A Review of Its Use in Patients With or at Risk Of

7/31/2019 A Review of Its Use in Patients With or at Risk Of

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Drugs 2006; 66 (2): 235-255ADIS DRUG EVALUATION 0012-6667/06/0002-0235/$44.95/0

2006 Adis Data Information BV. All rights reserved.

PerindoprilA Review of its Use in Patients With or at Risk ofDeveloping Coronary Artery Disease

Monique P. Curran, Paul L. McCormackand Dene Simpson

Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:R. Asmar

, LInstitut CardioVasculaire, Paris, France;A.M. Grandi

, Department of Clinical Medicine,University of Insubria, Varese, Italy; U. Kaul, Fortis Hospitals, New Delhi, India;H. Purcell, Royal BromptonHospital and Harefield NHS Trust, London, England; F. Ribichini, University of Piemonte Orientales,Novara, Italy;M.L. Simoons, Erasmus Medical Center - Thoraxcenter, Rotterdam, The Netherlands.

Data Selection

Sources: Medical literature published in any language since 1980 on perindopril, identified using MEDLINE and EMBASE, supplemented

by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published

articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE and AdisBase search terms were perindopril and (coronary artery disease or coronary disease). EMBASE

search terms were perindopril and (coronary artery disease or ischemic heart disease). Searches were last updated 13 January 2006.

Selection: Studies in patients with coronary artery disease who received perindopril. Inclusion of studies was based mainly on the methods

section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant

pharmacodynamic and pharmacokinetic data are also included.Index terms: Perindopril, coronary artery disease, ACE inhibitors, cardiovascular events, pharmacodynamics, pharmacokinetics,

therapeutic use, tolerability

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2361. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2372. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

2.1 Inhibition of the Renin-Angiotensin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2382.2 Effects on Endothelial Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

2.2.1 Dilatory Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2392.2.2 PERTINENT Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

2.3 Effects on Inflammation and Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402.4 Effects on Haemodynamics and Arterial Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

2.4.1 Small Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402.4.2 Large Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412.4.3 CAFE Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

2.5 Cardiac Remodelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2423. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2424. Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

4.1 EUROPA Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

4.1.1 Outcomes in Main Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2444.1.2 Subgroup Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

4.2 PREAMI Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245


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236 Curran et al.

4.3 PROGRESS Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

4.4 ASCOT-BPLA Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2487. Place of Perindopril in the Prevention of Cardiovascular Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

SummaryPerindopril (Coversyl) is a prodrug ester of perindoprilat, an ACE inhibitor. ThisAbstractagent has shown pharmacodynamic effects beyond those responsible for lowering

blood pressure (BP), including the improvement of endothelial function and the

normalisation of vascular and cardiac structure and function.

Perindopril has a well established role in the treatment of patients with

hypertension or heart failure. In the EUROPA trial, once-daily perindopril 8mgprevented cardiovascular events in patients with stable coronary artery disease

(CAD) without any apparent heart failure receiving standard recommended ther-

apy. In the ASCOT-BPLA trial, a calcium channel antagonist perindoprilregimen demonstrated significant cardiovascular benefits compared with a con-

ventional -blocker diuretic regimen in patients with hypertension who were atrisk of developing cardiovascular events. These trials demonstrate that while

perindopril, in addition to standard recommended therapy, has a potential role in

preventing cardiovascular events in hypertensive patients, its role in the manage-

ment of patients with stable CAD is clearly established.

Perindopril is a prodrug ester of perindoprilat, an ACE inhibitor. This agentPharmacological demonstrates pharmacodynamic effects beyond those responsible for lowering BPPropertiesinvolving the improvement of endothelial dysfunction and reduction in markers of

inflammation and thrombosis. In the PERTINENT trial, perindopril significantly

increased plasma levels of bradykinin, and improved endothelial cell nitric oxide

synthetase activity. Perindopril reduced levels of angiotensin II, D-dimer and von

Willebrand factor and reduced the rate of endothelial apoptosis.

Perindopril demonstrated anti-remodelling effects in small resistance arteries,

large arteries and in the heart. Perindopril reduced the media thickness-to-lumen

diameter ratio of small arteries and reduced peripheral vascular resistance in

patients with hypertension. In small coronary arterioles, the reduction in periarter-

iolar collagen area and total interstitial collagen volume density in perindoprilrecipients was associated with a significant increase in coronary blood flow and in

coronary reserve. Long-term treatment with perindopril reduced carotid and radial

artery wall hypertrophy. In patients with end-stage renal disease, perindopril,

independent of BP changes, reduced aortic pulse wave velocity. In the heart,

perindopril significantly reduced left ventricular mass in patients with hyperten-

sion.

Following oral administration, perindopril is rapidly absorbed, with peak

plasma concentrations being reached within 1 hour. Approximately 2050% of

the perindopril absorbed is converted to the active metabolite perindoprilat. Peak

plasma concentrations of perindoprilat occur after 37 hours; protein binding of

perindoprilat is 1020%. The apparent mean half-life for the majority of per-indoprilat elimination is about 310 hours, but perindoprilat has a prolonged

2006 Adis Data Information BV. All rights reserved. Drugs 2006; 66 (2)


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Perindopril: A Review 237

terminal elimination half-life of 30120 hours, reflecting slow dissociation from

ACE binding sites. Perindoprilat is eliminated in the urine. Food intake may

reduce biotransformation of perindopril to perindoprilat.

In the randomised, double-blind EUROPA trial, 12 218 patients with stable CADTherapeutic Efficacyand without heart failure were randomised to once-daily perindopril 8mg or

placebo. After a mean follow-up of 4.2 years, a significant (p = 0.0003) relative

risk reduction (RRR) of 20% for the primary endpoint (cardiovascular death,

nonfatal myocardial infarction [MI] and resuscitated cardiac arrest) occurred with

perindopril versus placebo. This benefit was consistent in predefined subgroups

and was irrespective of treatment with other standard recommended therapy,

including platelet inhibitors, lipid-lowering agents and -blockers.In the 12-month, randomised, double-blind PREAMI trial in 1252 elderly

patients with recent MI and preserved left ventricular ejection fraction, once-daily

perindopril 8mg, compared with placebo, was associated with a significant RRRof 38% (p < 0.001) for the primary endpoint (death, hospitalisation for heart

failure and cardiac remodelling). Significantly less left ventricular remodelling

occurred in perindopril recipients than in placebo recipients (27.7% vs 51.2%,

RRR 46%; p < 0.001).

