American Journal of Cardiovascular Drugs

https://doi.org/10.1007/s40256-018-00314-4

ORIGINAL RESEARCH ARTICLE

Efficacy and Safety of Incremental Dosing of a New Single‑Pill

Formulation of Perindopril and Amlodipine in the Management
of Hypertension
Neil R. Poulter1   · Eamon Dolan2 · Ajay K. Gupta3 · Eoin O’Brien4 · Andrew Whitehouse5 · Peter S. Sever5

© Springer Nature Switzerland AG 2019

Abstract
Background  Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recom-
mended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a
dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension.
Objective  This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/
amlodipine SPC in adults with mild-to-severe hypertension.
Methods  Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg)
daily, uptitrating as required on a monthly basis up to 14/10 mg until BP < 140/90 mmHg (< 130/80 mmHg in patients with
diabetes). The primary endpoint (proportion with controlled BP at each uptitrated dose) was evaluated at 6 months, and
safety was evaluated at 9 months; 24-h ambulatory BP measurement and BP variability were also investigated. Control-arm
participants (n = 1653) were randomized to irbesartan 150 mg daily, uptitrating over 3 months to irbesartan/hydrochloro-
thiazide 300/25 mg.
Results  Significant increases in BP control were observed with each dosage increment of perindopril/amlodipine, which
was well tolerated, rising from 21% (3.5/2.5 mg) to 30% (7/5 mg), 37% (14/5 mg), and 42% (14/10 mg) after 1, 2, 3, and
6 months, respectively. Reductions in mean systolic and diastolic BP occurred with each incremental dose of perindopril/
amlodipine. After 6 months, mean BP had fallen by 24.8/10.8 mmHg. Irbesartan-based therapy reduced clinic and 24-h BP
similarly to perindopril/amlodipine, but perindopril/amlodipine reduced BP variability more in comparison.
Conclusions  Incremental uptitration with dosage-adapted perindopril/amlodipine SPC is a safe and effective strategy for
managing hypertension.
Trial registration  EudraCT (No. 2006-005799-42).

Key Points 

In patients with mild-to-severe hypertension, perindo-

pril/amlodipine single-pill combination treatment led to
* Neil R. Poulter significant improvement in blood pressure (BP) control,
n.poulter@imperial.ac.uk BP response, and mean BP levels, which increased with
1
each dosage increment.
Imperial Clinical Trials Unit, School of Public Health,
Imperial College London, 1st Floor Stadium House, 68 Efficacy in terms of BP reduction was similar to that of
Wood Lane, London W12 7TA, UK the irbesartan/hydrochlorothiazide strategy.
2
Stroke and Hypertension Unit, Connolly Hospital,
Blanchardstown, Dublin, Ireland
Tolerance of the perindopril/amlodipine combination
3
was in accordance with the well-known safety profile of
William Harvey Research Institute, Queen Mary University
of London, London, UK
each individual product.
4
Conway Institute, University College Dublin, Dublin, Ireland
5
NHLI, Imperial College London, London, UK

Vol.:(0123456789)

