Combination therapy in the extended cardiovascular continuum

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CE: Tripti; JCM-D-14-00432; Total nos of Pages: 10;

JCM-D-14-00432

Narrative review

Combination therapy in the extended cardiovascularcontinuum: a focus on perindopril and amlodipineClaudio Borghi, Martino Morbini and Arrigo F.G. Cicero

The progression of cardiovascular disease could be

regarded as following atherosclerosis-related and age-

related pathways. The starting points for these pathways

are different – risk factors or aortic ageing – but they

conclude in the same way: end-stage heart disease.

Together these interlinked pathways form the extended

cardiovascular continuum. Renin–angiotensin–

aldosterone system (RAAS) inhibitors have been shown to

interrupt or slow the progression of cardiovascular disease

along one pathway, the cardiovascular atherosclerotic

continuum. Cardiovascular protection with RAAS inhibitors

varies; different RAAS inhibitors offer different levels of

protection. Similarly, calcium channel blockers (CCBs) also

have clearly shown protective effect of cardiovascular

system, especially as it regards cerebrovascular disease

risk. The AngloScandinavian Cardiac Outcomes Trial

(ASCOT) showed that a combination of the angiotensin-

converting enzyme (ACE) inhibitor perindopril and CCB

amlodipine offered better cardiovascular protection in at-

risk hypertensive patients than beta-blocker and thiazide.

By attenuating the deleterious effects of cardiovascular

disease at multiple stages of the extended cardiovascular

continuum on top of lowering blood pressure (BP),

opyright © 2015 Wolters Kluwer Health, Inc. Una

1558-2027 Copyright � 2015 Wolters Kluwer Health, Inc. All rights reserved.

perindopril and amlodipine could interrupt and slow the

progression of cardiovascular disease. These

antihypertensive agents have complementary vascular

effects that enhance cardiovascular protection and reduce

side-effects. Evidence from ASCOT shows that

antihypertensive and vascular effects of amlodipine with

and without perindopril have translated into real-life clinical

benefits. A strategy using ACE inhibitors and CCBs, such as

perindopril and amlodipine, to target multiple stages in both

pathways of cardiovascular disease could effectively reduce

cardiovascular risk and lower BP.

J Cardiovasc Med 2015, 16:000–000

Keywords: ACE inhibitor, amlodipine, calcium channel blocker,cardiovascular continuum, perindopril

Department of Internal Medicine, Aging and Clinical Nephrology, University ofBologna, Bologna, Italy

Correspondence to Claudio Borghi, Medical and Surgical sciences Department,S. Orsola-Malpighi University Hospital, Via Albertoni 15 – Pad. 2, 40138Bologna, ItalyTel: +39 516363243; fax: +39 51391320; e-mail: [email protected]

Received 29 July 2014 Revised 16 October 2014Accepted 16 October 2014

IntroductionThe largest risk factor for cardiovascular disease is hy-

pertension, making blood pressure (BP) control crucial

for preventing deleterious cardiovascular damage.1

Recent epidemiological data show that people with hy-

pertension have a lifetime risk of overall cardiovascular

disease at 30 years of age of 63.3% [95% confidence

interval (CI) 62.9–63.8] compared with 46.1% (45.5–

46.8) for those with normal BP, and developed cardio-

vascular disease 5.0 years earlier (95% CI 4.8–5.2). Thus,

it is important to detect all the reversible causes of

uncontrolled BP and, when available, manage them.2

BP reduction per se appears to effectively reduce this

risk. However, some patients with well controlled BP

have residual cardiovascular risk.3 The ideal antihyper-

tensive should therefore simultaneously lower BP and

attenuate the effects of cardiovascular disease.4 As a

result of the presence of residual risk and concomitant

disease in hypertensive patients, the latest European

guidelines recommend that risk assessment tools, such

as vascular age, are used to evaluate total cardiovascular

risk before the initiation of hypertensive treatment.1

Cardiovascular disease can be considered to progress via

an atherosclerotic chain of events leading from diverse,

unrelated risk factors through to end-stage heart dis-

ease.5,6 This model – the cardiovascular atherosclerotic

continuum – was first proposed over 20 years ago. More

recently, an alternative pathological chain of events – the

cardiovascular ageing continuum – has been suggested.7

The negative clinical sequelae of this newer continuum,

which originate from gradual dilation and stiffening of

the proximal aorta, affect the heart, kidneys and brain.

This newer continuum dovetails with the latter stages of

the traditional cardiovascular atherosclerotic continuum

to form the extended cardiovascular continuum

(Fig. 1).5,7 This combined model offers a more compre-

hensive view of how cardiovascular disease develops and

illustrates why BP control is particularly challenging in

hypertensive patients with cardiovascular disease.

Research has been conducted into the effect of renin–

angiotensin–aldosterone system (RAAS) inhibitors in the

cardiovascular atherosclerotic continuum.8 A recent

meta-analysis of the studies comparing RAAS inhibitors

vs. other treatments or placebo for mortality reduction

in hypertensive patients concluded that angiotensin-

converting enzyme (ACE) inhibitors are preferable to

angiotensin receptor blockers (ARBs) for reducing all-

cause and cardiovascular mortality, that is, avoiding the

progression of disease down the continuum.9

uthorized reproduction of this article is prohibited.