In the randomised, double-blind PROGRESS study in 6105 patients with a

previous history of stroke or transient ischaemic attack, the risk of stroke was

10% in recipients of perindopril indapamide and 14% in placebo recipients(RRR 28%; p < 0.0001) over a mean follow-up of 3.9 years. BP was reduced by 9/

4mm Hg in recipients of perindopril indapamide compared with placebo.Perindopril indapamide reduced the risk of nonfatal myocardial infarction by

38% (95% CI 14, 55) and congestive heart failure by 26% (p = 0.02).The randomised, open-label ASCOT-BPLA trial in 19 257 hypertensive

patients at moderate risk of developing cardiovascular events was terminated

prematurely (median follow-up of 5.5 years) because the risk reduction of

all-cause mortality was 11% lower in those treated with amlodipine perindoprilthan in those treated with atenolol thiazide. The RRR of 10% for the primaryendpoint (nonfatal MI and fatal CHD) in recipients of amlodipine perindoprilwas not significant; however, because of the early termination of the trial, the

study was not sufficiently powered for this endpoint.

Perindopril is generally well tolerated in patients with hypertension, heart failureTolerabilityor CAD. Generally, adverse events were mild and transient, with cough, gastroin-

testinal disturbances and asthenia/fatigue (all


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238 Curran et al.

lar disease continuum is currently being investigat-

ed. This review focuses on the efficacy and tolera-

bility of perindopril in the prevention of cardiovas-

cular events in patients with stable CAD without

heart failure, as well as in the prevention of these

events in patients with hypertension without CAD.

Acronyms of major trials are used throughout this

review (table I).

2. Pharmacodynamic Properties

The pharmacodynamic properties of perindopril

and its active metabolite, perindoprilat, are well

established (table II).

2.1 Inhibition of the

Renin-Angiotensin System

Perindopril is a prodrug ester of perindoprilat, an

ACE inhibitor that blocks the conversion of angi-

otensin I to angiotensin II.[2,3] The reduction of

angiotensin II in the plasma, leads to a reduction in

vasoconstriction and a decrease in peripheral vascu-

lar resistance. In addition, there is an associated

increase in plasma renin activity and reduced secre-

tion of aldosterone. ACE inhibitors, including per-

indopril, also disrupt the degradation of bradykinin

(a vasodilator) to an inactive heptapeptide.[2,3]

Bradykinin, possibly through its association with the

release of vasodilators (nitric oxide and pros-

taglandins), is thought to have beneficial effects on

Table I. Glossary: acronyms of clinical trials reported in this review

Acronym Definition

ALLHAT Antihypertensive and Lipid-Lowering treatment

to prevent a Heart Attack Trial

ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial-

Blood Pressure Lowering Arm

CAFEa Conduit Artery Function Evaluation

EUROPA EURopean trial On reduction of cardiac

events with Perindopril in stable coronary

Artery disease

GISSI Gruppo Italiano per lo Studio della

Sopravvivenza nellInfarto miocardico

HOPE Heart Outcomes Prevention Evaluation

INVEST INternational VErapamil-trandolapril STudy

PEACE Prevention of Events with Angiotensin

Converting Enzyme inhibitionPERFECTa PERindopril-Function in the Endothelium in

Coronary artery disease Trial

PERSPECTIVEa PERindoprilS Prospective Effect on Coronary

aTherosclerosis by angiographical and

IntraVascular ultrasound Evaluation

PERSUADEa PERindopril SUbstudy in coronary Artery

Disease and diabEtes

PERTINENTa PERindopril-Thrombosis, INflammation,

Endothelial dysfunction and Neurohormonal

activation Trial

PREAMI Perindopril Remodelling in Elderly with Acute

Myocardial Infarction

PROGRESS Perindopril pROtection aGainst REcurrent

Stroke Study

REASON pREtrax in regression of Arterial Stiffness in a

ContrOlled, double-bliNd study

TRACE TRandolapril Cardiac Evaluation

QUIET QUinapril Ischaemia Event Trial

VALUE Valsartan Antihypertensive Long-term Use

Evaluation

a Substudy of EUROPA.

vascular tone and left ventricular remodelling.[2]

tem.[2] Consequently, blockade of this system with In addition, to its high affinity for plasma ACE,

ACE inhibitors has been effective in reducing the perindopril binds to tissue (including lung, kidneyrisk of worsening angina, myocardial infarction and blood vessel) ACE.[9]

(MI), cardiac arrest, death from cardiovascular Perindopril dose-dependently decreases plasma

causes, revascularisation, stroke, diabetes mellitus ACE activity.[6,7] In patients with hypertension ad-

or renal impairment.[2] ministered a single dose of perindopril 8mg, maxi-

The efficacy and tolerability of the ACE inhibitor mum decreases in ACE activity (approximately

perindopril (Coversyl)1 in the treatment of patients 25% of predose activity) were sustained from 412

with hypertension[3] and congestive heart failure[4] hours; ACE activity was still approximately 50%

are well established. Its role in the prevention of that of the predose level at 24 hours and approxi-

cardiovascular events in the rest of the cardiovascu- mately 60% that of the predose level at 48 hours.[7]

1 The use of trade names is for identification purposes only and does not imply endorsement.



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2.2 Effects on Endothelial Dysfunction pertension (n = 168), perindopril 24 mg/day signif-

icantly improved flow-mediated dilatation (FMD) in

2.2.1 Dilatory Responses the brachial artery from baseline values (maximum

Perindopril restored normal dilatory responses in percentage increases from 5.1% to 6.4%: p < 0.01);

conduit[17] and coronary[16] arteries in patients with the change in FMD (+1.5%) was significantly dif-

hypertension. ferent (all p < 0.01) to that obtained with the other

antihypertensive agents, including nifedipine,Perindopril restored the normal flow-mediated

amlodipine, atenolol, nebivolol, telmisartan (0.5 toand cold-pressor test-induced coronary artery dilata-

+0.5).[17] All agents similarly reduced blood pres-tion in hypertensive patients with normal angiogra-

sure (BP).phy.[16]

Compared with other antihypertensive agents, In the PERFECT trial (n = 333), a substudy of the

perindopril was the only agent able to restore con- EUROPA trial in patients with stable CAD (see

duit endothelial function to normal values in a section 4.1 for study design details), mean FMD

randomised, open-label trial.[17] In patients with hy- went from 2.6% at baseline to 3.3% at 36 months in

Table II. Summary of the pharmacodynamic properties of perindopril

Effects on renin-angiotensin-aldosterone system

Dose-dependently inhibits ACE in plasma and tissues, improving the balance between angiotensin II and bradykinin[2,5-9]

Effects on blood pressure

SBP and DBP in pts with hypertension, maintaining reductions for at least 24h (reviewed by Hurst and Jarvis [3])

Effects on ischaemia

ST-segment depression and exercise-induced left ventricular systolic dysfunction in pts with CAD [10]

Effects on atherosclerosis

Anti-atherogenic effects in animal models of atherosclerosis[11,12]

Effects on inflammation, thrombosis and platelet aggregation

D-dimer levels in pts with CAD[13]

Plasminogen activator inhibitor-1 levels in hypertensive pts with diabetes mellitus[14]

Activity of ecto-ATP diphosphohydrolase and prostacycline release from human umbilical vein endothelial cells (inhibits plateletaggregation)[15]