1 Introduction
Raised blood pressure (BP) remains the biggest single con-
tributor to global mortality [1]. Despite this, most surveys
from around the world show that the BP of the majority of
those diagnosed as having hypertension is not controlled to
currently recommended BP targets [2, 3]. Insufficient use
of more than one antihypertensive agent is a contributing
factor to this inadequate management of raised BP [4].
Guidelines from America, Canada, and Europe, but not
the UK [5–8], that were in place at the time of the current
trial recommended that medication be initiated with two
antihypertensive agents, as opposed to one with the tra-
ditional stepped-care approach [9], for a large proportion
of patients with hypertension. These recommendations
are emphasized in more recent American and European
guidelines [10, 11]. The combinations of antihyper-
tensive agents recommended in recent guidelines differ
[5–8], but the latest British guidelines [8] recommend a
renin–angiotensin system (RAS) blocker plus a calcium
channel blocker (CCB) as the single optimal combination
of drugs, whereas this is one of the combinations “pre-
ferred” in European guidance [7, 11]. Observational and
trial data [12, 13] and health economic analyses [14] have
shown single-pill combinations (SPCs) of agents are asso-
ciated with improved adherence to therapy, BP control,
and cost effectiveness and are therefore recommended in
previous European guidelines [7] and emphasized as the
default position in the most recent iteration [11]. Extensive
data from randomized controlled trials show that the angi-
otensin-converting enzyme inhibitor (ACEI) perindopril
and the CCB amlodipine, both separately and together, are
well-tolerated and effective in the prevention of cardiovas-
cular morbidity and mortality [15–17]. Other “real-life”
observational data confirm the efficacy of this combination
[18, 19]. Consequently, an SPC of these two drugs has
been produced, including a new formulation and doses of
perindopril that are suitable for treatment initiation and
rapid uptitration [20].
A randomized trial was therefore designed to evaluate
the BP-lowering efficacy of the new SPC formulation in
a four-step strategy for treating hypertension in adults, in
keeping with European Medicines Agency (EMA) require-
ments for drug registration [21].
2 Methods
A phase III, international, multicentre, parallel-group, ran-
domized, double-blind trial was designed to evaluate the
BP-lowering efficacy of four incremental doses of the new
N. R. Poulter et al.
perindopril/amlodipine SPC among over 1000 patients
with mild-to-severe hypertension.
Men and women aged ≥ 18 years were potentially eligi-
ble for randomization if their physician deemed a change
in medication necessary (because of lack of efficacy or
poor tolerability of their current medication) and they had a
systolic blood pressure (SBP) < 165 mmHg and a diastolic
blood pressure (DBP) < 105 mmHg or were untreated and
had an SBP 150–179 mmHg and/or a DBP 95–114 mmHg.
Patients became eligible for randomization in the trial if
they had an SBP between 150 and 199 mmHg inclusive
and/or a DBP between 95 and 114 mmHg, inclusive, after
the placebo run-in. This placebo phase lasted 2  weeks.
Patients were ineligible for the trial if they were pregnant,
had impaired renal function (estimated glomerular filtra-
tion rate [eGFR] < 30 ml/min), had raised serum potassium
(> 5.5 mmol/l), or had secondary, malignant, or clinically
symptomatic hypertension.
Eligible patients were randomized to receive either the
perindopril/amlodipine SPC regimen (Fig. 1a), starting at
3.5/2.5 mg/day or an irbesartan-based regimen starting at
150 mg/day (which acted as a referent group for the trial)
(Fig.  1b) in accordance with the European summary of
product characteristics for both irbesartan and irbesartan/
hydrochlorothiazide. Drug dosages were uptitrated at three
1-monthly intervals, as shown in Fig. 1, if BP levels were
not controlled (controlled BP defined as SBP < 140 mmHg
and DBP < 90 mmHg for patients without diabetes and as
SBP < 130 mmHg and DBP < 80 mmHg for patients with
diabetes). Patients without SBP < 160 mmHg after 3 months
were reviewed again at 4 months when, if SBP remained
uncontrolled, they were withdrawn from the trial. Oth-
erwise, patients were all seen again 6 and 9 months after
randomization.
The four dosages available for those randomized to perin-
dopril/amlodipine were 3.5/2.5, 7/5, 14/5, and 14/10 mg (see
Fig. 1a). The four possible regimens for those randomized
to the irbesartan-based regimen were irbesartan 150 mg or
irbesartan/hydrochlorothiazide 150/12.5 mg, 300/12.5 mg,
or 300/25 mg (see Fig. 1b) in accordance with the European
summary of product characteristics for both irbesartan and
irbesartan/hydrochlorothiazide.
The primary endpoint of the trial was the proportion
of patients receiving each dose of perindopril/amlodipine
whose BP was controlled after the instigation of each dos-
age uptitration, relative to the proportion controlled at the
previous dose.
Secondary endpoints included a comparison after
6 months of follow-up with the irbesartan-based regimen
(Fig. 1b) in terms of BP control based on levels reported
in guidelines in place at the time of the study [5–8], BP
response (proportion showing BP control and/or a reduction
from baseline of SBP ≥ 20 mmHg or DBP ≥ 10 mmHg) and
Efficacy and safety of perindopril/amlodipine combination in hypertension management

(a)
Perindopril/amlodipine 14/10 mg

Perindopril/amlodipine 14/5 mg

Perindopril/amlodipine 7/5 mg

Perindopril/amlodipine 3.5/2.5 mg
Placebo

-0.5 0 1 2 3 4* 6 9
Time (months)

x x x
ABPM

(b)
Placebo

Irbesartan 150 mg

Irbesartan/HCTZ 150/12.5 mg

Irbesartan/HCTZ 300/12.5 mg

Irbesartan/HCTZ 300/25 mg

-0.5 0 1 2 3 4* 6 9
Time (months)

x x x
ABPM

Fig. 1  Trial design a perindopril/amlodipine-based regimen; b irbesartan/hydrochlorothiazide-based regimen. ABPM ambulatory blood pressure
measurement, HCTZ hydrochlorothiazide. *Optional for patients with systolic blood pressure > 160 mmHg at 3 months

