowest dosages. Doubling the dosage once at Week 4 and again at Week 8 was associated with further reductions in DBP of about 6
mm Hg in both treatment groups, resulting in a total
decrease from baseline of approximately 11 mm Hg
and 8 mm Hg in the enalapril and irbesartan groups,
respectively, at Week 12. In general, mean baseline
DBP was higher in patients who required dosage
titration either once or twice compared with those
of patients who were maintained on the lowest dosages of study medication (Table 3). Changes in SBP
205
Irbesartan vs enalapril in hypertension
A Mimran et al
206
Table 2 Percentage of patients receiving different doses of enalapril irbesartan at Weeks 4, 8, and 12
Enalapril
Week 4
Week 8
Week 12
Irbesartan
n
10 mg
(%)
20 mg
(%)
40 mg
(%)
n
75 mg
(%)
150 mg
(%)
300 mg
(%)
101
100
96
100
46
36
–
54
40
–
–
24
98
96
95
100
46
42
–
54
30
–
–
28
Safety and tolerability
There was no difference in the incidence of overall
adverse events reported in each treatment group
(43%, enalapril; 45%, irbesartan) (Table 4). The
most common adverse events in both treatment
groups were cough and headache. One patient in the
enalapril group was withdrawn from the study
because of cough and weakness. Cough was reported
as an adverse event in 10% of patients in the irbesartan group compared with 17% of patients in the
enalapril group (not statistically significant).
One patient (1%) in the irbesartan group and three
patients (2.9%) in the enalapril group discontinued
therapy because of adverse events (Table 4). Of the
three patients who discontinued treatment in the
enalapril group, one patient discontinued as a result
of cough and weakness, one patient as a result of
musculoskeletal pain and oedema which was sub¨
sequently diagnosed as Sjogren’s disease, and one
patient as a result of tinnitus, dizziness, and an episode of instability. The patient who discontinued
therapy in the irbesartan group experienced a severe, but non-serious hypertensive crisis after 69 days
of treatment, despite having been titrated to the
highest dosage (300 mg). This patient’s compliance
was inconsistent throughout the study, ranging form
slight undercompliance at Week 8, to moderate
overcompliance at Week 12.
Analysis of serum concentrations of potassium
and uric acid revealed no statistically significant
changes from baseline (Table 5).
Discussion
Figure 1 Change from baseline in seated SBP (a) and seated DBP
(b). There were no significant differences between treatment
groups at any timepoint.
were consistent with those for DBP (data not
shown).
Therapeutic response: At Week 12, 66% of
patients treated with irbesartan were normalised
(trough DBP ⬍90 mm Hg) compared with 63% in the
enalapril group. The percentage of patients normalised was similar at all timepoints in both treatment
groups (Figure 2).
This study is the first to compare an AII receptor
antagonist to the full dose range of the ACE inhibitor
enalapril in patients with mild-to-moderate hypertension. Monotherapy with irbesartan at dosages up
to 300 mg was as effective in lowering blood pressure as monotherapy with enalapril over the entire
approved dose range of enalapril (ie, up to 40 mg).
Reductions in seated and standing blood pressures
were evident within 2 weeks and treatment with
irbesartan for 12 weeks normalised blood pressure
in 66% of hypertensive patients compared with
63% of patients in the enalapril treatment group.
Maximum response was achieved by 4 weeks for
patients who remained on the lowest dosage of
irbesartan and remained constant thereafter. For
patients with moderate response at the lowest dosage, or higher baseline BP, there was a greater blood
Irbesartan vs enalapril in hypertension
A Mimran et al
207
Table 3 Mean DBP at baseline and at Weeks 4, 8, and 12 for patients receiving different dose regimens
Patients who remained on
lowest dosage
Seated DBP
(mm Hg)
Patients whose dosage was
doubled once
Patients whose dosage was
doubled twice
enalapril
(n = 35)
irbesartan
(n = 40)
enalapril
(n = 38)
irbesartan
(n = 28)
enalapril
(n = 23)
irbesartan
(n = 27)
Baseline
99.6
99.3
101.4
101.1
105.7
103.3
Week 4
Week 8
Week 12
85.8
84.1
84.4
83.9
84.1
83.7
93.5
88.4
85.9
93.4
87.8
88.0
100.6
99.2
94.9
102.1
98.6
95.7
Figure 2 Therapeutic response at Weeks 2, 4, 8, and 12.