Effects on endothelial function

Improves endothelium-dependent vasodilatation in coronary[16] and conduit[17,18] arteries in pts with hypertension[16,17] or CAD[18]

Bradykinin and nitric oxide synthetase activity in the endothelium [8,10,13,19]

Angiotensin II, tumour necrosis factor- and von Willebrand factor levels and rate of endothelial apoptosis in pts with CAD [13,19]

Effects on vascular structure and function

Large artery stiffness in pts with hypertension [20-23] or ESRF[24] and attenuated carotid wave reflections[21]

Arterial wall hypertrophy in large arteries in pts with hypertension[22,25]

Arterial wall hypertrophy in small resistance arteries in pts with hypertension [26,27]

Coronary periarteriolar fibrosis and total interstitial collagen volume density in pts with hypertension[27,28]

Effects on cardiac structure and function

Coronary reserve in pts with hypertension [16,28]

LVMI in pts with hypertension[27,29-33] or ESRF[34]

Diastolic wall and intraventricular septal thickness in pts with hypertension [29-32]

Other effects

Albuminuria in pts with hypertension and nephropathy[35]

No adverse effect on glycaemic control in pts with type 2 diabetes mellitus (reviewed by Hurst and Jarvis [3])

Does not adversely affect plasma lipid levels (reviewed by Hurst and Jarvis [3])

ATP = adenosine triphosphate; CAD = coronary artery disease; DBP = diastolic blood pressure; ESRF = end-stage renal failure; LVMI = left

ventricular mass index; SBP = systolic blood pressure; pts = patients; and indicate significant increases and decreases versus placeboor baseline.



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240 Curran et al.

the perindopril group and from 2.8% to 3.0% in the Unit) than in the 566 recipients of placebo (from 145

placebo group. The rate of change in endothelial to 135 %/Unit).[13]

function per 6 months was significant in recipients

2.3 Effects on Inflammation and Thrombosisof perindopril 8 mg/day (0.14%; p < 0.05), but not in

the placebo group (0.02%); however, the between-In the PERTINENT study, perindopril treatmentgroup difference in the rate of change in endothelial

was associated with a reduction in levels of D-dimerfunction was not significant (0.12%; p = 0.07) [data(a marker of fibrin turnover).[13] After 1 year ofpresented as an abstract].[18] Endothelial function intreatment, the change in plasma levels of this markerresponse to ischaemia (reactive hyperaemia) wasfrom baseline was significantly different (p < 0.05)assessed using brachial B-mode ultrasonography.in 148 recipients of perindopril (from 0.5 g/mL atbaseline to 0.3 g/mL) to that in the 143 recipients2.2.2 PERTINENT Trialof placebo (unchanged at 0.3 g/mL).[13]The PERTINENT trial, a substudy of the EURO-

Perindopril, but not losartan, reduced levels ofPA trial (see section 4.1), indicated that perindoprilplasminogen activator inhibitor-1 (PAI-1).[14] In a8mg once daily had a beneficial effect on markers of12-week, randomised, double-blind study in 85 hy-endothelial function in patients with stablepertensive patients with type 2 diabetes mellitus,[14]CAD.[13,19,36] Data were obtained from an ab-PAI-1 levels were significantly reduced from base-stract,[13] the EUROPA trial website[19] and a pub-line in recipients of perindopril 4 mg/day (by 10 ng/lished article of trial protocol.[36]

dL; p = 0.028), but not in losartan recipients; theAs part of the PERTINENT trial, human umbili-between-group difference was significant (p < 0.01).cal vein endothelial cells were isolated and incubat-There was no significant change in plasma fibrino-ed for 72 hours with serum from patients with CADgen levels in either treatment group.at baseline and after 1 year of treatment with either

perindopril (n = 43) or placebo (n = 44) to assess 2.4 Effects on Haemodynamics andendothelial nitric oxide synthetase (eNOS) activityArterial Structureand apoptosis; angiotensin II and bradykinin levels

in the plasma of these patients were also as-Perindopril has shown efficacy in reversing ab-

sessed.[19,36] After 1 year, plasma levels ofnormalities in structure and function of both small

bradykinin increased from baseline to a significantlyand large arteries.

greater extent (p < 0.05) with perindopril (from 14.8

2.4.1 Small Arteriesto 17.7 pg/mL) than with placebo (from 12.4 to

12.3), which in turn improved eNOS activity to a At the site of small resistance arteries, long-term

greater extent (p < 0.05) with perindopril (from 2.4 treatment with perindopril reduced arterial wall hy-

to 3.3 pmol/min/mg protein) than placebo (from 2.5 pertrophy in patients with hypertension in

to 2.9 pmol/min/mg protein). Perindopril also re- 12-month, randomised, double-blind studies (n =

duced angiotensin II levels (from 17.1 to 12.5 pg/ 25[26] and 30[27]).

mL; p < 0.05 vs placebo) and the rate of endothelial Perindopril 4 or 8 mg/day, but not atenolol, was

apoptosis (from 7.8% to 4.7%; p < 0.05 vs place- associated with a significant reduction in media

bo).[19] thickness-to-lumen diameter ratio (p < 0.05),[26,27]

The PERTINENT study also demonstrated that small artery diameter (p < 0.05)[26] and peripheral

perindopril treatment was associated with a reduc- vascular resistance (p < 0.01).[27] BP was signifi-

tion in von Willebrand factor (a marker of endotheli- cantly reduced in either treatment groups in these

al cell damage). After 1 year of treatment, plasma studies. Data from one of these studies indicated that

levels of this marker were reduced to a significantly perindopril, compared with atenolol, resulted in an

greater extent (p < 0.05) in the 591 recipients of increased coronary reserve after 1 year of treatmentperindopril (from 142 %/Unit at baseline to 128 %/ (p < 0.05).[27]



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Perindopril increased coronary blood flow and ther alone or in combination, had a favourable im-

coronary reserve in parallel with structural changes pact on all-cause mortality (RR 0.19; 95% CI 0.14,

in small coronary arterioles.[28] In a 12-month, 0.43; p = 0.0003) and cardiovascular mortality (RR

noncomparative study in 14 patients with hyperten- 0.18; 95% CI 0.06, 0.55; p = 0.003); treatment with

sion,[28] perindopril 4 or 8 mg/day significantly re- either atenolol or nitrendipine was not predictive of

duced the coronary periarteriolar collagen area by outcome. However, the researchers of this study

54% (p < 0.05) and the total interstitial collagen noted that this study was not designed to compare

volume density by 22% (p < 0.05). This was associ- the effects of different antihypertensive drugs on

ated with a reduction of minimal coronary resistance survival and, therefore, these results should be inter-

by 33% (p = 0.001), an increase in maximal corona- preted with caution.