DOI:10.2459/JCM.0000000000000240

mailto:[email protected]

http://dx.doi.org/10.2459/JCM.0000000000000240

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JCM-D-14-00432

2 Journal of Cardiovascular Medicine 2015, Vol 00 No 00

Fig. 1

Myocardialinfarctiona

Coronarythrombosis

Myocardialischaemia

Coronary arterydisease

Coronaryatherosclerosis

Left ventricularhypertrophy

Hypertensiondyslipidaemia

diabetessmokingobesity

End-stageheart disease

Congestiveheart failure

Ventricularenlargement

Ventricularremodelling

Arrhythmiasb

muscle lossCardiovascularatherosclerotic

continuum

Cardiovascularaging

continuum

Impaired myocardialsupply/demand

Left ventricularhypertrophy

Isolated systolichypertensionc

Aortic stiffeningaortic dilation

Fracture of aorticelastic lamellae

Myocardialischaemia

Aorticaging

Stages of the extended cardiovascular continuum, derived from the cardiovascular atherosclerotic continuum and the cardiovascular ageingcontinuum: both ACE inhibitors and CCBs positively influence the most part of stages. Shaded boxes in the centre indicate stages in which the twocontinua interact. ACE, angiotensin-converting enzyme; CCB, calcium channel blocker. aAlso leading to neurohormonal activation. bAlso leading tosudden cardiac death. cAlso leading to microvascular disease, pulse-wave nephropathy and encephalopathy, and end-stage renal disease anddementia. Modified from 5,7.

Many patients require more than one antihypertensive

agent to achieve appropriate BP control. In this

context, a combination of two agents in AngloScandina-

vian Cardiac Outcomes Trial (ASCOT) – the calcium

channel blocker (CCB) amlodipine and the ACE inhibi-

tor perindopril – provided better cardioprotection in

hypertensive patients at cardiovascular risk than an older

strategy based on beta-blocker and thiazide diuretic,

despite similar BP reduction.10 Mortality was also sig-

nificantly reduced. Amlodipine with and without perin-

dopril was better than atenolol with and without

thiazide at preventing the development of resistant

hypertension.11 Like other RAAS inhibitor–CCB

combinations, fixed-dose combination perindopril–

amlodipine has been shown to be effective at reducing

the BP in patients with grade 2 hypertension or with

severe hypertension (Fig. 2).12–20 ACE inhibitor–CCB

is one of the preferred combinations by the current

European hypertension guidelines.1 The aim of this

review is to explore the ways in which combination

antihypertensive therapy with ACE inhibitors and

CCBs, in particular the ASCOT combination of amlodi-

pine with and without perindopril, reduces the cardio-

vascular risk by lowering BP and perhaps attenuating

pyright © 2015 Wolters Kluwer Health, Inc. Unau

the deleterious effects of cardiovascular disease at the

vascular level.

Pathology in the extended cardiovascularcontinuumIn the model of the cardiovascular atherosclerotic con-

tinuum, multiple risk factors – for example, hyper-

tension, dyslipidaemia, diabetes mellitus, smoking and

obesity – lead to left ventricular hypertrophy, coronary

atherosclerosis and coronary artery disease (CAD; Fig. 1).

These early changes in the clinical progression of cardio-

vascular disease are explained by pathophysiological

changes: in this case, the development of inflammation

and oxidative/mechanical stress that both lead to

decreased nitric oxide bioavailability and tissue damage.5

Increased levels of angiotensin II, in particular, promote

endothelial dysfunction, which leads to increased pro-

duction of vasoactive molecules, cytokines, growth fac-

tors and procoagulant agents, acting as promoter of

atherosclerosis and arterial stiffening.21,22

At the coronary level, this pathophysiological deterioration

is thought to culminate in tissue injury, which manifests

as myocardial infarction, arrhythmias and muscle loss.5

thorized reproduction of this article is prohibited.

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JCM-D-14-00432

Extended cardiovascular continuum Borghi et al. 3

Fig. 2

Ena/nit Per/aml Olm/aml Tel/aml Los/aml Val/aml

164

138

167

125

133

163 170 160 165

130

133

131

185183195178

135

132

144

138

134

189

0

–20

–40

–20

–40

–60

Tra/ver Per/aml Olm/aml Tel/aml Val/aml

∆ SBP in severe hypertension

∆ SBP in grade 2 hypertension

∆ S

BP

(m

mH

g)

∆ S

BP

(m

mH

g)

(b)

(a)

0

SBP reduction over 8–18 weeks, with mean initial and final bloodpressure values [in white (mmHg)], of different renin–angiotensin–aldosterone system inhibitor/calcium channel blocker combinations ingrade 2 hypertensive patients (a) and in patients with severehypertension (b).12–20 Aml, amlodipine; Ena, enalapril; Los, losartan;Nit, nitrendipine; Olm, olmesartan; Per, perindopril; Tel, telmisartan; Val,valsartan; Ver, verapamil.

Pathological remodelling in the heart follows, character-

ized by ventricular remodelling and enlargement, until

congestive heart failure, end-stage heart disease and

death. Interrupting or slowing this pathological chain

of cardiovascular events delays or stops the progression

of cardiovascular disease.5,6

Unlike the cardiovascular atherosclerotic continuum

model, the model of the cardiovascular ageing continuum

only has one initial starting point: aortic ageing (Fig. 1).

Ageing-induced fatigue of the aorta causes elastin lamel-

lae to degenerate and ultimately to fracture, leading to

the dilation of the arterial wall. In reaction to arterial wall

thinning, collagen deposition, as well as local calcium

deposition, increases; this contributes to aortic stiffening.

