© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Contribution of perindopril to cardiology: 20 years of success
Kim Fox
Department of Cardiology, Royal Brompton & National Heart and Lung Hospital, Sydney Street, London SW3 6NP, UK
Corresponding author. Tel: +44 207 351 86 26; fax: +44 207 351 86 29. E-mail address: d.curcher{at}rbht.nhs.uk
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Abstract
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Cardiovascular risk factors such as hypertension and diabetes
are known to initiate a chain of events that include oxidative
stress, endothelial dysfunction, and vascular remodelling, and
that if left to progress unchecked, will eventually culminate
in end-stage cardiovascular disease. Perindopril is a long-acting
lipophilic inhibitor of tissue angiotensin-converting enzyme
(ACE) that has been studied in a variety of patient populations,
ranging from those with hypertension to more advanced-stage
cardiovascular disease. Although the role of ACE inhibitors
is well established for patients with hypertension or heart
failure, large morbidity–mortality trials have proved
the efficacy of perindopril in a comparatively wide range of
patients at risk of cardiovascular events, including patients
with a history of stroke or transient ischaemic attack, irrespective
of whether hypertension was present, and patients with stable
coronary artery disease without heart failure or substantial
hypertension. In addition, relative to a standard antihypertensive
regimen based on a ß-blocker/diuretic, a calcium antagonist/perindopril-based
regimen has been shown to provide more effective broad-spectrum
prevention of cardiovascular events in hypertensive patients.
Early studies revealed that, in addition to sustained 24 h antihypertensive
activity with once-daily dosing, perindopril is able to reverse
arterial remodelling in hypertensive patients. Furthermore,
subanalyses of data from morbidity–mortality trials have
shown that reversal of abnormal endothelial function and reductions
in central aortic pressure may help to account for benefits
observed with perindopril that extend beyond those expected
from reductions in brachial blood pressure alone. In summary,
although it is already a well-established antihypertensive drug,
pivotal clinical trials are still helping to unravel the true
potential of perindopril across the cardiovascular continuum.
Key Words: Cardiovascular disease continuum • ACE inhibitor • Perindopril • Hypertension • Coronary artery disease
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Introduction
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Angiotensin-converting enzyme (ACE) plays a key role in hypertension
and is induced in virtually every model of cardiac injury, and,
as a class of agents, ACE inhibitors are recognized as representing
one of the most comprehensive approaches to the treatment and
prevention of cardiovascular disease.
1,2 Among the available
ACE inhibitors, important structural and pharmacokinetic differences
exist, which may prove to have clinically significant ramifications.
3
Perindopril, discovered in the early 1980s, is one of the best studied ACE inhibitors in both preclinical and clinical settings. Originally developed for the treatment of hypertension, a number of morbidity–mortality trials have now revealed that perindopril benefits patients with a wide range of cardiovascular conditions, from hypertension, which is an important cardiovascular risk factor, right through to the end stages of cardiovascular disease (Figure 1). In this article, we document the history of perindopril from development to the present day.
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Figure 1 Clinical trials investigating the effects of perindopril on morbidity/mortality have provided evidence of benefits obtained along the cardiovascular disease continuum. Modified from Dzau et al. Circulation 2006;114:2850–2870.
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Perindopril development studies
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Perindopril is a third-generation ACE inhibitor that was created
with the aim of providing all the benefits of ACE inhibition,
including cardiovascular protection beyond blood pressure (BP)-lowering
alone, together with excellent tolerability (low incidence of
cough and absence of first-dose hypotension), and true 24 h
efficacy with once-daily dosing.
4
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Vascular and cardiac remodelling studies
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In hypertension, vascular remodelling of the arteries may have
adverse effects on end organs such as the brain, heart, and
kidney. In addition to effectively reducing BP, treatment strategies
should, therefore, help to normalize vascular structure. Accordingly,
a substantial component of the perindopril development process
has been devoted to studying the effects of the drug on cardiovascular
remodelling and revealing the ability of the drug to reverse
abnormalities in the structure and function of small and large
arteries.