ry blood flow (during dipyridamole-induced vasodi- In large arteries, perindopril also reduced arterial

lation) of 54% (p = 0.001) and an increase in corona- wall hypertrophy.[22,25] Nine months of treatment

ry reserve of 67% (p = 0.001). with perindopril (n = 38) was associated with a

significant (all p < 0.01) reduction from baseline in2.4.2 Large Arteries radial artery wall thickness, mass and thickness/Perindopril has been associated with a decrease radius ratio in a trial in elderly patients with hyper-

in arterial stiffness[21-24] and attenuation of wave tension.[22] Similar reductions in these parametersreflections[21] of the larger vessels. occurred in the recipients of hydrochlorothiazide

Perindopril 28 mg/day increased carotid artery plus amiloride (n = 39). SBP, DBP and PP decreaseddistensibility and compliance in 6-month (n = 41)[23] significantly in both groups. The decrease in radialand 9-month (n = 77)[22] randomised, double-blind artery thickness/radius ratio was significantly corre-studies in patients with hypertension. In the lated to the reduction in pulse pressure (p < 0.01).12-month, randomised, double-blind REASON The perindopril-associated improvements in the

study in patients with hypertension (n = 471),[21]

structural and functional properties of the commonaortic pulse wave velocity (PWV) was significantly carotid artery were BP-independent, according to(p < 0.001) reduced to a similar extent with per- data from a study in patients with essential hyperten-indopril 2 mg/day plus indapamide 0.625 mg/day sion and type 2 diabetes mellitus (presented as an(0.79 m/sec) as with atenolol 50 mg/day (0.99 m/ abstract; p values not reported).[25] In this 6-month,sec); however, only perindopril/indapamide attenu- double-blind study, responders (n = 57) to per-ated carotid wave reflections.[21] Central (carotid indopril (4 mg/day for 1 month and a reduction inand aortic) systolic blood pressure (SBP) and pulse SBP >10mm Hg) were randomised to perindopril 4pressure (PP) were reduced to a significantly greater or 8 mg/day. Carotid intima-media thickness wasextent (p < 0.001) with low-dose perindopril/in- significantly reduced with both perindopril dosages.dapamide, than with atenolol.

However, the reduction in office and ambulatory BPThe attenuation of aortic stiffness in patients with was significantly higher with perindopril 8 mg/dayend-stage renal failure treated with antihypertensive than 4 mg/day. With perindopril 8 mg/day, com-therapy was independent of BP changes in a cohort pared with 4 mg/day, carotid internal diameter, wallstudy in 150 patients with end-stage renal failure stress and elastic modulus were significantly lower,(mean follow-up 51 months).[24] Antihypertensive and distensibility was significantly higher; thesetherapy (mean 1.7 drugs) was received by 106 pa- effects were independent of BP reduction.tients; 49 patients were treated with perindopril, 56

2.4.3 CAFE Trialwith atenolol and 83 with nitrendipine. The adjusted

relative risk (RR) for a decrease in aortic PWV of The CAFE trial (n = 2073; intention-to-treat pop-

1 m/sec was 0.71 (95% CI 0.60, 0.96) for all-cause ulation) demonstrated that amlodipine perindoprilmortality and 0.79 (95% CI 0.69, 0.93) for cardio- had different effects on central aortic pressures andvascular mortality. Treatment with perindopril, ei- haemodynamics than an atenolol thiazide regi-



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242 Curran et al.

men, despite a similar impact on brachial BP (data marily in the liver (via hepatic esterase), but may

obtained from an oral presentation and abstract; also occur in the plasma and intestinal wall.[39] Ap-

details of dosages not reported).[37] In this substudy proximately 2050% of the perindopril absorbed is

of ASCOT-BPLA (see section 4.4 for study design converted to perindoprilat.[38,39] The Cmax of per-

details), radial artery applanation tonometry and indoprilat is achieved within 37 hours.[39]

pulse wave analysis were used to derive central Perindopril does not accumulate following re-aortic pressures and haemodynamic indices for up to peated once-daily administration, although per-5 years. Despite similar reductions in brachial SBP indoprilat accumulates approximately 1.5- to 2-fold,in each of the two treatment groups, central aortic reaching steady-state in approximately 36 days.[39]

SBP was lower by 4.3mm Hg (p < 0.0001) and Binding to plasma proteins by circulating per-central aortic PP was lower by 3.0mm Hg (p < indopril is approximately 60%, while that of per-0.0001) with the amlodipine perindopril than with indoprilat is only 1020%.[39] The volumes of distri-the atenolol thiazide regimen. Central pulse pres- bution for perindopril and perindoprilat were 0.22sure was a significant determinant of cardiovascular and 0.16 L/kg following a single 8mg oral dose ofevents and renal impairment (p < 0.05; adjusted for perindopril, indicating limited extravascular distri-baseline variables). bution.[3]

Animal studies indicate that perindopril distrib-2.5 Cardiac Remodelling

utes primarily to tissues with high ACE activity.[3]

Perindopril significantly reduces left ventricular The plasma half-life (t1/2) for the majority of a

mass index (LVMI) in patients with hypertension.[3] dose of perindopril is approximately 1 hour. At very

low plasma concentrations (


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Hypertension did not significantly affect the PROGRESS trial[43] in hypertensive and nonhyper-

pharmacokinetics of perindopril.[3] However, in pa- tensive patients with a history of stroke or transient

tients with chronic congestive heart failure, the ab- ischaemic attack (section 4.3), and in the ASCOT-

sorption and metabolism of perindopril was slower BPLA trial (section 4.4) in hypertensive patients at

than in healthy volunteers, while the clearance of moderate risk of developing CAD.[44]

perindoprilat was reduced (see section 6 for dosages

in these patients).[39,40]4.1 EUROPA Trial

Renal impairment has no effect on the

pharmacokinetics of perindopril, but decreased theThe EUROPA trial demonstrated that, in patientselimination of perindoprilat, such that dosage reduc-

with stable CAD without heart failure, perindopril intion is recommended in patients with renal insuffi-addition to standard therapy significantly improvesciency (section 6).[3,38,39] The dialysis clearance ofcardiovascular outcomes.[41]perindoprilat is approximately 70 mL/min.[38,39]

Data from this randomised, double-blind, mul-The AUC of a single-dose perindopril 8mg inticentre trial have been presented in published arti-patients with mild to severe hepatic cirrhosis wascles[41,45] and on the EUROPA trial website.[46] Vari-2-fold higher than that in healthy volunteers, but theous subanalyses of the EUROPA trial (including theAUC of perindoprilat was similar to that in healthyPERSUADE trial[47]) have been presented as ab-volunteers. Therefore, no dosage adjustment is re-stracts/oral presentations[42,48-50] or as a fully pub-quired in patients with hepatic impairment (sectionlished article.[47]6).[3,38]