Table 4 Safety results of enalapril and irbesartan
Patients (%)
Adverse drug experiences
Cough as an adverse drug
experience
Adverse events
Serious adverse events
Discontinuations
Enalapril
(n = 102)
Irbesartan
(n = 98)
26
15
19
7
43
1.0
2.9
45
4.1
1.0
Table 5 Mean change (95% confidence intervals) from baseline
in laboratory parameters at Week 12
Serum
concentration
Creatinine
(mg/dL)
Potassium
(mEq/L)
Uric acid
(mg/dL)
Hemoglobin
(g/dL)
Enalapril
(n = 96)
0.03 (0 to 0.06)
−0.01 (−0.11 to 0.09)
Irbesartan
(n = 94)
0.01 (−0.02 to 0.04)
0 (−0.0 to 0.10)
−0.03 (−0.20 to 0.15)
−0.11 (−0.33 to 0.11)
−0.16 (−0.27 to −0.05)
−0.10 (−0.25 to 0.04)
pressure response after doubling the dosage; dosage
had to be tripled in more resistant patients. Overall,
blood pressure continued to decrease in both treatment groups throughout the course of the doubleblind period. Patients who required incremental
increases in the dosage of irbesartan in order to achieve normalised blood pressure appeared to gain
additional benefits from increased exposure, including higher dosages (see Table 3). This is consistent
with results of previous studies that showed a doserelated anti-hypertensive effect of irbesartan,16 but
with no dose-related increase in adverse events.
In the present study, the incidence of overall
adverse events, adverse drug experiences, and serious adverse events reported in each treatment group
was similar, and the discontinuation rate as a result
of adverse events was low in both treatment groups.
The incidence of cough, as reported by patients in
response to questioning by physicians using a specific symptoms questionnaire, as well as open-ended
questions, was 17% in the enalapril group compared
with 10% in the group treated with irbesartan.
Although these percentages may appear to be
excessive, using a specific symptoms questionnaire
to elicit adverse events (as opposed to spontaneously reported symptoms) tends to sensitise
patients to any adverse event listed on the questionnaire. This study was not designed to specifically
compare the incidence of cough. Results of other
studies have shown that treatment with ACE inhibitors is associated with increased incidence of
cough11–13 whereas treatment with AII receptor
antagonists is not.18,19 The overall database incidence of cough is 2.7% for placebo and 2.8% for
irbesartan (Data on file, Bristol-Myers Squibb). In
addition, another study compared irbesartan with
enalapril in patients with severe hypertension. The
incidence of cough was significantly lower in the
group of patients treated with irbesartan compared
with the group treated with enalapril.20 These findings indicate that, similar to other AII receptor
antagonists, irbesartan does not induce cough. In
addition, there was no significant change in uric
acid concentration with irbesartan. Previous studies
have shown a significant increase in uric acid concentrations with losartan.21
Angiotensin II receptor antagonists are a relatively
recent development in the treatment of hypertension. A previous study comparing losartan with
enalapril
demonstrated
comparable
efficacy
Irbesartan vs enalapril in hypertension
A Mimran et al
208
between losartan 50 mg/day and enalapril 5 mg/day
titrated to 10 mg/day.17 In a study conducted by
Gradman et al,22 the effects of losartan 10 mg to
150 mg were compared with those of enalapril
20 mg in patients with mild-to-moderate hypertension. There was no significant difference in change
from baseline in trough supine DBP between
patients treated with losartan 10–150 mg and
patients treated with enalapril 20 mg. The mean
decrease in trough supine SBP was significantly
greater in patients receiving enalapril 20 mg compared with that of patients receiving losartan 10 mg,
25 mg, 100 mg, and 150 mg. However, no significant
difference was observed between the mean decrease
in trough supine SBP of patients receiving losartan
50 mg and enalapril 20 mg.
The high percentage of patients achieving blood
pressure control with irbesartan, combined with its
exceptional tolerability profile, suggests that irbesartan represents a valuable therapy for the long-term
treatment of hypertension.
10
11
12
13
14
15
16
17
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