When administered for 3 months, perindopril significantly improved the diameter and compliance of the brachial artery in patients with sustained essential hypertension.5 Furthermore, despite similar reductions in BP, distensibility of the common carotid artery was significantly enhanced by perindopril, but not changed by the diuretic combination amiloride + hydrochlorothiazide, in a 6-month trial of hypertensive patients.6 Indeed, perindopril dose-dependently improved carotid distensibility independent of brachial BP reduction in a 7-month trial of hypertensive patients with diabetes.7
At the site of small resistance arteries, long-term treatment with perindopril resulted in normalization of increased media-to-lumen ratios in hypertensive patients.8,9 When perindopril was compared with atenolol, both drugs significantly reduced BP, but only perindopril led to normalization of small artery morphology.9 A reduction in the left ventricular (LV) mass has been seen to occur in parallel with normalization of resistance artery structure in hypertensive patients treated with perindopril.8
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Studies of antihypertensive efficacy
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Use of long-acting formulations that provide 24 h antihypertensive
effect should ideally be used in the treatment of hypertension.
A common indicator of sustained BP control is provided by the
trough:peak BP ratio. Myers
10 reported that the ratio of changes
in placebo-corrected diastolic BP at 24 h vs. 6 h after dosing
with perindopril 2–8 mg ranged between 0.97 and 1.0. Perindopril
compares favourably with other ACE inhibitors in this regard.
11,12
Perindopril has been established as an effective and well-tolerated antihypertensive agent.13–15 Indeed, in a large community-based clinical trial, monotherapy with perindopril 4–8 mg/day was associated with a clinically and statistically significant reduction in BP of –19.7/10.5 mmHg in the overall population and –14.9/8.4 mmHg in hypertensive patients who were non-responsive to previous antihypertensive therapy.13,14 Previous antihypertensive agents used in non-responsive patients included ACE inhibitors, diuretics, calcium channel blockers, ß-blockers, angiotensin receptor blockers, and 
-blockers. The authors of the study suggested that a number of factors may have contributed to this antihypertensive effect of perindopril in this group of otherwise non-responsive patients, including the relatively consistent 24 h antihypertensive efficacy of perindopril and unique effects of the drug on arterial compliance, as described earlier. Compared with other antihypertensive agents, including calcium channel blockers, angiotensin receptor antagonists and ß-blockers, in a relatively recent study, perindopril was the only agent to normalize brachial artery endothelial function in hypertensive patients.16 It is therefore possible that the antihypertensive efficacy of perindopril in patients non-responsive to other agents may, in part, be a result of perindopril-induced improvements in endothelium-dependent vasodilation in peripheral conduit arteries.
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First morbidity–mortality data
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The beneficial effects of perindopril on mortality were first
demonstrated in a study of patients with end-stage renal failure
(ESRF).
17 In this study, 150 ESRF patients were randomized to
receive perindopril 4–8 mg/day every 48 h or nitrendipine
10–20 mg/day. If target BP was not achieved, atenolol
10–20 mg/day was also prescribed. Over a mean 51 months
of follow-up, use of perindopril, either alone or in combination,
had a favourable impact on all-cause and cardiovascular mortality
[relative risk reduction (RRR) 81 and 82%, respectively;
P <
0.005] that was independent of changes in BP. LV hypertrophy
was an independent predictor of mortality in this patient population.
Prior to publication of this study, it was reported that perindopril,
but not nitrendipine, induced a pressure-independent decrease
of LV hypertrophy in ESRF patients that was associated with
reduction of LV diameter and cavity volume.
18
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Pivotal morbidity–mortality trials
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In general, ACE inhibitors have been extensively studied in
patients with hypertension, heart failure (HF), or impaired
LV function after myocardial infarction (MI). Pivotal studies
involving perindopril have, however, involved a wide range of
patients, including patients without hypertension and patients
without apparent LV dysfunction. Acronyms of major studies,
and substudies thereof, discussed in this review are explained
in
Table 1.