A total of 13 655 patients were initially recruitedPerindopril, like other ACE inhibitors, may in-in the EUROPA trial.[41] After a run-in period of 4crease serum potassium levels by inhibiting aldos-weeks, during which all patients were treated withterone production. Therefore, concomitant adminis-

perindopril in addition to their normal medication,tration of perindopril with potassium-sparing diuret-12 218 patients were randomised to once-daily per-ics, potassium supplements or potassium-containingindopril 8mg (n = 6110) or placebo (n = 6108). Atsalt substitutes is not recommended.[39] ACE inhibi-randomisation, patients were taking platelet inhibi-tors, including perindopril, may increase serum lith-tors (92%), lipid-lowering agents (58%), -blockersium concentrations and increase the risk of lithium(62%), calcium channel antagonists (31%), nitratestoxicity when administered concomitantly with lith-(43%) and/or diuretics (9%).ium.[38,39]

At baseline, patients had no clinical evidence of

heart failure (10% with New York Heart Associa-4. Therapeutic Use tion [NYHA] class I, but none in class II or higher)

and had evidence of coronary heart disease, as docu-

The efficacy of perindopril in the secondary pre- mented by previous MI >3 months prior to screening

vention of cardiovascular events has been investi- (65%), percutaneous transluminal coronary angi-

gated in patients with stable CAD and no apparent oplasty (PCTA; 30%) or coronary artery bypass

heart failure enrolled in the EUROPA trial (section grafting (CABG; 29%) >6 months before screening,

4.1).[41] More specifically, the PREAMI trial (sec- or angiographic evidence of CAD (61%).[41] Men

tion 4.2) investigated the efficacy of perindopril in a were included if they had a history of chest pain and

group patients with CAD, namely elderly post-MI a positive electrocardiogram, echo or nuclear stress

patients with preserved left ventricular ejection frac- test (23%). Patients were aged >18 years (mean 60

tion (LVEF).[42] years). Hypertension (BP >160/95mm Hg or receiv-

The efficacy of perindopril as part of an an- ing antihypertensive treatment) was noted in 27% of

tihypertensive regimen in the primary prevention of patients; 85% were male and 12% had diabetes.cardiovascular events has been investigated in the Mean LVEF was 57%.[49]



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244 Curran et al.

4.1.1 Outcomes in Main Population subgroups of patients (table IV), including thoseAfter a mean follow-up of 4.2 years, the primary with previous MI (RRR 22.4%; p < 0.001), those

endpoint (cardiovascular death, nonfatal MI or re- with previous revascularisation (RRR 17.3%; p =suscitated cardiac arrest) was reached in 8.0% of 0.035), those receiving lipid-lowering agents (RRRperindopril recipients and 9.9% of placebo recipi- 16.3%; p = 0.042), those receiving -blockersents, giving a relative risk reduction (RRR) of 20% (26.4%; p-value not stated) and those receiving sta-(95% CI 9, 29; p = 0.0003) and a 1.9% absolute risk tins plus -blockers plus antiplatelet agents (RRRreduction (ARR).[41] This beneficial effect of per- 21.5%; p < 0.003).[41,45,48] The beneficial effect ofindopril was largely due to the reduction in the risk perindopril in patients with preserved LVEF (RRRof nonfatal MI (RRR 22%; p = 0.001; see table III). 22%; p < 0.001) were consistent with those in theThe effect of perindopril was noted after 1 year whole EUROPA study population (table IV).[49]

(RRR of 10%; p = 0.35) and increased gradually The treatment benefit on cardiovascular out-with continued treatment.[41] comes of perindopril treatment was consistent

Perindopril, compared with placebo, also re- among high-, intermediate- and low-risk patients.[50]

duced other secondary endpoints, although the RRR In a subanalysis, patients were categorised in tertileswas not significant for all endpoints (see table III). (approximately 4000 patients each) of modelledNotably, the RRR for hospital admission for heart risk.[50] The major risks associated with an adversefailure was significantly reduced with perindopril cardiovascular outcome included age >65 years,was 39% (p = 0.002).[41] male sex, previous MI, previous stroke or peripheral

During the run-in period when all patients were vascular disease, diabetes, smoking, angina, elevat-treated with perindopril, the BP was reduced from a ed serum cholesterol and elevated SBP. The risk wasmean 137/82mm Hg to 128/78mm Hg. The BP was lower in patients with previous revascularisationmaintained during the randomised phase of the trial, and on lipid-lowering therapy. The RRR of the

with the average BP being 5/2mm Hg higher in primary outcome (20%) with perindopril was con-placebo than in perindopril recipients.[41] sistent across the three tertiles of risk (low, interme-

diate and high).

4.1.2 Subgroup Analyses In patients with diabetes (PERSUADE sub-

The beneficial effects of perindopril on the pri- study[47]), the RRR of the primary endpoint was 19%

mary endpoint occurred in a variety of predefined with perindopril treatment. This result was statisti-

Table III. Frequency of cardiovascular outcomes in the randomised, double-blind, placebo-controlled, multicentre EUROPA trial. [41,46]

Patients (pts) with stable coronary artery disease (n = 12 218) received once-daily perindopril 8mg or placebo. Mean follow-up was 4.2

years and pts continued with their normal medication throughout the trial

Endpoint Frequency (% pts) Relative risk

perindopril 8 mg/day placebo reduction (%)(n = 6110) (n = 6108)

Cardiovascular mortality, MI or resuscitated 8.0 9.9 20**

cardiac arresta

Nonfatal MIb 4.8 6.2 22**

Fatal and nonfatal MIb 5.2 6.8 24**

Hospitalisation for heart failureb 1.0 1.7 39*

Total mortality, nonfatal MI, unstable angina, 14.8 17.1 14**

cardiac arrestb

Cardiac arrestb 0.1 0.2 46

Total mortalityb 6.1 6.9 11

a Primary endpoint.

b Selected secondary endpoint.MI = myocardial infarction; * p = 0.002, ** p 0.001 vs placebo.



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Table IV. Frequency of the primary endpointa in various subgroups in the randomised, double-blind, placebo-controlled, multicentre

EUROPA trial. Patients (pts) with stable coronary artery disease (n = 12 218) received once-daily perindopril 8mg or placebo. Mean follow-

up was 4.2 years and patients continued with their normal medication throughout the trial

Subgroup No. of pts Frequency (% pts) Relative riskperindopril 8 mg/day placebo reduction (%)

(n = 6110) (n = 6108)