mean BP levels (SBP, DBP, pulse pressure, and mean arte-
rial pressure). In addition, the emergence of cardiovascular,
glucometabolic, and renal endpoints throughout the trial
was evaluated in the perindopril/amlodipine group and also
compared with those receiving the irbesartan-based regimen
using an unadjusted Cox model (likelihood ratio test).
In light of data published after the trial was completed
[22], we decided post hoc to compare the visit-to-visit vari-
ability in BP between those randomized to the two treatment
regimens.
The overall safety of the perindopril/amlodipine regi-
men was assessed by extending the follow-up of all partici-
pants to 9 months after randomization, thereby allowing at
least 6 months of follow-up of each dose combination of
perindopril/amlodipine used. Substudies included recording
of 24-h ambulatory BP measurement (ABPM) as often as
possible at each stage of the trial (months 1, 3, and 6; Fig. 1)
among all volunteers who were prepared to take part.
Eligible patients underwent a 2-week placebo run-
in period to ensure satisfactory compliance (> 70%
and < 130%) and suitable BP levels (SBP 150–199 mmHg
and DBP 95–114 mmHg). Suitable patients were then ran-
domized to receive the starting dose of either perindopril/
amlodipine or irbesartan (Fig. 1). At each visit, BP was
measured three times, 1 min apart in the supine position
using a validated OMRON device (HEM705CP) on the same
arm before tablet ingestion (“trough”). The mean of the last
two of each set of three readings was used in analyses. At

baseline, eligible patients provided informed consent, gave a
medical history, and underwent a physical examination that
included measurement of height, weight, and leg edema.
An electrocardiogram (ECG) was also taken at baseline, as
were routine blood tests and a spot urine sample, which was
tested for microalbuminuria. The EuroQoL-5 Dimensions
(EQ-5D) well-being questionnaire [23] was self-completed.
At each visit thereafter, a physical examination was
repeated; compliance was assessed by a tablet count; adverse
effects, including leg edema, were evaluated; a venous blood
sample was taken for routine biochemistry and hematology;
and spot urine samples were checked for microalbuminuria.
At the final visit, an ECG was recorded and the EQ-5D ques-
tionnaire was repeated.
In total, 195 patients underwent ABPM recordings at
baseline, after which 144, 132, and 145 underwent ABPM
recording at 1, 3, and 6 months, respectively.
The study sample size was determined primarily on the
basis of the primary endpoint, whereby the study had 80%
power to detect prespecified differences in BP control rates
between each incremental dose titration of perindopril/
amlodipine. This was evaluated using the two-sided McNe-
mar test at 5% type I error, based on hypothesized incre-
mental control rates of 30, 50, 30, and 15%, respectively, for
the four doses evaluated (see Fig. 1a). We anticipated that,
at each study visit, the BP of 1% of participants for whom
it had been controlled at the previous visit would no longer
be controlled. Sample size was also adjusted for compli-
ance with EU safety data guideline requirements [21], which
stipulate the need for a follow-up of at least 6 months of
300–600 patients randomized to each dose. With an esti-
mated patient withdrawal rate of 5%, about 1500 patients had
to be included in the population receiving the perindopril/
amlodipine SPC.
Standard deviations (SDs) and coefficients of variation of
SBP measurements between four visits (months 2, 3, 6, and
9 after randomization) were calculated for each patient, and
the mean of these values in the two treatment groups were
compared using a t test from a logarithmic transformation,
as the distribution was skewed. A measure of within-visit
SBP variability was also calculated for each patient at each
visit (three readings per visit). These measures were aver-
aged across the four visits from 2 months onwards and their
distributions compared by treatment group.
All participants provided written informed consent to take
part in the trial, which was compliant with the Declaration of
Helsinki. The trial was registered with EudraCT (No. 2006-
005799-42). The National Research Ethics Service, London
MREC, granted ethical approval on 30 September 2007, and
the Medicines and Healthcare products Regulatory Agency
(MHRA) granted regulatory approval on 30 November
2007. The Ethics and Medical Research Committee, Dublin,
granted ethical approval for Ireland on 4 October 2007, and
N. R. Poulter et al.
the Irish Medicines Board provided regulatory approval for
Ireland on 23 November 2007.
3 Results
Starting in January 2008, a total of 5249 patients from 87
hospital- or general practice-based sites in England, Scot-
land, Northern Ireland, and the Netherlands were formally
screened for trial eligibility (Fig. 2). Of those screened, 4501
were selected for potential randomization, of whom 3270
were randomized into the trial by November 2008 (Fig. 2).
Of the 1617 randomized to perindopril/amlodipine, 73%
(n = 1177) completed treatment with at least 6 months of this
drug combination, with the commonest cause of withdrawal
(19%) being an adverse event.
At baseline in the perindopril/amlodipine group, the
mean age of randomized patients was 63 years, and 63% of
patients were male. Mean BP levels were 163.7/91.4 mmHg,
and half the patients had grade 2 hypertension. Before the
2-week placebo run-in period, only 17% of patients were
newly diagnosed and over two-thirds had metabolic syn-
drome, according to the International Diabetes Federation
definition (Table 1) [24]. Almost identical characteristics
were observed in those allocated to the irbesartan-based
regimen (Table 1).
BP control rates (< 140/90 mmHg) in the perindopril/
amlodipine group increased significantly with each incre-
ment of the dosage in the SPC (p < 0.005), rising from 21%
through to 30, 37, and 42% at 1, 2, 3, and 6 months, respec-
tively (Table 2). Similarly, response rates rose significantly
with each dosage increment, rising from 47% through to 62,
68, and 73% at 1, 2, 3, and 6 months, respectively.
Highly significant reductions in SBP and DBP were
observed with each incremental dosage combination of
the perindopril/amlodipine formulation (Table  3), with
mean BP levels of all participants allocated to perindopril/
amlodipine falling from 163.7/91.4 mmHg at baseline to
138.9/80.6 mmHg at 6 months (data not shown). However,
the reduction in BP between the second and third step of
uptitration (Fig. 1a) generated a relatively small reduction.
Similar mean BP reductions were observed with the irbesar-
tan-based therapy at 6 months (Table 4).
All four doses of perindopril/amlodipine were well toler-
ated, although, as expected, ankle edema (n = 88 [5.4%]) and
cough (n = 94 [5.8%]) were the side effects most frequently
recorded as causing study drug withdrawal and related to
study drug (Table 5). Overall, irbesartan-based therapy was
equally well-tolerated, but with less reported ankle edema
and cough.
More specifically, no angioedema was reported during the
course of the study. Nine hyperkalemia events were reported
Efficacy and safety of perindopril/amlodipine combination in hypertension management