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PROGRESS
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Although the value of antihypertensive therapy is unequivocal
with regard to the primary prevention of stroke, the PROGRESS
study was conducted in an effort to resolve clinical uncertainty
regarding the utility of perindopril-based therapy in patients
who had previously experienced a stroke or transient ischaemic
attack.
19 Patients (
n = 6105) who were randomized to active
treatment (perindopril 4 mg/day + indapamide 2.5 mg/day when
needed) or placebo were required to have no definite indication
for treatment with an ACE inhibitor, and there were no BP entry
criteria. It was recommended that patients with uncontrolled
hypertension received antihypertensive therapy with agents other
than ACE inhibitors prior to the study. The effects of therapy
on cardiovascular outcomes are illustrated in
Figure 2. Over the mean 3.9 year follow-up period, active treatment significantly
reduced the risk of the primary outcome (28% reduction in the
relative risk of stroke vs. placebo;
P < 0.0001). This included
a 50% reduction in haemorrhagic stroke and a 24% reduction in
ischaemic stroke. Active treatment also reduced the risk of
major cardiovascular events (non-fatal MI or death from cardiovascular
disease) by 26%, and the risk of non-fatal MI was reduced by
38%. With regard to the risk of stroke and major cardiovascular
events, benefits associated with perindopril-based therapy were
similar in hypertensive (mean baseline BP 159/94 mmHg) and non-hypertensive
patients (mean baseline BP 136/79 mmHg). There were only small
differences in BP reductions observed for patients classified
as hypertensive or non-hypertensive at baseline (–9.5/3.9
and –8.8/4.2 mmHg, respectively).
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Figure 2 Effects of perindopril-based treatment on stroke subtypes and major vascular events in patients with history of stroke or transient ischaemic attack participating in the PROGRESS study.19 Black squares indicate point estimates, with area proportional to number of events; horizontal lines, 95% confidence intervals; diamonds, point estimates and 95% confidence intervals for overall effect; vertical dashed line, point estimate for overall effect. MI, myocardial infarction. Adapted from Lancet 2001;358:1033–1041 (Figure 4 on p. 1037).
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EUROPA
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Prior to the EUROPA study, clinical trials had established the
efficacy of ACE inhibitors in the reduction of morbidity and
mortality among patients with hypertension, HF, or LV dysfunction
after MI. The EUROPA study was designed to assess whether the
protective effects of ACE inhibition would extend to a relatively
low risk general population of patients with stable coronary
artery disease (CAD) without HF or substantial hypertension.
20 In addition to the fact that it is a long-acting ACE inhibitor
with high lipophilicity, which may facilitate relatively high
penetration into the atherosclerotic plaque where it may counter
the deleterious effects of angiotensin II, improve endothelial
function, and hinder the development of atherosclerosis and
thrombosis,
2 perindopril was chosen as the ACE inhibitor for
the EUROPA trial because of its documented effects on reducing
cardiovascular remodelling.
