Original Article
Randomized evaluation of a novel, fixed-dose
combination of perindopril 3.5 mg/amlodipine 2.5 mg
as a first-step treatment in hypertension
Stéphane Laurent a, Gianfranco Parati b,c, Irina Chazova d, Yuriy Sirenko e, Andrejs Erglis f,
Aleksandras Laucevicius g, and Csaba Farsang h
Objective: To evaluate perindopril 3.5 mg/amlodipine
2.5 mg once daily, a novel fixed-dose combination adapted
for first-step treatment in patients with hypertension. This
fixed dose had to be equivalent to amlodipine 5 mg in
terms of blood pressure efficacy, but with an expected
better tolerability profile. We selected two drugs with
complementary modes of action, with doses chosen so
that each drug would contribute similarly to the overall
blood pressure-lowering effect
Methods: An international, randomized, double-blind,
placebo-controlled study with six equal parallel treatment
arms and an 8-week randomized treatment period, whose
design, clinical significance and non-inferiority criteria were
in accordance with European guidelines.
Results: In all, 1581 patients with mild-to-moderate
uncomplicated hypertension (mean age 51.7 years) were
randomized and 94.7% completed the study. The
combination was statistically and clinically superior to
placebo (between-group differences: SBP:
7.22 mmHg,
DBP:
4.12 mmHg, P < 0.001 for both). Rates of response
and normalization of blood pressure were greater with the
combination (P < 0.001 for both) and numerical differences
relative to placebo were apparent at 2 weeks. The
combination was superior to either component given singly
(P < 0.001 for both drugs, for SBP and DBP), and was non-
inferior to both component drugs given singly at their
lowest clinically-approved doses. The components of the
combination had similar effects on SBP (perindopril 3.5 mg:

16.3 mmHg; amlodipine 2.5 mg:
16.0 mmHg). Adverse
events relating to peripheral oedema were less frequent
with the combination than with amlodipine 5 mg.
Conclusions: The observed blood pressure-lowering
efficacy, rapidity of onset of effect and favourable safety
profile of the combination perindopril 3.5 mg/amlodipine
2.5 mg indicate its potential suitability for use as first-step
treatment in hypertension.
Keywords: amlodipine, antihypertensive agents, drug
combinations, hypertension/drug therapy, perindopril
Abbreviations: ACCOMPLISH, Avoiding Cardiovascular
Events in Combination Therapy in Patients Living with
Systolic Hypertension; ACE, angiotensin-converting
enzyme; ASCOT-BPLA, Anglo-Scandinavian Cardiac
Outcomes Trial–Blood Pressure Lowering Arm; EAE,
Journal of Hypertension
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
emergent adverse event; FAS, full analysis set; VALUE,
Valsartan Antihypertensive Long-term Use Evaluation; VAS,
Visual analogue scale
INTRODUCTION
I
t has been estimated that approximately 26% of the
adult population of the world had arterial hypertension
in the year 2000 [1], and the number of people in the
United states with hypertension increased by 30% between
the periods 1988–1994 and 1999–2000 [2]. Worldwide, 7.6
million premature deaths (some 13.5% of the overall total)
were attributed to elevated blood pressure in the year 2001
[3]. Rates of awareness, treatment and blood pressure con-
trol (to below 140/90 mmHg) have increased markedly in
recent years [4,5], but remain far from optimal, with only
approximately half of those receiving antihypertensive
treatment achieving blood pressure control [5,6].
It has been increasingly recognized that the majority of
hypertensive patients will require more than one drug to
achieve their blood pressure target [7–10], and in a recent
global study in 26 countries, only 30% of patients were
using a single antihypertensive drug [11]. Combination
therapy offers several potential advantages compared with
high-dose monotherapy. Regulation of blood pressure
involves multiple mechanisms and pathways, and the effect
of a given drug may be blunted by activation of compen-
satory responses. A meta-analysis has indicated that
Journal of Hypertension 2015, 33:653–662
a
Department of Pharmacology, European Georges Pompidou Hospital and University
Paris Descartes, Paris, France, bDept of Health Sciences, University of Milano-Bicocca,
Milan, cDept of Cardiovascular, Neural and Metabolisc Sciences, S. Luca Hospital,
Istituto Auxologico Italiano, Milan, Italy, dMinistry of Health of Russian Federation /
Cardiology Research Complex, Moscow, Russia, eNational Scientific Centre, ‘‘M.D.
Strazhesko Institute of Cardiology’’ National Academy of Medical Science, Kiev,
Ukraine, fPauls Stradins Clinical University Hospital, Riga, Latvia, gVilnius University
Hospital Santariskiu Clinics, Vilnius, Lithuania and hSemmelweis University, Budapest,
Hungary
Correspondence to Stéphane Laurent, Department of Pharmacology and INSERM
U970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris,
Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France. Tel: +33 1 56 09 39 91;
fax: +33 1 56 09 39 92; e-mail: stephane.laurent@egp.aphp.fr
Received 24 January 2014 Revised 3 October 2014 Accepted 3 October 2014
J Hypertens 33:653–662 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights
reserved.
DOI:10.1097/HJH.0000000000000440
www.jhypertension.com 653
Laurent et al.
combining two drugs from different classes with different
mechanisms of action can produce a blood pressure-low-
ering effect approximately five times greater than doubling
the dose of one drug [12]. Thus, the use of combination
therapy often produces greater antihypertensive effect with
lower doses of the component drugs, resulting in fewer
adverse effects [7,13]. The use of fixed-dose combinations
can also be more convenient, simplify treatment regimens
and optimize compliance [7,9,14], and the new European
hypertension guidelines states that single-pill, fixed-dose
combinations should be preferred whenever possible [9].
Traditionally, combination therapy has been viewed as a
second step that is frequently required after initial mono-
therapy. However, recent guidelines have stressed the
advantages of combination therapy as a first-step treatment,
especially in high-risk patients in whom early control is
desirable, or when a substantial reduction in blood pressure
is required [7–10]. First-step combination therapy may
avoid the frustration of vainly searching for effective mono-
therapy in such patients [9].
Our overall objective was to develop a new single-pill
combination adapted for first-line use that had to be at least
as efficient as amlodipine 5 mg in terms of blood pressure
efficacy, but with an improvement of its well known side
effects, particularly peripheral oedema. We selected two
drugs with complementary modes of action both on effi-
cacy and safety, with doses anticipated to reach at least the
efficacy of amlodipine 5 mg. Here we report results of a
randomized, double-blind, phase II study, designed in
accordance with the European guidelines [15], of the com-
bination perindopril 3.5 mg/amlodipine 2.5 mg. Publication
of the results of this study was subjected to the completion
of a full development programme for this new combination
of perindopril/amlodipine that ended in October 2013.
PATIENTS AND METHODS
Patients
Patients were male or female outpatients between the ages of
18 and 79 years (inclusive), with essential mild-to-moderate
hypertension without associated clinical conditions or
known target organ damage, who were either not being
treated or who were not controlled by antihypertensive
medication, or required a change of antihypertensive medi-
cation. The inclusion criteria for blood pressure were SBP at
least 150 mmHg and less than 180 mmHg and DBP at least
95 mmHg and less than 110 mmHg. The main exclusion
criteria included: obesity (BMI >30 kg/m2); history of
cerebrovascular disease, ischaemic heart disease, heart fail-
ure, cardiac rhythm disorders, renal disease, advanced retino-
pathy or angiodema; current peripheral vascular disease,
left ventricular hypertrophy, microalbuminuria, type 1 or
type 2 diabetes mellitus, liver disease, hypersensitivity,
contra-indication, or hypertension resistant to angiotensin-
converting enzyme (ACE) inhibitors or dihydropyridine
calcium antagonists. Typically enrolled patients were at low
to high cardiovascular risk according to current guidelines.
Study design
The main aim of the study was to evaluate the efficacy
and safety of the novel combination perindopril
654 www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
3.5 mg/amlodipine 2.5 mg as a potential first-line treat-
ment for hypertension. In line with the European guide-
lines for the evaluation of fixed-dose combinations in
hypertension [15], the following three main efficacy com-
parisons in terms of blood pressure-lowering effect were
performed:
1. Superiority of the combination compared with
placebo
2. Superiority of the combination compared with each
component administered singly
3. Non-inferiority of the combination compared with
the lowest approved doses of each component
(perindopril 5 mg and amlodipine 5 mg) adminis-
tered separately
Blood pressure normalization rates were also evaluated,
and the blood pressure-lowering effects of each component
administered singly were compared. The European guide-
lines also state that the combination should show a trend
towards better safety compared with the components at
their lowest approved doses.
To meet these objectives, the study was designed as an
international, randomized, double-blind, placebo-con-
trolled study with a factorial design and six parallel treat-
ment arms. The study was divided in two consecutive
periods, a run-in period on placebo lasting at least 2 weeks,
but not more than 3 weeks, followed by an 8-week double-
blind active treatment period. At the inclusion visit (W0),
treatments were randomized and patients allocated to one
of the six treatment groups:
1. Perindopril 3.5 mg/amlodipine 2.5 mg fixed combi-
nation
2. Perindopril 3.5 mg
3. Amlodipine 2.5 mg
4. Perindopril 5 mg
5. Amlodipine 5 mg
6. Placebo
Treatment allocation was by telephone using an inter-
active voice response system, and was centralized,
non-adaptive, balanced and stratified according to study
centre. Investigators and patients were blinded as to
treatment allocation. Treatment capsules and packaging
were identical for all treatments. A centralized decoding
procedure was available in case of emergency. Study
visits were scheduled at 2, 4 and 8 weeks after inclusion
(W2, W4 and W8, respectively). Patients took a single
treatment capsule orally each day, with water and before
breakfast. On study visit days, capsules were taken after
blood pressure measurement and clinical exploration.
There was no dose adjustment during the treatment
period.
The study was performed in 188 centres in six European
countries (France, Russia, Ukraine, Latvia, Lithuania and
Hungary) between May 2007 and December 2008. Among
the 164 centres that recruited at least one patient, 115 were
based in France (all general practitioners) and the rest were
specialists in public or private practice in the five other
countries.
Volume 33  Number 3  March 2015