Screened (n=5249)

Selected (n=4501)
Non-inclusion (n=1231)
• Blood pressure
• Consent withdrawal
• Medical reason
Inclusion/randomizaon • Forbidden treatment
(n=3270) • Biology

Perindopril/amlodipine Irbesartan/HCTZ
Paents withdrawing (n=440) (n=1617) (n=1653) Paents withdrawing (n=394)
• Adverse events (n=308) • Adverse events (n=209)
• Non-medical reason (n=58) • Non-medical reason (n=64)
• Lack of efficacy (n=49) • Lack of efficacy (n=95)
• Protocol deviaon (n=25) • Protocol deviaon (n=26)
Completed 6 months on Completed 6 months on
perindopril/amlodipine irbesartan/HCTZ
(n=1177) (n=1259)

Perindopril/amlodipine Irbesartan/HCTZ
FAS (n=1605) FAS (n=1628)

Fig. 2  Study patient disposition. HCTZ hydrochlorothiazide, FAS full analysis set

Table 1  Baseline characteristics in the randomized set

Characteristics PER/AML (n = 1617) IRB/HCTZ (n = 1653) All (n = 3270)

Demographic parameters
 Age (years) 62.6 ± 9.8 62.4 ± 9.8 62.5 ± 9.8
 Men 1024 (63) 1041 (63) 2065 (63)
Clinical parameters
 SBP (mmHg) 163.7 ± 11.6 163.5 ± 11.5 163.6 ± 11.5
 DBP (mmHg) 91.4 ± 9.2 91.3 ± 9.1 91.3 ± 9.1
 BMI (kg/m2) 29.3 ± 4.8 29.7 ± 5.1 29.5 ± 4.9
 Supine heart rate (bpm) 67.2 ± 11.2 67.8 ± 11.4 67.5 ± 11.3
Arterial hypertension
 Hypertension severity
  Grade I 605 (37) 622 (38) 1227 (38)
  Grade II 812 (50) 850 (51) 1662 (51)
  Grade III 200 (12) 181 (11) 381 (12)
 Isolated systolic HTN 684 (42) 705 (43) 1389 (42)
 Duration of HTN (months) 90.5 ± 86.9 90.3 ± 90.4 90.4 ± 88.6
 Family history of HTN 848 (53) 833 (51) 1681 (52)
 Previous treatment for HTN 1341 (83) 1363 (83) 2704 (83)
Other specific medical history
 Diabetes 216 (13) 233 (14) 449 (14)
 Metabolic syndrome 1107 (68) 1117 (68) 2224 (68)
 History of leg edema 135 (8) 165 (10) 300 (9)

Data are presented as N (%) or mean ± standard deviation

AML amlodipine, BMI body mass index, bpm beats per minute, DBP diastolic blood pressure, HCTZ hydrochlorothiazide, HTN hypertension,
IRB irbesartan, PER perindopril, SBP systolic blood pressure
 N. R. Poulter et al.