Risk factors, such as hyperglycaemia, participate in the

process by promoting protein cross-linking by glycation

reactions.23

Aortic stiffening increases aortic systolic pressure and

decreases aortic diastolic pressure, leading to isolated


systolic hypertension and disturbance of myocardial

oxygen requirements, which increases as the heart has

to work harder to pump blood against a higher aortic

systolic pressure, and myocardial oxygen supply decreases

because stiffening reduces aortic diastolic pressure,

duration of diastole and myocardial perfusion. The conse-

quent disruption of oxygen demand and supply causes

atherosclerosis-independent myocardial ischaemia.

Aortic stiffening also increases characteristic impedance

and early wave reflection; this means that an 80-year-old

has an aortic pulse pressure three or more times that of a

20-year-old (60–70 vs. 20 mmHg).7 The compromised

ability to cushion aortic pressure spikes results in these

spikes being transmitted to small arteries in organs with

high resting blood flow. The resulting high pulsatile

stresses (shear and tensile) in small arteries of the brain

and kidney cause thrombosis, microinfarction and micro-

rupture, which in the long term may dispose these

individuals to dementia and end-stage renal disease.

In the latter stages of cardiovascular disease, the cardio-

vascular atherosclerotic and ageing continua merge; the

interlinked continua form the extended cardiovascular

continuum (Fig. 1). Cardiac muscle loss, cardiac remo-

delling, ventricular enlargement, congestive heart failure

and end-stage heart disease are sequential final stages in

both continua. Left ventricular hypertrophy, myocardial

ischaemia and arrhythmias are also the stages found in

both component continua, but their causes in each con-

tinuum are different (Fig. 1).

Hypertension may speed up this process,24,25 and both

small and large arteries are affected: increased wall : lumen

ratio and rarefaction of small arteries lead to an increase in

mean BP; higher mean BP promotes large artery stiffness;

and increased large artery stiffness induces increased pulse

pressure, which damages small arteries and drives the

development of left ventricular hypertrophy, carotid

intima-media thickening and plaque rupture.

Cardiovascular events have been shown to be associated

with these different types of target organ damage. In this

way, cross-talk between small and large arteries amplifies

the vicious circle of arterial damage.24,25 Antihyperten-

sive treatment that acts on both small and large arteries

may not only interrupt this vicious circle, but also possibly

give rise to a ‘virtuous’ circle of pharmacological arterial

remodelling at both levels. The consequence of this dual-

level effect could be a reduction in central pulse pressure,

target organ damage and cardiovascular events.

Angiotensin-converting enzyme inhibitorsand calcium channel blockers in the extendedcardiovascular continuumAntihypertensive benefitsCombining a RAAS inhibitor with a CCB is an effective

strategy for reducing BP in hypertension (Fig. 2). It is

known to reduce hypertension more effectively than


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JCM-D-14-00432


component monotherapy.1 Current European hyperten-

sion guidelines have reaffirmed that both ACE inhibitors

and CCBs are useful options for the initiation and main-

tenance of antihypertensive treatment, either in mono-

therapy or in combination.1,26 ACE inhibitors lower BP

by preventing ACE from converting angiotensin I into

angiotensin II, a powerful vasoconstrictor, and by limiting

the degradation of the vasodilating peptide bradykinin.22

CCBs lower BP by preventing the contraction of vascular

smooth muscle in the tunica media of arteries, which

leads to passive vasodilation and their preventive effects

seems to be largely related to their ability to reduce BP.27

On the other side, a general comparison of RAAS inhibi-

tor trials with similar BP reduction in different popu-

lations shows that the effect on outcomes in these trials

varies substantially (Table 1),10,28–38 and that ACE

inhibitors may be better than ARBs at reducing the

outcomes in hypertension.9,39

Nonantihypertensive benefitsRAAS inhibitors have been found to have beneficial

effects at many stages throughout the cardiovascular

atherosclerotic continuum.8,40 They prevent angiotensin

II from playing its fundamental role in the pathogenesis

of atherosclerotic vascular disease, at both local and

systemic levels.21

ACE inhibitors have the added advantage compared with

ARBs of preventing the degradation of bradykinin, which

subsequently accumulates at the level of endothelial


Table 1 Trials with similar BP reductions, suggesting that different renineffects10,28–38

Study Inclusion Treatment

HOPE28 Cardiovascular disease/risk Ramipril vs. placeboEUROPA29 Cardiovascular disease Perindopril vs. placeboACCOMPLISH30 Hypertension /cardiovascular risk Benazepril/amlodipine vs.

benazepril/HCTZASCOT-BPLA10 Hypertension /cardiovascular risk Perindopril/amlodipine vs.

atenolol/bendroflumethiazPEACE31 Cardiovascular disease Trandolapril vs. placeboPRoFESS32 Recent stroke Telmisartan vs. placeboACTIVE 133 Stroke risk/AF Irbesartan vs. placeboTRANSCEND34 Cardiovascular risk Telmisartan vs. placeboONTARGET35 Cardiovascular risk Telmisartan/ramipril vs. ramROADMAP36 Diabetes Olmesartan vs. placebo

ORIENT37 Diabetes Olmesartan vs. placeboALTITUDE38 Diabetes Aliskiren vs. placebo

ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patien"http://www.wikidoc.org/index.php?title¼The_Atrial_Fibrillation_Clopidogrel_Trial_With_Atrial Fibrillation Clopidogrel Trial With Irbesartan For Prevention Of Vascular EventsPrevention Of Vascular Events; AF, atrial fibrillation; ALTITUDE, Aliskiren Trial in Type 2 DBPLA, Anglo-Scandinavian Cardiac Outcome Trial - Blood Pressure Lowering Arm; BPPerindopril in stable coronary Artery disease; HCTZ, hydrochlorothiazide; HOPE, HeaONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global EndpoOlmesartan reducing incidence of endstage renal disease in diabetic nephropathy triaAngiotensin-Converting_Enzyme_Inhibition_Trial&action¼edit&redlink¼1" \o "Preventioexist)"Prevention Of Events With Angiotensin-Converting Enzyme Inhibition Trial; PRoFESAvoiding_Second_Strokes&action¼edit&redlink¼1" \o "Prevention Regimen ForEffectiveAvoiding Second Strokes; ROADMAP, Randomized Olmesartan and Diabetes MicrTelmisartan_Randomised_Assessment_Study_In_Ace_Intolerant_Subjects_With_Cardioment Study In Ace Intolerant Subjects With Cardiovascular Disease (page does not eCardiovascular Disease.

cells, increasing the activity and expression of cellular

nitric oxide synthase. Nitric oxide has vasodilatory,

antiaggregatory and antiproliferative properties, and

inhibits angiotensin-II-induced smooth muscle cell

(SMC) migration.22

Angiotensin receptor blockade does not preserve brady-

kinin and provokes an important increase in angiotensin

II, which can bind to a variety of receptors.41 Therefore,

they may not offer the same degree of cardiovascular

protection as ACE inhibition.9,42–44 CCBs, by contrast,

confer cardiovascular protection in proportion to their

ability to reduce BP, having shown to significantly reduce

the need for revascularization, hospitalization for angina,

nonfatal myocardial infarction, stroke and transient

ischaemic attacks in normotensive patients with CAD.45

ComplementarityIn terms of vascular disease coverage, efficacy and side-

effect reduction, ACE inhibitors and CCBs go well

together. The therapeutic logic of combining ACE

inhibitors and CCBs was demonstrated in a meta-analysis

of 179 122 hypertensive or high-risk patients, which

showed that ACE inhibitors provide protection against

coronary heart disease and CCBs against stroke, inde-

pendently of BP reduction.46 Other studies have also

shown that the combination of these two classes could

provide well balanced vascular protection.47 ACE inhibi-

tors and CCBs exert complementary vascular effects at

many stages of the extended cardiovascular continuum,


–angiotensin–aldosterone system inhibitors have different vascular

Baseline BP(mmHg)

DBP(mmHg) Outcome

139/79 �3/�1 Less cardiovascular death, MI and stroke137/82 �5/�2 Less cardiovascular death and MI145/80 �1/�1 Less cardiovascular death, MI and stroke

ide164/95 �3/�2 Less cardiovascular death, MI and stroke

133/78 �3/�1 NS144/84 �4/�2 NS138/83 �3/�2 NS141/82 �4/�2 NS

ipril 142/82 �2/�1 More renal dysfunction136/81 �3/�2 Less microalbuminuria, more cardiovascular

death with ARB141/78 �3/�2 More cardiovascular deaths with ARB137/74 �1/�0.5 Less albuminuria, more cardiorenal events

ts Living with Systolic Hypertension; ACE, angiotensin-converting enzyme; ACTIVE,Irbesartan_For_Prevention_Of_Vascular_Events&action¼edit&redlink¼1" \o "The(page does not exist)"The Atrial Fibrillation Clopidogrel Trial With Irbesartan Foriabetes Using Cardio-Renal Endpoints; ARB, angiotensin receptor blocker; ASCOT-, blood pressure; EUROPA, EUropean trial on Reduction Of cardiac events with

rt Outcomes Prevention Evaluation; MI, myocardial infarction; NS, nonsignificant;int Trial; ORIENT, "http://www.nature.com/hr/journal/v29/n9/abs/hr200696a.html"l; PEACE, "http://www.wikidoc.org/index.php?title¼Prevention_Of_Events_With_

n Of Events With Angiotensin-Converting Enzyme Inhibition Trial (page does notS, "http://www.wikidoc.org/index.php?title¼Prevention_Regimen_For_Effectively_

ly Avoiding Second Strokes (page does not exist)"Prevention Regimen ForEffectivelyoalbuminuria Prevention; TRANSCEND, "http://www.wikidoc.org/index.php?title¼vascular_Disease&action¼edit&redlink¼1" \o "Telmisartan Randomised Assess-xist)"Telmisartan Randomised Assessment Study In Ace Intolerant Subjects With