Efficacy evaluation
Blood pressure was measured at each study visit, before
study treatment was taken, 24  3 h after the last treatment
intake, using an automatic arm blood pressure device
(Microlife BP3AC1–1) that had been validated according
to the international protocol of the European Society of
Hypertension [16]. The same instrument was used for all
measurements in an individual patient, and different cuff
sizes were available to match patients’ arms. Blood pressure
was measured after at least 10 min of rest, and the mean of
three measurements made at 1-min intervals was recorded.
Print-outs of all measurements were retained. Ambulatory
blood pressure monitoring was performed at 8 weeks in a
subgroup of patients receiving perindopril 3.5 mg/amlodi-
pine 2.5 mg (n ¼ 174), perindopril 5 mg (n ¼ 187) and amlo-
dipine 5 mg (n ¼ 173).
The primary efficacy criterion was supine DBP, and the
main analytical approach was the change from baseline to
the last post-baseline value. Other efficacy criteria included
supine SBP, pulse pressure (defined as SBP
DBP),
mean blood pressure (defined as 2/3 DBP þ 1/3 SBP),
normalization of blood pressure (defined as SBP
<140 mmHg and DBP <90 mmHg) and response to treat-
ment (defined as SBP <140 mmHg and DBP <90 mmHg
and/or SBP decrease 20 mmHg from baseline and/or
DBP decrease 10 mmHg from baseline).
Safety evaluation
Safety was evaluated by conventional adverse event report-
ing, physical examination, 12-lead ECG and laboratory
testing of blood samples. Adverse events were regarded
as emergent if they occurred or worsened between the first
intake of study drug and 7 days after the last study drug
intake. In addition, specific safety analyses relevant to the
study drugs were performed. Each patient was given an
automatic arm blood pressure device and kept a blood
pressure diary based on SBP and DBP measured twice
every week (mean of three measurements, taken in the
morning). Any case of DBP at least 100 mmHg and/or SBP
at least 160 mmHg had to be reported to the investigator.
Possible orthostatic hypotension was investigated at the
W2, W4 and W8 visits, when, in addition to the supine
blood pressure measurements taken to evaluate efficacy,
blood pressure was also measured 1 and 3 min after
standing up. The last value recorded in the supine position
was compared with the standing blood pressure measure-
ments. A reduction in SBP of at least 20 mmHg and/or in
DBP of at least 10 mmHg maintained at both the 1-min and
3-min standing measurements was reported as an adverse
event of orthostatic hypotension.
Leg oedema was also assessed at the W0, W2, W4 and
W8 visits by means of a specific clinical examination by the
investigator evaluating localization, chronicity, severity and
any improvement when in the supine position of unilateral
or bilateral oedema, sensations of pain, heaviness and local
heating. Additionally, a patient self-assessment of symp-
toms of heaviness and swelling using a visual analogue
scale (VAS), and measurement of ankle circumference 2 cm
above the malleolus using a measuring tape designed for
the purpose were also performed at these visits.
Journal of Hypertension
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Perindopril/amlodipine as first step
Statistical methods
The main efficacy analyses were performed in the full
analysis set (FAS), defined as all randomized patients
who took at least one dose of study treatment and had
at least one baseline and at least one post-baseline value of
DBP. Analyses were also performed in the per-protocol set
(PPS), consisting of patients in the FAS who had an overall
treatment duration of at least 45 days, SBP and DBP
measurements at W8 and no other major protocol devi-
ations. The safety set consisted of all patients who took at
least one dose of study treatment.
Superiority comparisons were made comparing the
change from baseline to the last post-baseline value avail-
able using a general linear model, with baseline value and
study centre as covariates. For superiority relative to
placebo, a clinically relevant difference was defined as
2 mmHg for DBP and 3 mmHg for SBP for the point esti-
mate. Non-inferiority comparisons were made using non-
inferiority limits of 2 mmHg for DBP and 3 mmHg for SBP,
in line with the European guidelines [15]. Rates of response
to treatment and normalization of blood pressure were
compared using a chi-square test. The type I error rate
was set at 5% in two-tailed situations and 2.5% in one-
tailed situations.
Sample size calculations indicated that for superiority
comparisons, a sample size of 224 patients per group would
give a nominal power of 94%, for a true between-group
difference in DBP of 3 mmHg and a SD of 9 mmHg. If the
true between-group difference was 5 mmHg, the same
sample size would give a power of 94% and a CI that
did not include 2 mmHg (indicating a clinically relevant
difference). In non-inferiority comparisons, the same
sample size of 224 patients per group would give a power
of 94% if the non-inferiority limit was 2 mmHg, the true
between-group difference in DBP was 1 mmHg and its SD
was 9 mmHg. With an estimated patient withdrawal rate of
5%, it was concluded that approximately 250 patients per
group should be included in the study.
RESULTS
Patient disposition
A total of 2053 patients were selected in 188 study
centres, 1581 patients were included and randomized, 84
randomized patients were withdrawn and 1497 patients
(94.7%) completed the study (Fig. 1, Table 1). The number
of patients withdrawn in the combination group (9 patients,
3.6%) was similar to that in the placebo group (11 patients,
4.4%), and numerically lower than that in the other treat-
ment groups (14–19 patients, 5.3–6.9%).
Demographic and clinical characteristics at
baseline
The mean age of randomized patients was 51.7 years, with
13.3% of patients aged at least 65 years. The ratio of men
(46.7%) to women (53.3%) was well balanced, mean BMI
was 26.8 kg/m2 and most patients were of Caucasian origin
(98.6%). The mean time since diagnosis of hypertension
was 4 years and 8 months, and 61.0% of the patients had
received an antihypertensive drug treatment during the
www.jhypertension.com 655
Laurent et al.

2053 patients selected

472 patients not included, due to:

Blood pressure criteria (229)
Biology criteria (107)
Consent withdrawn (52)
Unauthorized disease or risk factor (21)
Unauthorized treatment (15)
Poor compliance during run-in (2)
Other reason (20)
Two or more reasons listed above (26)

1581 patients randomized

84 patients withdrawn, due to:

Adverse event (33)
Non-medical reason (21)
Lack of efficacy (16)
Protocol deviation (9)
Other reason (5)

1497 patients completed (94.7%)

FIGURE 1 Flow of patients through the study. Details of individual treatment groups are given in Table 1.