Table 2  Blood pressure ­controla and ­responseb to treatment with the perindopril/amlodipine uptitration strategy
Control and response n (%) Within-group ­differencec p value
% (SE; 95% CI)

Baseline–1 month (n = 1605)
 BP control 342 (21) – –
 Response 748 (47) – –
1–2 months (n = 1534)
 BP control 457 (30) 8.4 (1.3; 5.9–10.9) < 0.001
 Response 953 (62) 15.7 (1.5; 12.7–18.6) < 0.001
2–3 months (n = 1468)
 BP control 538 (37) 6.3 (1.3; 3.7–8.9) < 0.001
 Response 1002 (68) 5.3 (1.4; 2.6–7.9) < 0.001
3–6 months (n = 1398)
 BP control 587 (42) 4.6 (1.5; 1.6–7.6) 0.003
 Response 1022 (73) 3.9 (1.4; 1.0–6.7) 0.008

BP blood pressure, CI confidence interval, DBP diastolic BP, SBP systolic BP, SE standard error
a
 SBP < 140 [< 130] mmHg and DBP < 90 [< 80] mmHg in patients without and [with] diabetes
b
 BP control and/or reduction in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg
c
 Proportions (%) between the start and end of each study period

Table 3  Effect of the highest dose of individual uptitration steps in the perindopril/amlodipine strategy on mean systolic and diastolic blood
pressure
SBP DBP
a
Pre-titration BP Post-titration BP Difference Pre-titration BP Post-titration BP Differencea

Step 1 (BL–1 mo) 163.7 ± 11.6 149.6 ± 14.2 − 14.1 (0.3; − 14.8 to 91.4 ± 9.2 85.5 ± 9.0 − 5.8 (0.2; − 6.2 to
 PER/AML 3.5/2.5 mg − 13.5) − 5.5)
 (n = 1605)
Step 2 (1–2 mo) 154.2 ± 11.8 147.1 ± 12.7 − 7.1 (0.3; − 7.8 to 87.2 ± 8.9 83.7 ± 8.9 − 3.5 (0.2; − 3.9 to
 PER/AML 7/5 mg − 6.5) − 3.1)
 (n = 1197)
Step 3 (2–3 mo) 151.3 ± 10.9 147.5 ± 12.0 − 3.8 (0.4; − 4.5 to 85.1 ± 8.9 83.3 ± 8.7 − 1.8 (0.2; − 2.2 to
 PER/AML 14/5 mg − 3.1) − 1.4)
 (n = 884)
Step (3–6 mo) 150.4 ± 10.5 143.8 ± 11.7 − 6.6 (0.4; − 7.5 to 84.2 ± 8.6 80.6 ± 8.6 − 3.6 (0.3; − 4.1 to
 PER/AML 14/10 mg − 5.7) − 3.1)
 (n = 671)

Data are presented in mmHg

AML amlodipine, BL baseline, BP blood pressure, CI confidence interval, DBP diastolic BP, mo month(s), PER perindopril, SBP systolic BP, SE
standard error
a
 Data are presented as difference (SE; 95% CI)

Table 4  Office blood pressure levels and changes after 6 months by treatment regimen

PER/AML (N = 1605) IRB/HCTZ (N = 1628) Net difference in reductions p value

after 6 mo ± SD
BL mean ± SD Average reduction after BL mean ± SD Average reduction after
6 mo ± SD 6 mo ± SD

SBP 163.7 ± 11.6 − 22.0 ± 13.4 163.4 ± 11.5 − 22.5 ± 14.3 0.7 ± 0.4 0.116

DBP 91.4 ± 9.2 − 10.1 ± 7.6 91.3 ± 9.1 − 9.6 ± 8.3 − 0.5 ± 0.2 0.05

AML amlodipine, BL baseline, DBP diastolic blood pressure, HCTZ hydrochlorothiazide, IRB irbesartan, mo month(s), PER perindopril, SBP
systolic blood pressure, SD standard deviation
Efficacy and safety of perindopril/amlodipine combination in hypertension management

Table 5  Emergent adverse events leading to study drug withdrawal and related to study drug
EAE leading to study drug withdrawal and related to study PER/AML (N = 1617) IRB/HCTZ (N = 1653)
drug in at least 0.2% of the patients
NEAE N (%) NEAE N (%)