20
During the EUROPA study, 12 218 patients with stable CAD without clinical evidence of HF or uncontrolled hypertension (>180/100 mmHg) were randomized to perindopril 8 mg/day or placebo for 
3 years.20 After a mean follow-up of 4.2 years, the relative risk of the primary endpoint (cardiovascular mortality, non-fatal MI, or resuscitated cardiac arrest) was reduced by 20% with perindopril vs. placebo (P = 0.0003) (Table 2). The beneficial effect of perindopril on the primary endpoint was consistent across predefined subgroups, regardless of age, whether patients had hypertension, diabetes, or previous MI, and in patients receiving lipid-lowering drugs or ß-blockers (Figure 3). Most of the EUROPA study population was receiving antiplatelet therapy. Post hoc analysis of the EUROPA study data showed that the treatment effect associated with perindopril was constant in patients with high- (>3%), medium- (1–3%), and low- (1%) level cardiovascular risk per year.21 It has been noted that the 22% reduction in the risk of MI cannot be explained by the –5/2 mmHg reduction in BP alone, thereby suggesting that a mechanism other than BP reduction was contributing to improved outcome with perindopril.2,20 In relation to the magnitude of the reduction in BP associated with perindopril, it should be borne in mind that baseline BP levels in EUROPA were 137/82 mmHg, that half of the population was normotensive (BP < 140/80 mmHg), that hypertensive patients were already receiving treatment with non-ACE inhibitor antihypertensive agents, and that hypotension was cited as a reason for withdrawal in only 1.0% of patients.20 Most of EUROPA patients (58%) had measurements of LV ejection fraction (LVEF) before randomization. The mean LVEF of this population was 57.0 ± 10.4%, and only 3% had an impaired LV function, confirming that EUROPA patients did not have asymptomatic LV dysfunction. In patients with preserved LV function (LVEF 40%), there was a significant RRR of 16% of the primary endpoint.22 In a subgroup of EUROPA patients with a previous revascularization (54.9%), perindopril reduced relative risk of the primary endpoint by 17.3% (P = 0.036) and risk of MI by 23% (P = 0.015). Of note, in the subpopulation of revascularized patients without a history of MI, perindopril was associated with an RRR of 31.7% for fatal and non-fatal MI (P = 0.026).23
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Table 2 Effects of perindopril on cardiovascular outcomes in patients with stable coronary artery disease participating in the EUROPA study20
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Figure 3 Effects of perindopril on cardiovascular outcomes in subgroups of patients with stable coronary artery disease participating in the EUROPA study.20 Black squares indicate point estimates, with area proportional to number of events; horizontal lines, 95% confidence intervals; vertical dashed line, point estimate for overall effect. MI, myocardial infarction. Adapted from Lancet 2003;362:782–788 (Figure 3 on p. 785).
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The European Medicines Agency and the US Food and Drug Administration
have, after the publication of the EUROPA results, extended
perindopril’s indication to include secondary prevention
in CAD patients.
24 Notably, results from the EUROPA trial have
also contributed to the recent European Society of Cardiology
recommendation that ACE inhibitor therapy be instigated in all
patients with CAD and hypertension, diabetes, previous MI, or
LV dysfunction, as well as patients with HF.
25
Insights into perindopril’s mode of action
Experimental studies comparing different ACE inhibitors have demonstrated that certain properties of perindopril may contribute to the therapeutic efficacy observed with the drug in trials such as EUROPA. Being lipophilic, perindopril compares very favourably among ACE inhibitors in terms of tissue penetration, which is a factor consistently shown to be correlated with anti-atherosclerotic effects.4 Potentiation of bradykinin, which counteracts the harmful effects of angiotensin II and contributes to the longer term anti-ischaemic effects of ACE inhibitors, is also particularly pronounced for perindopril.4
The PERTINENT26 substudy of EUROPA20 is offering important new insights into mechanisms that could have contributed to the beneficial effects of perindopril on mortality and morbidity in patients with stable CAD. Results demonstrating that after 1 year of treatment, improvements in endothelial function occurred in patients receiving perindopril, have been published.27 Analysis of blood drawn from more than 1000 EUROPA participants revealed that perindopril independently and significantly reduced levels of von Willebrand factor (P < 0.001 vs. placebo), a procoagulant product of the endothelium and marker of endothelial damage, high levels of which were associated with cardiovascular events at baseline (P = 0.013). Endothelial function was also investigated more directly, at the cellular level, by cultivating human umbilical vein endothelial cells with serum taken from 87 EUROPA patients, revealing a 27% upregulation of endothelial nitric oxide synthase activity—which plays a pivotal role in the maintenance of endothelial function—after 1 year of treatment with perindopril, as well as a 31% reduction in the rate of apoptosis (Table 3). Levels of tumour necrosis factor-, an inducer of apoptosis and negative modulator of endothelial nitric oxide synthase, were reduced by 13% from baseline during treatment with perindopril. Perindopril also helped to restore the balance between angiotensin II (27% reduction; P < 0.05) and bradykinin (17% increase; P < 0.05) (Table 3). The only significant correlation was between bradykinin and endothelial nitric oxide synthase activity (r = 0.43; P < 0.05), indicating that the bradykinin pathway is instrumental in facilitating perindopril-induced improvements in endothelial function.