year preceding selection. Mean supine DBP and SBP were
100.5 and 161.4 mmHg, respectively. There were no
relevant differences between the treatment groups for
any of these characteristics (Table 2).
Patients were all hypertensive, most of them being grade
2 patients (76%), and could have additional risk factors, but
no diabetes or symptomatic organ damage. Recorded risk
factors were smoking (15%), men aged over 55 (16.4%),
women aged over 65 (8.4%), dyslipidaemia (84.1%), fasting
plasma glucose above 5.6 mmol/l (40.9%), BMI at least 30
and abdominal obesity (37.5%). Participants therefore
mostly qualify as a moderate-to-high risk population.
Efficacy results
Superiority of the combination versus placebo
In the FAS, during the 8-week treatment period, the
decrease in SBP was greater in the perindopril 3.5 mg/
amlodipine 2.5 mg combination group (22.0 mmHg) than
with placebo (14.2 mmHg), with a significant between-
group difference of
7.22 mmHg [95% CI (
9.60,
4.84),
P < 0.001]. Supine DBP also decreased by 13.6 mmHg in the
combination group, compared with 9.3 mmHg in the
placebo group, giving an estimated between-group differ-
ence of
4.12 mmHg [95% CI (
5.63,
2.61), P < 0.001]
(Table 3). These differences, relative to placebo, exceeded
the predefined limits for clinical relevance of 3 mmHg for
SBP and 2 mmHg for DBP. Similar results were obtained in
the per-protocol analysis set, with P values below 0.001 for
both comparisons (data not shown). The combination
group also showed significantly greater reductions in pulse
pressure and mean blood pressure compared with placebo
(P < 0.001 in both cases) (Table 3).
The proportion of patients with normalization of their
blood pressure at the end of the treatment period was
significantly greater in the combination group (43.5%) than
with placebo (26.6%), with a between-group difference of
16.9% (P < 0.001). As early as the W2 visit, there was a
numerical difference between the groups (combination:
30.6%, placebo: 16.2%).

TABLE 1. Disposition of patients and composition of the efficacy analysis sets in the randomised treatment groups
Per 3.5 mg/Amlo 2.5 mg Placebo Per 3.5 mg Amlo 2.5 mg Per 5 mg Amlo 5 mg
Randomized (n) 248 250 273 274 272 264
Withdrawn [n (%)], due to 9 (3.6) 11 (4.4) 16 (5.9) 19 (6.9) 15 (5.5) 14 (5.3)
Adverse event 3 (1.2) 0 6 (2.2) 9 (3.3) 7 (2.6) 8 (3.0)
Lack of efficacy 2 (0.8) 3 (1.2) 3 (1.1) 2 (0.7) 3 (1.1) 3 (1.1)
Non-medical reason 2 (0.8) 5 (2.0) 3 (1.1) 5 (1.8) 3 (1.1) 3 (1.1)
Protocol deviation 1 (0.4) 2 (0.8) 3 (1.1) 2 (0.7) 1 (0.4) 0
Other 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 0
Completed [n (%)] 239 (96.4) 239 (95.6) 257 (94.1) 255 (93.1) 257 (94.5) 250 (94.7)
Full analysis set [n (%)] 246 (99.2) 248 (99.2) 268 (98.2) 270 (98.5) 270 (99.3) 261 (98.9)
Per-protocol set [n (%) 236 (95.2) 235 (94.0) 248 (90.8) 252 (92.0) 257 (94.5) 245 (92.8)

Percentages relate to the number of patients randomized. Amlo, amlodipine; Per, perindopril.

656 www.jhypertension.com Volume 33  Number 3  March 2015

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 Perindopril/amlodipine as first step

TABLE 2. Demographic and medical characteristics of randomized patients (N ¼ 1581) at baseline, expressed as mean  SD unless specified
Per 3.5 mg/Amlo 2.5 mg Placebo Per 3.5 mg Amlo 2.5 mg Per 5 mg Amlo 5 mg All
Age (years) 51.6  11.8 51.8  11.7 52.0  11.1 51.8  11.2 51.1  11.6 51.8  11.0 51.7  11.4
Age 65 years [n (%)] 38 (15.3) 35 (14.0) 38 (13.9) 32 (11.7) 31 (11.4) 36 (13.6) 210 (13.3)
Male sex [n (%)] 116 (46.8) 116 (46.4) 128 (46.9) 128 (46.7) 129 (47.4) 122 (46.2) 739 (46.7)
BMI (kg/m2) 26.8  2.8 26.7  2.5 27.0  2.4 26.9  2.5 26.8  2.8 26.7  2.5 26.8  2.6
Hypertension duration (months) 63.4  72.3 59.6  82.1 54.3  63.6 52.3  64.6 52.1  64.8 55.2  73.9 56.0  70.3
Previous antihypertensive drug [n (%)] 151 (60.9) 157 (62.8) 167 (61.2) 174 (63.5) 155 (57.0) 161 (61.0) 965 (61.0)
Supine DBP (mmHg) 100.7  4.0 100.5  3.9 100.7  4.0 10.6  4.0 100.1  4.1 100.6  4.0 100.5  4.0
Supine SBP (mmHg) 161.8  7.5 160.9  7.3 161.5  7.8 161.0  7.6 160.7  7.3 162.3  7.5 161.4  7.5
Supine pulse pressure (mmHg) 61.0  7.9 60.4  7.9 60.8  8.6 60.4  7.7 60.7  8.3 61.6  8.1 60.8  8.1
Supine mean blood pressure (mmHg) 121.1  3.9 120.7  3.8 120.9  3.8 120.7  4.0 120.3  3.7 121.2  3.8 120.8  3.9

Amlo, amlodipine; Per, perindopril.