All 300 293 (18.1) 179 168 (10.2)

 Cough 94 94 (5.8) 9 9 (0.5)
 Edema peripheral 88 88 (5.4) 6 6 (0.4)
 Dizziness 13 13 (0.8) 38 38 (2.3)
 Pain in extremity 6 6 (0.4) 1 1 (0.1)
 Headache 5 5 (0.3) 18 18 (1.1)
 Fatigue 5 5 (0.3) 3 3 (0.2)
 Orthostatic hypotension 5 5 (0.3) 5 5 (0.3)
 Cellulitis 3 3 (0.2) 0 0 (0.0)
 Lethargy 3 3 (0.2) 2 2 (0.1)
 Malaise 3 3 (0.2) 5 5 (0.3)
 Rash 3 3 (0.2) 3 3 (0.2)
 Erectile dysfunction 3 3 (0.2) 3 3 (0.2)
 Rash pruritic 3 3 (0.2) 1 1 (0.1)
 Muscle spasms 2 2 (0.1) 4 4 (0.2)
 Sensation of heaviness 2 2 (0.1) 3 3 (0.2)
 Dizziness postural 1 1 (0.1) 3 3 (0.2)
 Nausea 2 2 (0.1) 3 3 (0.2)
 Renal impairment 1 1 (0.1) 3 3 (0.2)
 Creatinine renal clearance decreased 1 1 (0.1) 9 9 (0.5)
 Gout 1 1 (0.1) 3 3 (0.2)
 Hypotension 1 1 (0.1) 6 6 (0.4)
 Vomiting 0 0 (0.0) 4 4 (0.2)

AML amlodipine, EAE emergent adverse events, HCTZ hydrochlorothiazide, IRB irbesartan, N number of affected subjects, NEAE number of
EAE, PER perindopril

in 9 of 1617 (0.6%) patients in the perindopril/amlodipine
group, and 19 such events were recorded in 17 of 1653
(1.0%) patients in the irbesartan/hydrochlorothiazide group.
Serious emergent adverse events were reported in 124
patients (7.7%) in the perindopril/amlodipine group and in
127 patients (7.7%) in the irbesartan/hydrochlorothiazide
group.
At 6  months, patients who underwent ABPM exhib-
ited considerable and similar falls in BP in both treat-
ment groups (Table 6). The mean 24-h BP reduction was
18.2/10.6 mmHg and 17.2/9.7 mmHg for the perindopril
and irbesartan combinations, respectively. However, not
surprisingly, after 1 month, the 24-h mean BP had fallen
by 11.0/6.2 mmHg in the perindopril 3.5 mg/amlodipine
2.5 mg group compared with 6.9/3.7 mmHg in the irbesartan
150 mg group (p = 0.0083). Neither treatment group had an
impact on nocturnal dipping patterns at 6 months.
Among the 2956 patients with at least two BP measure-
ments from 2 months onwards, patients receiving irbesartan/
hydrochlorothiazide showed significantly larger visit-to-visit
SBP variability than those receiving perindopril/amlodipine
(Table 7). Mean within-visit SD (averaged across visits)
was also higher in the irbesartan/hydrochlorothiazide group
than in the perindopril/amlodipine group (4.22 vs. 3.80;
p < 0.001).
Clinical events of special interest (composite of cardio-
vascular, renal, and glucometabolic endpoints) were infre-
quent in both treatment groups (Fig. 3), but significantly
fewer (p = 0.036) occurred among those allocated to per-
indopril/amlodipine (n = 179 [11.2%]) than among those
allocated to the irbesartan-based regimen (n = 225 [13.8%])
from baseline to the end of the trial.
4 Discussion
Among those allocated to perindopril/amlodipine as a new
SPC formulation, BP control, BP response, and mean BP
levels were significantly improved with each dosage increase
of the formulation, as measured at 1, 2, 3, and 6 months.
Overall, after 6 months, this regimen achieved BP control
in 42% of patients, with a further 31% having either SBP
reduced by  ≥ 20 mmHg or DBP by  ≥ 10 mmHg. More than
half of the BP-lowering effects were achieved at 1 month
 N. R. Poulter et al.