Male[41,46] 10 439 8.2 10.1 19.3b

Female[41,46] 1 779 6.9 8.8 22.0b

Age 55 years[41,45,46] 3 948 6.5 8.9 27.3**

Age 5665 years[41,45,46] 4 439 6.9 8.1 14.3

Age >65 years[41,45,46] 3 831 10.7 12.9 18.2*

Previous MI[41,45,46] 7 910 8.9 11.3 22.4***

No previous MI[41,45,46] 4 299 6.4 7.3 12.1

Previous revascularisation[41,45,46] 6 709 6.6 8.0 17.3*

No previous revascularisation[41,45,46] 5 509 9.6 12.2 21.5**

Hypertension[41,45,46] 3312 9.8 12.0 18.6

No hypertension[41,45,46] 8 906 7.3 9.1 19.9**

Diabetes mellitus[41,45,47] 1 502 12.6 15.5 18.9

No diabetes mellitus[41,45,47] 10 716 7.4 9.0 19.0**

Lipid-lowering agents[41,45,46] 6 831 7.0 8.3 16.3*

No lipid-lowering agents[41,45,46] 5 387 9.3 11.9 22.3**

Calcium-channel antagonists[41] 3 955 9.9 11.7 15.8b

No calcium-channel antagonists[41] 8 263 7.1 9.0 22.2b

-blockers[41,46] 7 650 7.6 10.2 26.4b

No -blockers[41,46] 4 568 8.7 9.4 7.0b

-blockers + statins + antiplatelets[48] NA NA NA 21.5**

Preserved LVEFc[49] 9 478d 7.8 9.9 22***

a Cardiovascular mortality, MI or resuscitated cardiac arrest.

b p-Value not stated.

c LVEF 40%.

d 9 810 (80%) pts had LVEF assessment.

LVEF = left ventricular ejection fraction; MI = myocardial infarction; NA = data not available; * p < 0.05, ** p < 0.01, *** p < 0.001 vs placebo.

cally nonsignificant, but the study did not have 4.2 PREAMI Trial

sufficient power to detect a significant differenceThe PREAMI trial (data obtained from an oralbetween the treatment groups. Nevertheless, the

presentation,[42] published review of a conference[51]

RRR of the primary endpoint in patients with diabe- and a published article of trial protocol[52]) indicatedtes was of similar magnitude to that in the EUROPAthat perindopril in addition to standard medicationpatients as a whole (RRR 20%) and those without asignificantly reduces the risk of the primarydiagnosis of diabetes (RRR 19%).endpoint (death, hospitalisation for heart failure andIn a subgroup analysis of the EUROPA patientscardiac remodelling [8% increase in LV end dias-that corresponded to the PREAMI population (sec-tolic volume]) in elderly post-MI patients with pre-tion 4.2; >65 years, LVEF >40% and previous acuteserved LVEF.MI), the RRR of the primary endpoint after 3 years

In this 12-month randomised, double-blind tri-was 36% (p = 0.03).[42]

al,[42,51,52] 1252 patients aged 65 (mean 72) yearswere randomised within a mean 11 days of an acute

MI to perindopril (4 mg/day for the first month then8 mg/day; n = 631) or placebo (n = 621). Patients



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246 Curran et al.

had documented acute MI, LVEF 40% (mean 4.4 ASCOT-BPLA TrialLVEF 59%), and good apical (4 and 2 chamber)

views of the left ventricle. LV asynergy was 12.2%The ASCOT-BPLA trial investigated the long-in perindopril recipients and 12.7% in placebo recip- term effects on cardiac outcomes of a standard an-

ients. At the time of trial entry, patients were treated tihypertensive regimen (-blocker diuretic) with awith antithrombotics (98%), -blockers (71%), lip- newer regimen (calcium channel antagonist ACEid-lowering drugs (50%), nitrates (82%), calcium inhibitor) in patients with hypertension at moderatechannel antagonists (21%), ACE inhibitors (78%) risk of developing cardiovascular events.[44] In thisand/or diuretics (27%). Ventricular shape, dimen- randomised, PROBE (open-label and blindedsions and functions were assess by quantitative two- endpoint evaluation) trial, 19 257 patients with hy-dimensional echocardiography. pertension and at least three other cardiovascular

Perindopril, compared with placebo, was associ- risk factors were randomised to stepwise regimensated with a significant RRR of 38% (p < 0.001) for of amlodipine 510 mg/day adding perindopril 4 orthe combined primary endpoint.[42] The reduction in 8 mg/day as required, or atenolol 50100 mg/daythe combined primary endpoint was attributed to the adding bendroflumethiazide 1.252.5 mg/day plussignificant benefit of perindopril in cardiac remodel-

potassium as required. If adequate BP control couldling. Significantly less progressive LV remodelling

not then be achieved, patients in either treatmentoccurred with perindopril than placebo (27.7% vs

arm could also be treated with doxazosin gastroin-51.2%, RRR 46%; p < 0.001).[51] The RRR for total

testinal transport system 48 mg/day. By study end,mortality (0%) or hospitalisation for heart failure

only 15% in the amlodipine group and 9% in the(27%) were not significant.

atenolol group remained on monotherapy, 78% of

patients were taking at least two study drugs. At the4.3 PROGRESS Trial end of the trial, 79.2% of the total patients allocated

to the amlodipine perindopril arm were receivingA perindopril-based regimen was effective inamlodipine and 54.2% of the total patients allocated

lowering major cardiac events (secondary endpoint)to this arm were also receiving perindopril. Thus, of

in patients with and without hypertension with athose patients treated with amlodipine, 68.4% were

history of cerebrovascular disease in the PRO-receiving both amlodipine and perindopril. At the

GRESS trial.[43,53] In this double-blind, multicentreend of the trial, 73.9% of the total patients allocated

trial, 6105 patients were randomised to once-dailyto the atenolol bendroflumethiazide arm were

perindopril 4mg plus the diuretic indapamide asreceiving atenolol and 55.7% of the total patients

required, or placebo. Over a mean follow-up of 3.9allocated to this arm were also receiving ben-

years, major coronary events (nonfatal MI or deathdroflumethiazide (thus, of those patients receiving

from coronary heart disease [CHD]) occurred inatenolol, 75% were receiving both atenolol and ben-fewer recipients of the perindopril-based regimendroflumethiazide). Patients were aged 4779 (mean

than with placebo (3.8% vs 5.0%; RRR 26%; p =63) years and mean BP at baseline was 164/95mm0.02). In recipients of active treatment, comparedHg. The primary endpoint was the combinedwith placebo, there was a reduction in the risk ofendpoint of nonfatal MI and fatal coronary heartcongestive heart (3.7% vs 4.9%; RRR 26%; p =disease; analysis was by intention-to-treat.0.02) and MI (2.0% vs 3.1%; RRR 38%, 95% CI