Comparisons of the combination versus the
component drugs given singly
The first comparison was to evaluate the superiority of the
combination compared with its two component drugs
administered singly at the doses used in the combination
(perindopril 3.5 mg and amlodipine 2.5 mg). In the FAS, the
reduction from baseline in SBP with the combination was
22.0 mmHg, compared with 16.3 mmHg with perindopril
3.5 mg and 16.0 mmHg with amlodipine 2.5 mg, with
estimated between-group differences of
5.01 mmHg
(P < 0.001) and
5.20 mmHg (P < 0.001), respectively.
For DBP, the reduction from baseline with the combination
(13.6 mmHg) was significantly larger than with perin-
dopril 3.5 mg (9.3 mmHg) and with amlodipine 2.5 mg
(10.3 mmHg; Table 4), with after adjustment estimated
between-group differences of
3.64 mmHg (P < 0.001)
and
2.97 mmHg (P < 0.001), respectively. For the
reduction in pulse pressure with the combination
(
8.4 mmHg) was also numerically greater than with peri-
ndopril 3.5 mg (
6.7 mmHg) and with amlodipine 2.5 mg
(
5.7 mmHg). The same was true for mean blood pressure,
with a reduction of 16.4 mmHg with the combination com-
pared with 11.9 mmHg with perindopril 3.5 mg, and
12.2 mmHg with amlodipine 2.5 mg.
The second comparison was to evaluate the non-inferi-
ority of the combination when compared with the two
component drugs administered singly at their lowest clin-
ically approved doses (perindopril 5 mg and amlodipine
5 mg). The combination reduced SBP by 22.0 mmHg, com-
pared with 18.2 mmHg for perindopril 5 mg and 21.8 mmHg
for amlodipine 5 mg, giving estimated between-group
differences of
2.78 and
0.29 mmHg, respectively, and
upper 95% CIs that were within the 3 mmHg predefined
non-inferiority limit (Table 4). The combination was there-
fore significantly non-inferior to both of the component
drugs administered at their lowest clinically approved doses
(P < 0.001 versus perindopril 5 mg, and P ¼ 0.003 versus
amlodipine 5 mg). Similarly, the combination also reduced
DBP by 13.6 mmHg, compared with 10.5 mmHg for peri-
ndopril 5 mg and 12.6 mmHg for amlodipine 5 mg, giving
estimated between-group differences of
2.59 and

0.76 mmHg, respectively, with upper 95% CIs that were
within the 2 mmHg predefined non-inferiority limit (Table 4).
The combination was again significantly non-inferior to both
of the component drugs administered at their lowest
clinically approved doses (P < 0.001 in both cases). Blood
pressure was normalized in 43.5% of patients receiving the
combination compared to 33.3% with perindopril 5 mg and
37.9% with amlodipine 5 mg. The reduction in pulse pressure
with the combination (
8.4 mmHg) was similar to that
obtained with perindopril 5 mg (
7.8 mmHg) and amlodi-
pine 5 mg (
9.2 mmHg), with estimated between-group
differences of only
0.22 and 0.45 mmHg, respectively
(Table 4). The same was true for mean blood pressure, with
a reduction of 16.4 mmHg in the combination group com-
pared with 13.1 mmHg with perindopril 5 mg and 15.7 mmHg
with amlodipine 5 mg, with estimated between-group differ-
ences of
2.7 and
0.6 mmHg, respectively.
The decreases in mean 24-h SBP/DBP were greater with
the combination than with perindopril 5 mg [
3.8/
2.4,

TABLE 3. Blood pressure-lowering effect of the combination perindopril 3.5 mg/amlodipine 2.5 mg: superiority comparisons versus
placebo
Treatment Baseline Last value Change from baseline Differencea [95% CI] P value
Supine DBP (mmHg)
Per 3.5 mg/Amlo 2.5 mg 100.7  4.0 87.1  9.0
13.6  9.2
4.12 [
5.63,
2.61] <0.001
Placebo 100.5  3.9 91.2  9.2
9.3  9.2
Supine SBP (mmHg)
Per 3.5 mg/Amlo 2.5 mg 161.8  7.5 139.9  13.8
22.0  14.0
7.22 [
9.60,
4.84] <0.001
Placebo 161.0  7.4 146.7  15.4
14.2  16.1
Pulse pressure (mmHg)
Per 3.5 mg/Amlo 2.5 mg 61.1  7.8 52.7  10.0
8.4  10.9
3.07 [
4.77,
1.37] <0.001
Placebo 60.4  7.9 55.5  11.1
4.9  12.2
Mean blood pressure (mmHg)
Per 3.5 mg/Amlo 2.5 mg 121.1  4.0 104.7  9.8
16.4  9.8
5.17 [
6.83,
3.51] <0.001
Placebo 120.7  3.8 109.7  10.4
11.0  10.4

Amlo, amlodipine; Per, perindopril.

a
Estimated difference, combination minus placebo

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Laurent et al.

TABLE 4. Blood pressure-lowering effect of the combination perindopril 3.5 mg/amlodipine 2.5 mg
Treatment Baseline Last value Change from baseline Differencea [95% CI] P value
Supine DBP (mmHg)
Per 3.5 mg/Amlo 2.5 mg 100.7  4.0 87.1  9.0
13.6  9.2
Superiority comparisons
Perindopril 3.5 mg 100.7  4.0 91.0  10.1
9.7  9.9
3.64 [
5.12,
2.16] <0.001
Amlodipine 2.5 mg 100.6  4.0 90.3  9.8
10.3  9.7
2.97 [
4.45,
1.49] <0.001
Non-inferiority comparisons (limit 2 mmHg)
Perindopril 5 mg 100.1  4.1 89.6  9.9
10.5  9.7
2.59 [
4.07,
1.11] <0.001
Amlodipine 5 mg 100.6  4.0 88.0  8.7
12.6  8.9
0.76 [
2.25, 0.73] <0.001
Supine SBP (mmHg)
Per 3.5 mg/Amlo 2.5 mg 161.8  7.5 139.9  13.8
22.0  14.0
Superiority comparisons
Perindopril 3.5 mg 161.4  7.7 145.1  16.5
16.3  17.0
5.01 [
7.35,
2.67] <0.001
Amlodipine 2.5 mg 161.2  7.6 145.1  15.5
16.0  15.3
5.20 [
7.53,
2.87] <0.001
Non-inferiority comparisons (limit 3 mmHg)
Perindopril 5 mg 160.7  7.3 142.5  15.0
18.2  14.8
2.78 [
5.11;
0.45] <0.001
Amlodipine 5 mg 162.3  7.5 140.5  14.3
21.8  15.4
0.29 [
2.64; 2.06] 0.003
Pulse pressure (mmHg) (descriptive statistics only)
Per 3.5 mg/Amlo 2.5 mg 61.1  7.8 52.7  10.0
8.4  10.9
Perindopril 3.5 mg 60.8  8.6 54.1  11.3
6.7  12.0
1.37 [
3.04, 0.30] –
Amlodipine 2.5 mg 60.5  7.7 54.8  11.1
5.7  11.1
2.23 [
3.90,
0.56] –
Perindopril 5 mg 60.6  8.3 52.8  10.7
7.8  11.1
0.22 [
1.89, 1.44] –
Amlodipine 5 mg 61.6  8.1 52.5  10.5
9.2  11.5 0.45 [
1.23, 2.14] –
Mean blood pressure (mmHg) (descriptive statistics only)
Per 3.5 mg/Amlo 2.5 mg 121.1  4.0 104.7  9.8
16.4  9.8
Perindopril 3.5 mg 120.9  3.8 109.0  11.4
11.9  11.4
4.10 [
5.74,
2.47] –
Amlodipine 2.5 mg 120.8  4.0 108.6  10.8
12.2  10.6
3.72 [
5.35,
2.09] –
Perindopril 5 mg 120.3  3.7 107.3  10.8
13.1  10.4
2.68 [
4.31,
1.06] –
Amlodipine 5 mg 121.2  3.8 105.5  9.7
15.7  10.1
0.59 [
2.23, 1.06] –