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JCM-D-14-00432


as summarized in Table 2.27,48–59 When these effects are

combined, they result in real-life clinical benefits, as

shown by the evidence reported in Table 3 for perin-

dopril and amlodipine.10,16,29,59–65

General benefits of fixed-dose antihypertensive combi-

nations vs. free-dose equivalents include better speed of

response, BP reduction, BP control and adherence.1,66 But

ACE inhibitor–CCB combinations may also have specific

complementary advantages compared with other antihy-

pertensive combinations.10 In a meta-analysis of prospec-

tive, randomized controlled trials in hypertensive patients,

ACE inhibitors seemed to be better than ARBs at reducing

peripheral oedema in patients taking CCBs (risk reduction

0.74; 95% CI 0.64–0.84; P< 0.0001).61 This results seems

also to be magnified in the setting of real-life clinical

practice StudY of optiMized Blood pressure lowerIng

therapy with fixed cOmbination perindopril/amlodipine

(SYMBIO), carried out in 2132 patients with uncontrolled

hypertension or poor tolerance on previous ACE inhibitor

and CCB, in which the combined treatment with perin-

dopril and amlodipine is associated with a 58% reduction in

the number of patients with amlodipine-related ankle

oedema compared with baseline.62

Perindopril–amlodipine in the extendedcardiovascular continuumAntihypertensive benefitsPerindopril, whose inhibition of angiotensin II production

is responsible for its primary effect, has been shown to be


Table 2 Beneficial vascular effects of perindopril and amlodipine in th

Stage where vascular effect occurs Perindopril

Cardiovascular atherosclerotic continuumRisk factor (hypertension)48 "" Vasodilatio

# Vasoconstri" eNOS expre" Nitric oxide

Coronary atherosclerosis27,48,49 # Adhesion ofCoronary artery disease27,48 " Antiremodel

" Endothelial# Apoptosis

Coronary thrombosis27,48 # SMC prolifeMyocardial infarction27,48 # SMC growth

# SMC migrat# Matrix degra" t-PA activity# PAI-1 levels

Cardiovascular ageing continuumIsolated systolic hypertension50,56 # Central aort

# Central aort

Impaired myocardial supply/demand51,57 " Coronary re" Maximum co

Cardiovascular atherosclerotic/ageing continuaLeft ventricular hypertrophy52,58 # Left ventricuMyocardial ischaemia48,53,59 # Left ventricu

# Size of ST-sVentricular remodelling54 # Ventricular rCongestive heart failure55 # Cardiothora

eNOS, endothelial nitric oxide synthase; LDL, low-density lipoprotein; MMP, matrix metsmooth muscle cell; t-PA, tissue plasminogen activator.

effective at normalizing BP in a large range of patients.67,68

Compared with other ACE inhibitors, it has a long duration

of action,69 and its efficacy increases with uptitration.70

With ARBs, although 24-h ambulatory BP monitoring

indicates there is an increase in antihypertensive efficacy

with dose uptitration, the increase is slight.71 Perindopril

also preserves target organ perfusion.72

Different ACE inhibitors have different affinities for the

binding sites of human endothelial ACE; perindopril has

the highest selectivity for the bradykinin-binding site vs.

the ACE-binding site, which may explain why it is

effective at preventing endothelial apoptosis.73 More

lipophilic ACE inhibitors, such as perindopril and rami-

pril, also have more potent activity on tissue ACE, which

may explain the differences in atherosclerotic properties

between ACE inhibitors.69

Similarly, the CCB amlodipine is generally well tolerated

in monotherapy or combination and has been shown to be

an effective antihypertensive agent that safely lowers BP

over 24 h, particularly isolated systolic hypertension.56,74

Isolated systolic hypertension is a key stage of the

cardiovascular ageing continuum (Fig. 1). In addition

to delaying the progression of cardiovascular disease,

antihypertensive treatments that impact isolated systolic

hypertension also delay the progression of nephropathy

and dementia.7,56

Combining perindopril and amlodipine has been shown

to reduce BP more effectively than either monotherapy


e extended cardiovascular continuum27,48–59

Beneficial vascular effect

Amlodipine

n "" Vasodilationction " eNOS activationssion " NO productionproductionmonocytes # LDL oxidation

ling effect # Modified LDL aggregationfunction # MMP-1 production

ration # SMC proliferation# SMC migration

ion " t-PA activitydation

ic SBP # Central aortic SBPic PP # Central aortic PP

## SBPserve # Coronary vascular resistanceronary blood flow

lar mass index # Left ventricular mass indexlar wall motion score " Coronary flowegment change # ST-segment depressionemodellingcic ratio

alloproteinase; PAI-1, plasminogen activator inhibitor 1; PP, pulse pressure; SMC,

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JCM-D-14-00432


Table 3 Clinical benefits with perindopril and amlodipine10,16,29,59–65

Study n Population Study length Treatment Main findings with perindopril and amlodipine

DIAMOND60 2845 Uncontrolled BP onmonotherapy oruntreated hypertension

4 Weeks FDC perindopril/amlodipinea BP reduced from 159.5/99.3 to 132.7/83.2 mmHg(P<0.001); nearly three-quarters (73%) reached target BP

STRONG16 1250 Hypertension 60 Days FDC perindopril/amlodipine4/5 mg

BP fell to 41.9/23.2 mmHg from 167.4/101.4 mmHg(P<0.0001); target BP achieved by two-thirds (66.1%)

Makani et al.61 17206 Meta-analysis of hypertensionwith CCB-associatedperipheral oedema

9 Weeksb RAAS inhibitor/CCB vs. CCB RAAS inhibitor/CCB reduces the risk of CCB oedema versusCCB alone; ARBs less effective than ACE inhibitors atreducing CCB oedema

CAPE59 250 Chronic stable angina 10 Weeks Amlodipine 5/10 mg ST-segment depression reduced by 60 vs. 44% with placebo(P¼0.025); angina (P¼0.042) and nitroglycerin use(P¼0.0006) also reduced