Table 6  Ambulatory blood pressure changes after 6 months by treatment regimen

Ambulatory BP PER/AML (N = 71) IRB/HCTZ (N = 74) Net difference in reductions p ­valuea
after 6 mo (95% CI)a
BL ± SD Average reduction BL ± SD Average reduction
after 6 mo (95% CI) after 6 mo (95% CI)

24-h SBP 145.3 ± 11.9 18.2 (15.9–20.5) 142.8 ± 9.8 17.2 (15.2–19.2) 1.0 (− 2.1–4.1) 0.51
24-h DBP 85.6 ± 10.9 10.6 (9.2–11.9) 85.2 ± 8.4 9.7 (8.5–10.3) 0.9 (− 1.0–2.7) 0.35
Daytime SBP 152.1 ± 12.7 19.7 (17.2–22.3) 149.4 ± 10.4 18.1 (15.7–20.5) 1.6 (− 1.8–5.1) 0.36
Daytime DBP 90.7 ± 10.7 11.8 (10.3–13.4) 90.4 ± 9.3 10.3 (8.9–11.7) 1.6 (− 0.5–3.7) 0.13
Nighttime SBP 131.0 ± 13.2 15.8 (13.2–18.5) 128.7 ± 12.3 15.2 (12.8–17.7) 0.6 (− 3.0–4.2) 0.76
Nighttime DBP 75.3 ± 9.8 8.4 (6.5–10.3) 74.6 ± 9.3 8.8 (7.1–10.5) 0.4 (− 2.9–2.1) 0.74
Nocturnal SBP fall (%)b 13.8 ± 6.7 − 0.95 (− 2.40–0.56) 13.7 ± 7.1 − 0.34 (− 2.06–1.39) 0.61 (− 2.90–1.66) 0.59

AML amlodipine, BL baseline, BP blood pressure, CI confidence interval, DBP diastolic blood pressure, HCTZ hydrochlorothiazide, IRB irbesar-
tan, mo month(s), PER perindopril, SBP systolic blood pressure, SD standard deviation
a
 Net difference in BP reduction between the two treatment groups at 6 mo and p value
b
 Nocturnal SBP fall as a percentage of daytime SBP

Table 7  Measures of visit-to-visit (between visit) blood pressure vari-
ability, stratified by allocated treatment
Measures of between- PER/AML IRB/HCTZ p value
visita BP variability (n = 1461) (n = 1495)
Mean SBP (mmHg) 141.7 139.5 < 0.001
Mean SD 7.09 7.57 0.0014
Mean CV 0.050 0.504 < 0.001
AML amlodipine, BP blood pressure, CV coefficient of variation,
HCTZ hydrochlorothiazide, IRB irbesartan, PER perindopril, SBP
systolic blood pressure, SD standard deviation
a
 Between visits at 2, 3, 6, and 9 months
(Table 2). This regimen was well tolerated and metaboli-
cally neutral (data not shown). However, for 5.8% and 5.4%
of participants, respectively, cough and/or ankle edema led
to withdrawal of study drug and was deemed related to the
drug, in keeping with previous data [15–17]. Overall, at
6 months, those in the irbesartan-based arm experienced
BP-lowering effects similar to those receiving amlodipine/
perindopril, and this stepped-care irbesartan-based regimen
was well-tolerated.
In a recent survey of the English population, about 63%
of treated hypertension was controlled to < 140/90 mmHg
[25]. However, participants in the current study were high-
risk patients with hypertension, 14% of whom had diabetes
and therefore had more stringent BP targets for control
(< 130/80 mmHg). Furthermore, starting BPs were high,
despite 83% having previously received treatment. Conse-
quently, to achieve 42% control among such patients with
a single pill in only 6 months provides reassuring evidence
of the efficacy of this regimen. In the most recent sets of
European and American guidelines [10, 11], ideal con-
trol is described as < 130/80 mmHg, so the control rates
reported here would be reduced at least for the nondiabetic
population if these more contemporary BP targets were
applied.
The overall BP reduction of 25/11  mmHg achieved
among those allocated to perindopril/amlodipine is similar
to that achieved by the same combination of drugs in the
ASCOT trial [17], although third- and fourth-line agents
were also added in the latter context.
It was surprising that the overall BP reduction achieved
by the strategy of initiating therapy with a two-drug SPC,
with uptitrations as required, was not more effective, in
terms of BP reduction, than the stepped-care strategy used
in the referent arm of the trial. This may in part reflect the
rapid introduction of the second drug (diuretic) rather than
uptitration of the irbesartan to full dose before adding the
thiazide, which would be normal practice in stepped care.
However, the ACCELERATE trial [26] compared the effects
of initiating therapy with two drugs versus monotherapy, fol-
lowed by the later introduction of combination therapy, and
the former approach did not maintain superior BP reduction
after a total of 24 weeks’ follow-up.
It is also perhaps surprising that overall, in terms of BP
reduction in this trial, independent of the strategy of starting
with one or two agents, the angiotensin-receptor antagonist
(angiotensin-receptor blocker [ARB])/thiazide regimen was
as effective as the ACEI/CCB regimen. This may in part
reflect the limited effect of the third dosage of perindopril/
amlodipine used (Table 3). Therefore, this third dose (per-
indopril/amlodipine 14/5 mg) will no longer be included
in the clinical development of this new combined formula-
tion for treating hypertension. In general, similar clinic BP
reductions might have been expected from the ACEI and the
ARB and from the thiazide and the CCB [27, 28]. However,
depending on the specific agents used, differential effects on
24-h BP control might have been anticipated [29].
Efficacy and safety of perindopril/amlodipine combination in hypertension management