All statistical comparisons shown are combination versus reference group. Amlo, amlodipine; Per, perindopril.
a
Estimated difference, combination minus reference group.

P < 0.05 for superiority.

95% CI (
5.8,
1.8)/(
3.8,
1.0), respectively], and similar
to amlodipine 5 mg [0.0/
0.3, 95% CI (
2.1, 2.0)/(
1.7,
1.2), respectively] (Fig. 2).
Comparison of the effects of the components given
singly
The effects of the components on supine SBP when
administered singly at the doses used in the combination
were compared. The reduction in SBP in the perindo-
pril 3.5 mg group was 16.3 mmHg, compared with a
similar reduction of 16.0 mmHg in the amlodipine 2.5 mg
group, with an estimated between-group difference
of only
0.19 mmHg. Using an equivalence limit of
3 mmHg, the two components were shown to be
statistically equivalent (P ¼ 0.008 by Schuirman equi-
valence test).

(a)
Vs perindopril 5 mg: –3.8 [–5.8;-1.8]

Vs amlodipine 5 mg: 0.0 [–2.1;2.0]

–6 –5 –4 –3 –2 –1 0 1 2 3
Favors perindopril 3.5/amlodipine 2.5

(b)
Vs perindopril 5 mg: –2.4 [–3.8;-1.0]

Vs amlodipine 5 mg: –0.3 [–1.7;1.2]

–6 –5 –4 –3 –2 –1 0 1 2 3
Favors perindopril 3.5/amlodipine 2.5
FIGURE 2 Estimation of the differences between the perindopril 3.5 mg/amlodipine 2.5 mg combination and other treatment group in the ambulatory blood pressure
monitoring on mean SBP (a) and DBP (b).

658 www.jhypertension.com Volume 33  Number 3  March 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

 Perindopril/amlodipine as first step

TABLE 5. Summary of emergent adverse events, expressed as the number (%) of patients reporting one or more event
Per 3.5 mg/Amlo 2.5 mg Placebo Per 3.5 mg Amlo 2.5 mg Per 5 mg Amlo 5 mg
Any EAE 47 (18.9) 40 (15.9) 51 (18.7) 51 (18.6) 44 (16.2) 57 (21.6)
Treatment-related EAE 19 (7.6) 10 (4.0) 18 (6.6) 21 (7.7) 17 (6.3) 26 (9.8)
Serious EAE (including death) 0 1 (0.4) 1 (0.4) 1 (0.4) 4 (1.5) 3 (1.1)
Treatment-related serious EAE 0 0 0 0 0 0
EAE leading to treatment stop 3 (1.2) 2 (0.8) 7 (2.6) 11 (4.0) 7 (2.6) 9 (3.4)
Non-serious 3 (1.2) 2 (0.8) 6 (2.2) 11 (4.0) 7 (2.6) 7 (2.7)
Serious 0 0 1 (0.4) 0 1 (0.4) 2 (0.8)
Treatment-related 2(0.8) 1 (0.4) 3 (1.1) 9 (3.3) 4 (1.5) 5 (1.9)
Serious treatment-related 0 0 0 0 0 0

Amlo, amlodipine; EAE, emergent adverse event; Per, perindopril.