SYMBIO62 2132 Hypertension not controlled byACE inhibitor and/or CCB

3 Months FDC perindopril/amlodipinea BP decreased from 158.5/93.6 to 132.9/80.7 mmHg(P<0.0001); almost three quarters (74%) achieved targetBP; at baseline, 15% of amlodipine-treated patients hadankle oedema; over 3 months, oedema decreased by 58%(6%; P<0.001)

PRORYV63 2249 Hypertension 3 Months FDC perindopril/amlodipinea BP fell from 168/97 to 132/80 mmHg (P<0.001); target BPreached by 80%

PEARL64 262 Hypertension 3 Months FDC perindopril/amlodipinea 24-h BP reduced from 146.1/84.3 to 127.6/75.9 mmHg(P<0.001); office BP fell from 159.8/94.3 to 131.1/80.0 mmHg (P<0.001)

EUROPA29 12218 Stable coronary heart disease 4 Years Perindopril 8 mg vs. placebo Primary endpointc reduced by 20% versus placebo(P¼0.0003); perindopril reduced nonfatal MI by 22%(P¼0.001)

EUROPA CCB65 2122 Stable coronary heart disease 4 Years Perindopril/CCB vs.placebo/CCB

Primary endpointc reduced by 35% (P<0.05); adding perindopril to CCB reduced all-cause mortality by 46%(P<0.01)

ASCOT-BPLA10 19257 High-risk hypertension with�3 risk factors

5 Years Amlodipine 5/10 mg�perindopril 4/8 mg

Cardiovascular mortality reduced by 24% versus ateno-lol�diuretic (P¼0.007); all-cause mortality reduced by11% (P¼0.0247)

ACE, angiotensin-converting enzyme; ASCOT-BPLA. Anglo-Scandinavian Cardiac Outcome Trial - Blood Pressure Lowering Arm; BP, blood pressure; CAD, coronaryartery disease; CAFE, Conduit Artery Function Evaluation; CCB, calcium channel blocker; DIAMOND, "http://www.wikidoc.org/index.php?title¼Distensibility_ Impro-vement_With_Alt-711_Remodeling_In_Diastolic_Heart_Failure_Sponsor&action¼edit&redlink¼1" \o "Distensibility Improvement With Alt-711 Remodeling In DiastolicHeart Failure Sponsor (page does not exist)"Distensibility Improvement With Alt-711 Remodeling In Diastolic Heart Failure Sponsor; EUROPA, EUropean trial onReduction Of cardiac events with Perindopril in stable coronary Artery disease; EUROPA CCB, EUropean trial on Reduction Of cardiac events with Perindopril in stablecoronary Artery disease Calcium Channel Blocker; FDC, fixed-dose combination; MI, myocardial infarction; NS, nonsignificant; PEARL, PErindopril/Amlodipine Reductionof blood pressure Level; RAAS, renin–angiotensin–aldosterone system; STRONG, SafeTy and efficacy analysis of coveRsyl amlodipine in uncOntrolled and NewlydiaGnosed hypertension; SYMBIO, StudY of optiMized Blood pressure lowerIng therapy with fixed cOmbination perindopril/amlodipine. a Perindopril/amlodipine dosagesof 5/5, 5/10, 10/5 or 10/10 mg. b Mean duration. c Cardiovascular mortality, nonfatal myocardial infarction and cardiac arrest with successful resuscitation.

on its own, which might be explained by the fact that

these two drugs have complementary mechanisms of

action.75 Table 2 shows that some mechanisms of action

are common to both molecules: for example, perindopril

and amlodipine are potent vasodilators and increase the

levels of endothelial nitric oxide synthase and nitric

oxide. In addition to its blockade of calcium channels,

amlodipine may exert an additional BP-lowering effect

through the stimulation of kinin-mediated nitric oxide

synthesis.27 In contrast to perindopril, amlodipine acti-

vates or releases kallikrein, which stimulates kinin for-

mation. Perindopril prevents the breakdown of kinins.

The clinical effects of combination antihypertensive

therapy with perindopril and amlodipine have been stu-

died in a range of trials, whose main findings have been

summarized in Table 3. These effects of perindopril and

amlodipine translated into effective BP reduction in

ASCOT,10 in which amlodipine with and without perin-

dopril reduced brachial BP in hypertensive patients at

cardiovascular risk by 27.5/17.7 mmHg over 5.5 years.

Interestingly, the brachial BP reduction with amlodipine

with and without perindopril was only partly able to


account for the greater-than-expected reduction in the

events observed compared with atenolol with and with-

out thiazide. To further investigate this phenomenon, a

number of ASCOT substudies were conducted to see

how perindopril and amlodipine influence the BP targets

other than brachial BP, such as central BP, pressure wave

reflection, 24-h BP, nighttime BP and BP variability.

They showed that perindopril and amlodipine do indeed

have an effect on these alternative BP parameters.76

In 2199 patients in the Conduit Artery Function Evalu-

ation (CAFE) study,50 there were marked differences in

central aortic SBP (4.3 mmHg; 95% CI 3.3–5.4 mmHg;

P< 0.0001) and central aortic pulse pressure (3.0 mmHg;

95% CI 2.1–3.9 mmHg; P< 0.0001) in favour of amlodi-

pine with and without perindopril, even though brachial

BP reduction was similar to that obtained with atenolol

with and without thiazide. In a wave reflection substudy

in 259 patients,77 amlodipine with and without perin-

dopril reduced wave reflection index more than atenolol

with and without thiazide (20� 11% vs. 23� 13%;

P¼ 0.02), in addition to lowering carotid SBP, a proxy

for central SBP, more effectively (127� 12 vs.