Because the RRR of all-cause mortality in14%, 55%).[43,53] The risk of stroke (study powered

amlodipine perindopril recipients, compared withfor this primary endpoint) was significantly reducedatenolol bendroflumethiazide recipients, was 11%in recipients of the perindopril-based regimen com-(p = 0.0247), the trial was stopped early (medianpared with placebo (10% vs 14%; RRR 28%; p 70 years). In patients with hypertension, this start-protective effects, suggest that some of these agenting dose is titrated to gain optimum BP control. The

may have a wide impact in cardiovascularusual maintenance dose is 4 or 8mg administered

medicine.[2,60]once daily.[38,39] The maximum daily dose is 8mg

(EU)[38] or 16mg (US).[39] The starting dose in pa- Earlier trials[61-65] have demonstrated the benefits

tients with heart failure (who would also generally of ACE inhibition (captopril, enalapril, ramipril,

receive a non-potassium-sparing diuretic and/or trandolapril and zofenopril) in patients with conges-

digoxin, and/or a -blocker) is 2mg once daily, tive heart failure or LV dysfunction, with a reduc-which may be increased to 4mg once daily if tolerat- tion of cardiovascular events being evident in some

ed (EU).[38] In stable CAD patients, perindopril of these trials.[63,64] More recently, a number ofshould be initiated at the dosage of 4 mg/day for 2 studies have investigated the efficacy of ACE inhib-



15/21


itors (including quinapril, ramipril, perindopril, out stable CAD and without heart failure at high risk

trandolapril) in the prevention of cardiovascular of cardiovascular events. In the HOPE study, there

events in patients with stable CAD and normal was a 22% reduction in the composite measure of

LVEF.[41,66-68] This role was investigated, but not death from cardiovascular disease, MI and stroke

proven, in the QUIET trial,[66] in which normoten- with ramipril compared with placebo.[67] The large

sive, nonhyperlipidaemic patients were treated with EUROPA trial[41] (section 4.1) has further added to

quinapril or placebo. Because this trial enrolled low- the evidence in favour of ACE inhibitor therapy in

risk patients and there was a low event rate at trial patients with stable CAD. This study enrolled a

end, it was not sufficiently powered for the broad group of patients with stable CAD withoutendpoint. Moreover, a large proportion of the pa- heart failure, regardless of their level of cardiovas-tients discontinued the study drug early or violated cular risk. In contrast to the HOPE study,[67] thestudy protocol by receiving additional antihyperten- EUROPA trial specifically included lower risk pa-sive therapy. Similarly, the PEACE trial[68] showed tients (one third of the patients were 160/the baseline characteristics of the patients may have95mm Hg or receiving antihypertensive therapy),been involved.the reduction in BP in perindopril versus placebo

In contrast, the HOPE[67] and EUROPA[41] (sec- recipients was small (5mm Hg SBP and 2mm Hgtion 4.1) trials were both adequately powered and DBP; section 4.1), this reduction in the SBP shouldboth demonstrated a significant benefit of the ACE translate into a 10% reduction in MI, based oninhibitors ramipril and perindopril on cardiovascular previous observational data.[69,70] Given that the re-endpoints in patients with CAD. The earlier PRO- duction in nonfatal MI in the study was 20%, argua-GRESS trial[43] (n = 6105) suggested a role for the bly some mechanism other than BP reduction is theACE inhibitor perindopril in the prevention of major explanation for the effects of perindopril. The PER-coronary events in patients with cerebrovascular TINENT substudy[19] provided a possible explana-disease. Perindopril-based therapy, compared with tion for this discrepancy, namely the beneficial ef-placebo, not only reduced the risk of stroke, but also fects of perindopril on endothelium dysfunction,significantly reduced the risk of nonfatal MI and of thrombosis and inflammation (section 2). Data fromcongestive heart failure over a 4-year period (section

the PREAMI trial[42] (section 4.2) suggest that the4.3).[43]

role of perindopril in cardiac remodelling may also

contribute to its beneficial effects. Results from theThe HOPE trial[67] demonstrated that the benefitsongoing PERSPECTIVE substudy[71] may also shedof ACE inhibition included patients with and with-



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250 Curran et al.

light on the role of perindopril on the progression lines on the management of chronic stable angina

and regression of atherosclerosis in patients with recommend that ACE inhibitors are used as routine

CAD. Further studies will be required to determine secondary prevention for patients with known

whether the beneficial effects seen with high-dose CAD.[77] ACC/AHA guidelines on the management

ramipril (HOPE) or high-dose perindopril (EURO- of patients with ST-elevation MI, recommend that

PA) in patients with stable CAD are class effects of unless contraindicated, an ACE inhibitor should be

ACE inhibitors or are attributable to the specific prescribed in these patients.[78] US guidelines (Sev-

properties of these two agents.[69] Further studies enth Report of the The Joint National Committee on

may also help to clarify the importance of dosage on Prevention, Detection, Evaluation, and Treatment of

the cardiovascular effects versus the BP-lowering High Blood Pressure; JNC 7) recommend that hy-

effects of ACE inhibitors in patients with CAD. pertensive patients with a compelling cardiovascular

risk factor, such as CAD, should initiate therapySeveral trials have shown the benefits of ACE

with a hypertensive drug with proven efficacy in

inhibitors (including enalapril and captopril) follow- reducing that risk factor.[60]ing acute MI, including their ability to attenuate

ventricular remodelling.[72-75] The GISSI 3 trial[76] In Europe, perindopril has recently received an

demonstrated that an ACE inhibitor (lisinopril) was approval for the extension of its previous indication

able to attenuate remodelling after an MI in patients in hypertension and heart failure to include the re-

with large infarct (wall motion asynergy 27%). duction of risk of cardiac events in patients withData from the PREAMI trial[42] provide information stable CAD with a history of MI and/or revascu-

regarding the benefits of perindopril in a specific larisation (section 6).[59] The US FDA has also ap-

group of post-MI patients, namely elderly patients proved an extension for perindopril for the treatment

(aged >65 years) with preserved LVEF and a small of patients with stable CAD to reduce the risk of

infarct (section 4.2). The trial demonstrated the cardiovascular mortality or nonfatal MI.[39]

value of providing elderly post-MI patients, withWhile evidence supports a role for ACE inhibi-

optimum standard treatment and perindopril, nottors in the prevention of cardiovascular events in

just in the few weeks after the MI, but also for up topatients with CAD or heart failure, their role in

1 year in order to prevent cardiac remodelling. Incardiovascular prevention in the rest of the cardio-

this trial, perindopril, compared with placebo, wasvascular disease continuum is less apparent. Treat-

associated with a significant RRR for the combinedment guidelines generally agree that the goal of

primary endpoint of 38%. Given that the EUROPAtreating hypertension is to reduce cardiovascular

and HOPE trials did not demonstrate the benefit ofand renal morbidity and mortality, although the rec-

the ACE inhibitor on clinical outcomes until after 1ommended treatment strategies for achieving this

year, the shortness of the follow-up period (1 year)goal vary.[60,79-81] Current guidelines (including

may account for the lack of impact of perindopril on those of the National Institute for Health andthe clinical outcomes (death, hospitalisation for

Clinical Excellence[79] and those of the US JNCheart failure) in the PREAMI trial. However, a

7[60]) generally recommend thiazide or thiazide-likesubanalysis of the EUROPA trial corresponding to

diuretics as the first-line treatment for most patientsthe PREAMI population demonstrated a significant

with hypertension, with the addition of-blockersRRR (36%) for the primary EUROPA endpoint after

as the next step. The British Hypertension Society3 years of treatment (section 4.1).