Safety results A specific analysis was made of adverse effects associ-

Adverse events that occurred or worsened during the treat- ated with either amlodipine or perindopril and more formal
ment period [emergent adverse events (EAEs)] are summar- comparisons were made between the combination and
ized in Table 5. The incidence of all EAEs in the each component at its lowest approved dose (perindopril
combination group was 18.9%, slightly higher than with 5 mg and amlodipine 5 mg). Oedema of the lower limb,
placebo (15.9%) and similar to the perindopril 3.5 mg whether reported as an EAE or noted on clinical examin-
(18.7%) and the amlodipine 2.5 mg (18.6%) groups. The ation, occurred less frequently in the combination group
amlodipine 5 mg group had the highest overall incidence at than with amlodipine 5 mg (Table 6).
21.6%. No angiodema was reported during the study, Hypotension was not reported as an EAE in any
although two patients reported facial oedema (one each of the three treatment groups, and only one patient
in the perindopril 3.5 mg and amlodipine 5 mg groups). (in the amlodipine 5 mg group) reported orthostatic
Serious EAEs were infrequent: there were no cases in the hypotension as an EAE. Orthostatic hypotension calculated
combination group and one case with placebo, compared from blood pressure measurements was more frequent
with four and three cases in the perindopril 5 mg and in the amlodipine 5 mg group (15 patients, 5.7%) than in
amlodipine 5 mg groups, respectively. There was one death the combination group (10 patients, 4.1%), but the differ-
during the study: a 47-year-old man in the perindopril 5 mg ence was not significant. The incidences of headache
group was drowned 15 days after the first drug intake in an and cough were similar in the three treatment groups
incident that was not related to the study drug. No clinically (Table 6).
relevant changes or differences between treatment groups Laboratory analysis of blood samples showed that poten-
were detected in blood biochemistry or haematology in tially clinically significant cases of hyperkalaemia
laboratory analyses. (>5.8 mmol/l) and low calculated creatinine clearance
TABLE 6. Specific safety evaluations, expressed as the number of patients affected
Per 3.5 mg /Amlo 2.5 mg Per 5 mg Amlo 5 mg
(N ¼ 249) (N ¼ 272) (N ¼ 264)
Lower limb oedema (reported as EAE) n (%) 4 (1.6) 4 (1.5) 13 (4.9)
Difference [95% CI] 0.14 [
2.32, 2.75]
3.32 [
6.36,
0.28]
Lower limb oedema (by clinical examination) n (%) 4 (1.6) 6 (2.2) 14 (5.3)
Difference [95% CI]
0.60 [
3.31, 2.13]
3.70 [
6.82,
0.57]
Ankle circumference (change >20 mm) n (%) 2 (0.8) 3 (1.1) 8 (3.0)
Difference [95% CI]
0.30 [
2.47, 1.90]
2.23 [
5.12, 0.33]
Lower limb oedema (composite of investigator assessments) n (%) 5 (2.0) 9 (3.3) 19 (7.2)
Difference [95% CI]
1.30 [
4.05, 1.45]
5.19 [
8.76,
1.62]
Lower limb oedema: subjective symptoms by VAS n (%) 14 (5.6) 14 (5.1) 20 (7.6)
(change >20 mm)
Difference [95% CI] 0.48 [
3.41, 4.36]
1.95 [
6.24, 2.33]
Flush n (%) 1 (0.4) 0 5 (1.9)
Difference [95% CI] 0.40 [
1.03, 2.24]
1.49 [
3.98, 0.64]
Hypotension (reported as EAE) n (%) 0 0 0
Orthostatic hypotension (reported as EAE) n (%) 0 0 0
Orthostatic hypotension (calculated) n (%) 10 (4.1) 10 (3.7) 15 (5.7)
Difference [95% CI] 0.38 [
2.98, 3.74]
1.61 [
5.35, 2.14]
Headache (reported as EAE) n (%) 3 (1.2) 3 (1.1) 1 (0.4)
Difference [95% CI] 0.10 [
2.13, 2.49] 0.83 [
1.08, 3.12]
Cough (reported as EAE) n (%) 2 (0.8) 3 (1.1) 1 (0.4)
Difference [95% CI]
0.30 [
2.47, 1.90] 0.42 [
1.41, 2.53]
Hyperkalaemiaa n (%) 2 (0.8) 3 (1.1) 3 (1.1)
Calculated creatinine clearance lowb n (%) 3 (1.2) 2 (0.7) 5 (1.9)

Amlo, amlodipine; CI, confidence interval; EAE, emergent adverse event; Per, perindopril; VAS, visual analogue scale (20 mm).
a
Potentially clinically significant high potassium concentration (>5.8 mmol/l).
b
Potentially clinically significant low calculated creatinine clearance (<60 ml/min).