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133� 15 mmHg; P< 0.001). Nighttime SBP, an indicator

of cardiovascular outcomes and stroke, was reduced

more by amlodipine with and without perindopril (D

2.2 mmHg; 95% CI –3.4 to 0.9 mmHg) in a separate

substudy of ASCOT in 1905 patients.78 Decrease in

the nighttime BP is generally acknowledged as a better

predictor of cardiovascular events than office BP.1 How-

ever, exceptions with decreased nighttime BP do exist:

for example, in ONgoing Telmisartan Alone and in

combination with Ramipril Global Endpoint Trial

(ONTARGET), in which nighttime SBP was reduced

more by telmisartan than by ramipril (D �4.1 mmHg;

P¼ 0.011), cardiovascular protection in the telmisartan

arm was no better.79 This provides a further illustration in

the difference in cardioprotection between ACE inhibi-

tors and ARBs.39 A complementary BP variability analysis

in ASCOT showed that both short-term and long-term

BP variability were reduced with the amlodipine with

and without perindopril regimen.10,50

In real-life clinical practice, a single-pill combination of

perindopril arginine–amlodipine has confirmed the comp-

lementary modes of action of perindopril and amlodipine

by effectively further reducing BP in patients not at target

BP despite previous treatment with various classes of

antihypertensive agents (Table 3).64 A single-pill combi-

nation of perindopril–amlodipine reduced 24-h ambulat-

ory BP to 18.5/8.4 mmHg from 146.1/84.3 mmHg in

outpatients with uncontrolled essential hypertension

(�140/90 or �130/80 mmHg with high or very high cardi-

ovascular risk) after 3 months (P< 0.001), with 100% of the

daytime BP decrease maintained during the night.64

Reduction in BP with perindopril–amlodipine is rapid:

after 4 weeks, perindopril–amlodipine reduced BP to 26.8/

16.1 mmHg from 159.5/99.3 mmHg (P< 0.001) in 2845

patients with untreated hypertension (>160/100 mmHg)

or hypertension uncontrolled by monotherapy (>140/

90 mmHg).60 BP control (<140/90 mmHg) was achieved

in 2091 (73%) patients.

In the above-cited SYMBIO,62 at study inclusion,

patients receiving an ACE inhibitor (77% of patients)

and CCBs (59%), either as individual drugs or in combi-

nation, were switched to treatment with Coveram (5/5,

5/10, 10/5 or 10/10 mg). Dosages were determined at the

discretion of the treating physician and were titrated to

optimize the management of hypertension. BP decreased

from 158.5/93. to 25.5/12.9 mmHg after 3 months; in

patients with the most severe (grade 3) hypertension,

BP decreased to 45.4/20.0 mmHg. Similar results were

obtained with the fixed-dose combination in the SafeTy

and efficacy analysis of coveRsyl amlodipine in uncOn-

trolled and Newly diaGnosed hypertension (STRONG)

study, which was performed in 1250 hypertensive

patients.16 Perindopril–amlodipine has also been shown

to improve hypertension in patients with a range of

comorbidities, such as impaired kidney disease, diabetes

and hypercholesterolaemia.75


Nonantihypertensive benefitsIn the cardiovascular atherosclerotic continuum, perin-

dopril reduces apoptosis and adhesion of monocytes, has

an antiremodelling effect and improves endothelial func-

tion. Perindopril has also been shown to reduce the size of

noncalcified plaques in coronary patients.80 Amlodipine

has complementary vascular effects in coronary athero-

sclerosis and CAD, reducing low-density lipoprotein oxi-

dation, aggregation of modified low-density lipoprotein

and metalloproteinase 1 production.27 In the Prospective

Randomized Evaluation of the Vascular Effects of Norvasc

Trial (PREVENT),81 amlodipine reduced the progression

of atherosclerosis in the carotid arteries and in the pre-

specified subgroup of patients with SBP above mean.

In the NOrvasc for Regression of Manifest Atherosclerotic

Lesions by Intravascular Sonographic Evaluation

(NORMALISE) substudy of Comparison of AMlodipine

versus Enalapril to Limit Occurrences of Thrombosis

(CAMELOT),82 the change in atheroma volume

measured by intravascular ultrasound was lower with

amlodipine than with placebo. By preventing free

radical reactions spreading in the membrane of vascular

SMCs, amlodipine prevents the oxidation of low-density

lipoprotein and membrane phospholipids, which in turn

impedes the formation of foam cells, dysfunction of

endothelium and spread of inflammation.27 The positive

charge of amlodipine disrupts the formation of foam

cells by stopping altered low-density lipoprotein from

aggregating.

Coronary thrombosis and myocardial infarction are inhibi-

ted by both perindopril and amlodipine via a decrease in

SMC proliferation and migration, and increased activation

of tissue plasminogen activator.27 Perindopril also slows

SMC growth, prevents matrix degradation and lowers

plasminogen activator inhibitor 1 levels.