Fig. 3  Emergent clinical events of special interest (composite of cardiovascular + renal + glucometabolic endpoints) during the 9-month treat-
ment period. CV cardiovascular, HCTZ hydrochlorothiazide, HR hazard ratio, N number

The BP recordings used for analyses in this report dif-
fer from those normally used in clinical practice, in that
they were measured in the supine position and at “trough,”
although it is hard to see how these aspects of measurement
would differentially affect the two pairs of drugs.
Despite similar clinic and 24-h BP levels, after 6 months
in the two treatment arms, in-trial BP variability (in both
visit-to-visit and 24-h recordings) differed significantly
between regimens, in favor of the perindopril/amlodipine
combination. In a series of articles published in 2010 [22, 30,
31], Rothwell and colleagues brought focus to the possibility
that the variability of BP over a lengthy period was a bet-
ter predictor of major cardiovascular outcomes (particularly
stroke) than the absolute mean BP level. They also showed
in the ASCOT trial that the variability of three BPs recorded
at each study visit predicted stroke better than the overall
mean BPs achieved in the trial. Hence, we decided post hoc
to evaluate any differences in within-visit and between-visit
BP variability between the two regimens included in the
PREMIUM database. These findings in favor of perindopril/
amlodipine are more compatible with the apparently dif-
ferential effects of the two-drug regimens on the composite
of the small number of clinical events of special interest
experienced in this trial (Fig. 3). The biggest contributor to
the differences in these events between the two treatment
regimens was “renal impairment,” which was largely driven
by hypokalemia, presumably due to hydrochlorothiazide
use rather than as a result of a stepped-care approach. The
possibility that the combination of RAS blockers and dihy-
dropyridine CCB might generate superior cardiovascular
protection than a RAS blocker plus thiazide diuretic for the
same degree of clinic BP reduction was raised by the results
of the ACCOMPLISH trial [28].
In light of two publications [32, 33] that showed more
effective early BP lowering with a perindopril/amlodipine
SPC compared with a stepped-care approach to manage-
ment, we evaluated the impact of BP control at 1 month
(irrespective of the regimen involved) on the rates of clini-
cal events of special interest. Figure 4 shows a significantly
reduced rate of these events among those whose BP was con-
trolled at 1 month versus those whose BP was not controlled.
These data are consistent with several other reports that sug-
gest that early, effective BP lowering may be an important
component of good BP management.

Fig. 4  Incidence of a composite of clinical events of special interest with time in patients controlled or not controlled at 1 month. CI confidence
interval, HR hazard ratio, M1 1 month
In summary, all four doses of the perindopril/amlodi-
pine SPC produced a significant increase in the proportion
of patients with mild-to-severe hypertension experiencing
BP control. Overall, the various doses of this regimen, pro-
vided as an SPC, lowered BP by about 25/11 mmHg within
a 6-month period, and the regimen was well tolerated.
Compliance with Ethical Standards  References
Funding  This study was funded by Servier. Medical writing and edito-
rial support, under the guidance of the authors, was provided by John
Plant (Servier).
Conflicts of interest  Neil Poulter has received financial support from
several pharmaceutical companies that manufacture BP-lowering
agents, for consultancy (Servier), research projects and staff (Pfizer,
Servier), and arranging and speaking at education meetings (Astra Ze-
neca, Lri Therapharma, Napi, Servier, and Pfizer). He holds no stocks
or shares in any such companies. In the last 3 years, Ajay Gupta has
received financial support to attend a conference and an honorarium
for a presentation from Servier, but these funds were for activities un-
related to this manuscript. During the conduct of this study, he was
part of an independent safety and adjudication committee and received
consulting fees for that work. Andrew Whitehouse has claimed travel
expenses during the conduct of the study to attend study sites and the
funder’s offices. Eamon Dolan, Eoin O’Brien, and Peter Sever have
no conflicts of interest that are directly relevant to the content of this
article.
N. R. Poulter et al.
Ethical approval  All procedures performed in studies involving human
participants were in accordance with the ethical standards of national
research committees and with the Helsinki declaration.
Informed consent  Informed consent was obtained from all individual
participants included in the study.
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