Journal of Hypertension www.jhypertension.com 659

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Laurent et al.
(<60 ml/min) occurred with similar incidence in the three
treatment groups (Table 6).
DISCUSSION
The main conclusions of this study are that the combination
perindopril 3.5 mg/amlodipine 2.5 mg produced significant
and clinically relevant decreases in blood pressure relative
to placebo in patients with uncomplicated mild-to-
moderate hypertension. The combination was superior to
either component given singly, and was also non-inferior
to the component drugs given singly at their lowest
approved doses, using guideline-recommended criteria
for clinical relevance and non-inferiority [15]. Additionally,
the two components appeared to contribute similarly to
the blood pressure-lowering effect due to the optimization
of the dosage selection. The combination also showed
improved safety compared with the lowest approved doses
of its components in terms of the incidence of peripheral
oedema, which is a recognized dose-dependent adverse
effect of amlodipine. These results indicate that the com-
bination could potentially be suitable for first-step anti-
hypertensive therapy.
Recent clinical guidelines have stressed the potential
advantages of initiating antihypertensive therapy using a
fixed-dose combination, in terms of simplified treatment
regimens and improved blood pressure control [7,9,10]. For
example, a higher proportion of patients achieved target
blood pressure when treatment was initiated with low-dose
combination therapy than with either sequential monother-
apy or a stepped-care approach [17]. Similarly, a simplified
treatment algorithm involving initial treatment with a fixed-
dose combination was more effective than a conventional
approach initiated with a single drug in terms of achieving
blood pressure targets [18]. Further evidence has come from
two recent studies published since the major clinical guide-
lines appeared. Analysis of over 160 000 newly diagnosed
hypertensive patients from the Cardiovascular Research
Network Hypertension Registry showed that initial treat-
ment with combination therapy was associated with
increased odds of blood pressure control at 12 months
compared with single-drug initial therapy [19]. Finally, data
from over 106 000 patients retrieved from 180 practice sites
showed that treatment initiation with a fixed-dose combi-
nation provided superior hypertension control in the first
year relative to initiation with either free combinations or
single-drug therapies [20]. Rapid attainment of blood pres-
sure control can lead to improved outcomes; in the Val-
sartan Antihypertensive Long-term Use Evaluation (VALUE)
trial, reaching blood pressure control by 6 months was
associated with significant benefits for subsequent major
outcomes, regardless of the type of treatment [21].
The combination of an ACE inhibitor and a calcium
channel blocker (CCB) is rational, given their different
mechanisms of action, and is one of the preferred combi-
nations of the European guidelines [9]. Although the main
benefits of antihypertensive therapy are due to the lowering
of blood pressure per se [9], there is evidence that such a
combination might be expected to have a favourable
impact on outcomes relative to other possible combi-
nations. A recent large meta-analysis of 20 hypertension
660 www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
trials published between 2000 and 2011 concluded that
treatment with an ACE inhibitor was associated with a
significant reduction in all-cause mortality of approximately
10% relative to other classes of drug; no reduction in
mortality was demonstrated with angiotensin receptor
blocker treatment [22]. In the large Anglo-Scandinavian
Cardiac Outcomes Trial–Blood Pressure Lowering Arm
(ASCOT-BPLA) trial [23], treatment with amlodipine and
perindopril prevented more major cardiovascular events
and reduced all-cause mortality compared with a regimen
of atenolol and thiazide diuretic. This benefit was shown for
the first time to be supported by a greater reduction on
central blood pressure with the combination of amlodipine
and perindopril while office blood pressure was equally
reduced in both arms [24]. Finally, in the Avoiding
Cardiovascular Events in Combination Therapy in Patients
Living with Systolic Hypertension (ACCOMPLISH) trial, the
combination of an ACE inhibitor (benazepril) and amlodi-
pine was significantly more effective in reducing cardio-
vascular events than the same ACE inhibitor and
hydrochlorothiazide despite similar BP reduction, resulting
in the trial being stopped prematurely [25].
The European hypertension guidelines stress that great
effort should be devoted to limitation of drug-related side
effects, in part, because adverse events are the most import-
ant causes of treatment non-compliance [9]. In the present
study, the combination was safe and well tolerated. There
were no serious EAEs in the combination group, and most
EAEs occurred with similar incidence in all the treatment
groups. An exception was peripheral oedema, which was
significantly less frequent with the combination than in the
amlodipine 5 mg group. Peripheral oedema is a known
dose-dependent adverse effect of amlodipine [13], and the
lower incidence of peripheral oedema with the combi-
nation than with amlodipine 5 mg was probably due
primarily to the lower amlodipine dose in the combination.
However, there is the possibility of a specific interaction
between the CCBs and the ACE inhibitors. In two studies,
the addition of an ACE inhibitor to CCB therapy appeared to
counteract the microcirculatory changes responsible for
oedema, and either reduced the incidence of peripheral
oedema [26] or prevented increases in ankle-foot volume
and pretibial subcutaneous tissue pressure [27], despite an
unchanged CCB dose. Adverse effects of ACE inhibitor
therapy are reportedly not dose-dependent [13], and in
the present study, the incidence of cough and hyperkalae-
mia was similar and low in all treatment groups. A potential
disadvantage of initiating antihypertensive therapy with a
combination of drugs might be hypotension. However, no
EAEs relating to hypotension or orthostatic hypertension
were reported in the combination group, and orthostatic
hypertension calculated from blood pressure measure-
ments occurred less frequently in the combination group
than with amlodipine 5 mg, although the difference was
not significant.
The main limitations of the study were its relatively short
randomized treatment period (8 weeks) and the exclusion
of very high risk patients who were obese, or who had
complications such as microalbuminuria, or a history of
cardiovascular disease or diabetes mellitus. This was, how-
ever, necessitated by the inclusion of a placebo group.
Volume 33  Number 3  March 2015

Patients known to be refractory to ACE inhibitors and CCB
were not recruited in this study as they would not be
considered for such treatment in general practice.
Overall, the combination perindopril 3.5 mg/amlodipine
2.5 mg showed blood pressure-lowering efficacy that was
superior to placebo and non-inferior to perindopril 5 mg and
amlodipine 5 mg, their lowest approved doses in hyperten-
sion. Additionally, both components of the combination
appeared to contribute approximately equally to its blood
pressure-lowering effect. This may explain why the combi-
nation was well tolerated and showed a lower incidence of
dose-dependent side effects compared with amlodipine
5 mg. Therefore, the combination seems well suited for
use as a first-step treatment in patients with hypertension.
ACKNOWLEDGEMENTS
Funded by Servier.
Conflicts of interest
The authors received honoraria or research grants from
Servier. The authors have no other relevant affiliations or
financial involvement with any organization or entity in
conflict with the subject matter or materials discussed in the
study apart from those disclosed.
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Laurent et al.
Reviewers’ Summary Evaluations
Reviewer 1
This is a wide trial performed with a multicenter, random-
ized, double-blind approach to compare a novel, fixed-
dose combination (perindopril 3.5 mg/amlodipine 2.5 mg)
with amlodipine 5 mg as a first step therapy in hyper-
tension. Efficacy, safety and quick onset of the effect of
the combination is encouraging. The study suffers of an
approach largely based on regulatory requirements and the
number of centers appears to be too large to ensure a high
quality profile.
662 www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Reviewer 2
Strength: A thorough evaluation of feasibility of treating
hypertension with a combination pill consisting of very low
doses of perindopril and amlodipine. Combination pills are
likely to be well accepted by patients and physicians and
may improve the overall blood pressure control.
Weaknesses: Selected population: hypertension without
known risk factors and multiple exclusion criteria. Exclu-
sion of obesity and diabetes removed the majority of
patients seen in usual clinical practice. Exclusion of patients
whose blood pressure did not respond to components of
the pill may have overestimated the real life effectiveness of
the pill.
Volume 33  Number 3  March 2015