In the cardiovascular ageing continuum (Fig. 1), the

relative decrease in pressure wave reflection using amlo-

dipine with and without perindopril may play a role in

the prevention of isolated systolic hypertension and left

ventricular hypertrophy.7 Moreover, both perindopril and

amlodipine counteract the disruption of myocardial

oxygen supply and demand: perindopril by increasing

coronary reserve and maximum coronary blood flow,

and amlodipine by decreasing coronary vascular resist-

ance.51,57

Perindopril and amlodipine are also able to slow the

advance of cardiovascular disease. Both perindopril and

amlodipine are able to reduce left ventricular hypertro-

phy and myocardial ischaemia (Table 2). In myocardial

ischaemia, perindopril has been shown to reduce left

ventricular wall motion score and the magnitude of

ST-segment changes, whereas amlodipine improves

coronary flow and decreases the rate of ST-segment

depression.48,53,59 Perindopril has the ability to slow

the progress of severe heart disease by reducing


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JCM-D-14-00432


ventricular remodelling and the cardiothoracic ratio in

congestive heart failure.54,55

The above benefits lead to a reduction in cardiovascular

risk with perindopril or amlodipine monotherapy. In the

4-year EUropean trial on Reduction Of cardiac events with

Perindopril in stable coronary Artery disease (EUROPA)

study in 12 218 low-risk patients with no heart failure,

high-dose perindopril monotherapy reduced the com-

bined primary endpoint of cardiovascular mortality, non-

fatal myocardial infarction and resuscitated cardiac arrest

by 20% vs. placebo (P< 0.0003; Table 3).29 Monotherapy

with amlodipine also reduces cardiovascular risk in stable

CAD: in 1991 patients with normal BP (DBP

<100 mmHg) and CAD (>20% stenosis), patients on

amlodipine 10 mg once a day (n¼ 663) over 2 years had

fewer cardiovascular events compared with placebo

[n¼ 655; 16.6 vs. 23.1%; hazard ratio (HR) 0.69; 95% CI

0.54–0.88; P¼ 0.003].45 The main drivers for this were a

42% reduction in hospitalization for angina (HR 0.58; 95%

CI 0.41–0.82; P¼ 0.002) and 27% reduction in coronary

revascularization (HR 0.73; 95% CI 0.54–0.98; P¼ 0.03).

Cardiovascular risk is also reduced when perindopril is

combined with dihydropyridine CCBs. A comparison

between EUROPA stable CAD patients who received

either perindopril–CCB (n¼ 1022) or placebo–CCB

(n¼ 1100) at every visit showed that perindopril–CCB

reduced all-cause mortality by 46% (P< 0.01) and the

primary endpoint – cardiovascular mortality, nonfatal

myocardial infarction and resuscitated cardiac arrest –

by 35% (P< 0.05).29,65 The investigators concluded that

because of the common prescription of beta-blockers in

nearly half of patients, dihydropyridine CCBs – like

amlodipine or nifedipine – were the type most likely

prescribed. Of course, it has to be kept in mind that the

positive results observed with perindopril and amlodipine

derive from a post hoc analysis; therefore, the type of CCB

could not be retrieved and the frequent use of a dihydro-

pyridine was rational but not proven. Certain results from

ASCOT back these findings and suggest that amlodipine

with and without perindopril could reduce events in

hypertensive patients with additional risk factors.10 In

comparison with atenolol with and without thiazide,

amlodipine with and without perindopril reduced the total

number of cardiovascular events and procedures by 16%

(HR 0.84; 95% CI 0.78–0.90; P< 0.0001), and cardio-

vascular death, myocardial infarction and stroke by 16%

(HR 0.84; 95% CI 0.76–0.92; P¼ 0.0003).

The reduction in ASCOT of cardiovascular and all-cause

mortality with amlodipine with and without perindopril

vs. atenolol with and without thiazide diuretic provided

the impetus for combining perindopril and amlodipine in

a single pill (Table 3).10

Additional benefitsAs well as better speed of response, BP reduction,

BP control and adherence,1,66 fixed-dose perindopril–


amlodipine would have an effect in more stages of the

extended cardiovascular continuum than amlodipine

monotherapy (Fig. 2). It also offers extraprotection

against ventricular remodelling and congestive heart fail-

ure. Combination treatment is likely to be more effective

on outcomes,65 even though it acts at the same number of

stages as perindopril monotherapy. Early prescription of

perindopril and amlodipine appears important, as most of

the treatment benefits of both drugs occur in early or

middle stages of the extended cardiovascular continuum

(Fig. 2).

In summary, the early use of perindopril–amlodipine

could have important additional advantages vs. mono-

therapy in terms of antihypertensive potency, speed of

response, breadth of cardiovascular continuum coverage,

pharmacological complementarity and side-effect

reduction.7,48,75

ConclusionCombining the model of cardiovascular ageing con-

tinuum into the established model of the cardiovas-

cular atherosclerotic continuum is a novel way to

understanding cardiovascular disease. A strategy based

on a combination of ACE inhibitors and CCBs (and the

ASCOT combination of amlodipine with and without

perindopril, in particular) that targets multiple stages in

this new model, the extended cardiovascular conti-

nuum, appears to slow the pathophysiological pro-

gression of cardiovascular disease and to be clinically

effective. This strategy would not only effectively lower

BP, but also attenuate the effects of cardiovascular

disease at many stages in the extended cardiovascular

continuum.

AcknowledgementsFinancial disclosure: C.B. has received honoraria 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

this article apart from those disclosed.

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Combination therapy in the extended cardiovascular continuum

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