recommends agents that act on the renin-angiotensin

Based on the outcomes of these trials, current system (ACE inhibitors or angiotensin receptor

guidelines have emphasised the importance of an blockers [ARBs]) as first-line treatment for younger,

ACE inhibitor in the management of patients with non-Black patients.[81] Current European guidelines

CAD.[60,77] The latest American College Cardiology recommend leaving the choice of agent to individual(ACC)/American Heart Association (AHA) guide- practitioners.[80] In order to reach the target BP



17/21


recommended in these guidelines, two or more an- differences in weight, heart rate, biochemical vari-

tihypertensive agents are often required. ables and BP accounted for about half of the differ-

ences in the coronary events, but a yet unidentifiableData from large studies, including the AL- variable, unrelated to BP, may explain the benefit ofLHAT,[63] INVEST[82] and VALUE[83] trials, havethe amlodipine perindopril regimen.[86] Prelimina-compared the efficacy of various antihypertensivery data from the CAFE trial[37] (a substudy of theregimens in preventing cardiovascular endpoints inASCOT-BPLA) suggests that amlodipine per-patients with hypertension. Generally, these trialsindopril provides a cardioprotective effect that ex-did not find that one type of hypertensive regimentends beyond BP reduction alone (section 2.4.3).was superior to another in the prevention of cardio-Despite a similar impact on brachial BP, amlodipinevascular events. In the VALUE trial,[83] the primary perindopril was significantly more effective thanoutcome of time to cardiac events was similar be-an atenolol thiazide regimen at lowering centraltween hypertensive patients with high cardiac risk

aortic SPB and central aortic PP. Data from thetreated with valsartan or amlodipine; however, val-sartan lowered BP to a significantly lesser extent EUROPA trial (and its various substudies) and the

than amlodipine and was associated with a signifi- preliminary data from the PREAMI study add fur-

cantly higher incidence of MI and stroke. Results of ther weight to the suggestion that the cardioprotec-a meta-analysis of >30 hypertension trials by the tive effect of perindopril is involved in the outcomeBlood Pressure Lowering Treatment Trialists Col- of the ASCOT-BPLA trial. Further trials will belaboration (BPLTTC) suggest that the size of the needed to determine whether the outcomes of theabsolute BP reduction was the most important deter- ASCOT-BPLA trial are the result of a class effect ofminant of relative reduction in cardiovascular out- ACE inhibitors, or are specifically related to thecome rather than the choice of antihypertensive characteristics of the ACE inhibitor used in thisagent.[84] The outcomes from these trials have been

study.challenged by the results of the recent ASCOT-Recent meta-analyses support the evidence inBPLA trial (section 4.4).

favour of ACE inhibitors in the primary preventionThe ASCOT-BPLA trial in hypertensive patients

of cardiovascular events.[87,88] A meta-analysis of 28at moderate risk of developing cardiovascular

trials compared the effect of ACE inhibitors or calci-events demonstrated that amlodipine perindopril

um channel antagonists with diuretics, -blockers orwas more effective than an atenolol thiazide in

placebo on CHD or stroke in 179 122 patients withreducing the incidence of cardiovascular events and

hypertension or high cardiovascular risk.[87] Thisall-cause mortality and the risk of subsequent new-

meta-analysis demonstrated that the risk of CHDonset diabetes (section 4.4). The effective BP lower-

was reduced by the use of ACE inhibitors (21%ing achieved by amlodipine perindopril in the first

reduced risk versus placebo; p < 0.001) and by BPyear of follow-up is likely to have contributed to thelowering. BP lowering and the use of calcium chan-differential cardiovascular benefits. The mean be-nel antagonists independently reduced the incidencetween-group difference in SBP and DBP recordingsof stroke. Another meta-analysis of 21 trials involv-in the amlodipine perindopril compared with theing 137 536 patients by the BPLTTC (oral presenta-atenolol thiazide regimen was 2.7/1.9mm Hg,tion)[88] concluded that ACE inhibitors reduced thewhich based on previous observational data,[85]

risk of CHD by 9% beyond BP reduction. In con-should translate into a difference in the rate oftrast, the effect of ARBs for CHD was nonsignifi-coronary events and strokes of 8% and 11%. How-cant (7%). The BPLTTC concluded that there was aever, in the ASCOT-BPLA trial, respective rateshighly significant benefit (p = 0.001) with ACEwere 16% and 23%, suggesting that the amlodipine

inhibitors compared with ARBs on MI and cardio- perindopril regimen had a benefit that extendedbeyond BP reduction. Multivariate adjustment for vascular death.[88,89]



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252 Curran et al.

2. Bertrand ME. Provision of cardiovascular protection by ACEThe tolerability of perindopril, especially in pa-inhibitors: a review of recent trials. Curr Med Res Opin 2004

tients with hypertension and heart failure, is well Oct; 20 (10): 1559-693. Hurst M, Jarvis B. Perindopril: an updated review of its use inestablished (section 5). As with other ACE inhibi-

hypertension. Drugs 2001; 61 (6): 867-96tors, the most common adverse events are cough and4. Simpson D, Noble S, Goa K. Perindopril: in congestive heart

gastrointestinal symptoms, which are generally mild failure. Drugs 2002; 62 (9): 1367-77and reversible on withdrawal of treatment. Per- 5. Zhuo JL, Froomes P, Casley D, et al. Perindopril chronically

inhibits angiotensin-converting enzyme in both the endotheli-indopril 8 mg/day was well tolerated in the EURO-um and adventitia of the internal mammary artery in patients

PA trial, with cough and hypotension causing with- with ischemic heart disease. Circulation 1997 Jul 1; 96 (1):174-82drawal from treatment in only a few patients. More-

6. Bussien JP, dAmore TF, Perret L, et al. Single and repeatedover, most patients (93%) were still on a targetdosing of the converting enzyme inhibitor perindopril to nor-

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ogen in hypertensive type 2 diabetic patients. Am J Hypertens2002 Apr; 15 (4 Pt 1): 316-20Disclosure

15. Kishi Y, Ohta S, Kasuya N, et al. Perindopril augments ecto-

ATP diphosphohydrolase activity and enhances endothelialanti-platelet function in human umbilical vein endothelialDuring the peer review process, the manufacturercells. J Hypertens 2003 Jul; 21 (7): 1347-53

of the agent under review was also offered an oppor-16. Antony I, Lerebours G, Nitenberg A. Angiotensin-converting

tunity to comment on this article; changes based on enzyme inhibition restores flow-dependent and cold pressortest-induced dilations in coronary arteries of hypertensive pa-any comments received were made on the basis oftients. Circulation 1996 Dec 15; 94 (12): 3115-22

scientific and editorial merit.17. Ghiadoni L, Magagna A, Versari D, et al. Different effect of

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