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Table 3 Effects of perindopril on markers of endothelial function in patients with stable coronary artery disease assessed as part of the PERTINENT26 substudy of EUROPA20
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ASCOT-BPLA
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In order to reach target BP, it is agreed that two or more antihypertensive
agents will be required in most patients, but the issue of as
to which antihypertensive agents should be used in first-line
treatment is controversial. The ASCOT-BPLA trial was the first
to investigate whether a modern antihypertensive treatment regimen
based on amlodipine and perindopril could provide further benefits
in terms of reducing cardiovascular events beyond those provided
by standard therapy with atenolol and a thiazide diuretic in
hypertensive patients.
28 A total of 19 257 patients with untreated
or poorly controlled hypertension (BP > 160/100 mmHg or >140/90
mmHg, respectively) and at least three other cardiovascular
risk factors were randomized to amlodipine 5–10 mg/day,
adding perindopril 4–8 mg/day as needed, or atenolol 50–100
mg/day, adding bendroflumethiazide 1.25–2.5 mg/day and
potassium as needed. After 5.5 years, median follow-up, the
study was stopped prematurely because, compared with patients
treated with atenolol/bendroflumethiazide, all-cause mortality
was reduced by 11% in the amlodipine/perindopril group (
P <
0.05) (
Table 4). At the end of the study, most patients
were taking at least two study drugs (78%). The primary endpoint
(non-fatal MI, including silent MI, and fatal coronary heart
disease) was lowered by 10% with amlodipine/perindopril (
Table 4),
but, as a result of loss of power due to early trial termination,
statistical significance was not attained. There were, however,
significant reductions across a range of other endpoints, including
total coronary events, total cardiovascular events and procedures,
cardiovascular mortality, fatal and non-fatal stroke, development
of diabetes, and development of renal impairment, in the amlodipine/perindopril
treatment arm (
Table 4).
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Table 4 Effects of an amlodipine/perindopril-based antihypertensive treatment regimen vs. an atenolol/bendroflumethiazide-based regimen on cardiovascular outcomes in hypertensive patients participating in the ASCOT-BPLA study28
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The CAFE substudy of 2199 patients from the ASCOT-BPLA trial
demonstrated that, despite similar effects on brachial systolic
BP in the two treatment groups, central aortic systolic BP was
4.3 mmHg lower and central aortic pulse pressure was 3.0 mmHg
lower in the amlodipine/perindopril treatment group compared
with the atenolol/thiazide group (
P < 0.0001 for both differences).
29 Central pulse pressure was significantly associated with a composite
outcome of total cardiovascular events/procedures and development
of renal impairment. An analysis of the factors contributing
to differential clinical outcomes in ASCOT-BPLA concluded that
conventional risk factors and differences in brachial BP may
not fully account for the better cardiovascular outcomes observed
in the amlodipine/perindopril arm of the study.
30 An accompanying
editorial speculated that part of the advantage of the new drugs
might be due to a reduction in pulse pressure of the central
arteries.
31 The results of the CAFE study lend credence to this
theory.
In the light of the significance of the ASCOT-BPLA findings, the National Institute for Health and Clinical Excellence together with the British Hypertension Society has published a revision to the official treatment recommendations for the pharmacological management of patients with hypertension.32 The revised guidelines recommend an ACE inhibitor as first-line therapy for antihypertensive patients aged < 55 years. If initial therapy was with a calcium channel blocker or a thiazide diuretic and a second drug is required, the guidelines recommend adding an ACE inhibitor.
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PREAMI and PEP-CHF
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The recently published PREAMI
33 and PEP-CHF
34 studies have helped
to fill in gaps in the knowledge regarding the potential benefits
of ACE inhibitors in specific groups of post-MI and HF patients.
There is a wealth of data showing that ACE inhibitors reduce
morbidity and mortality in patients with LV dysfunction after
MI, but the PREAMI study has demonstrated that progressive LV
remodelling can occur in elderly post-MI patients with preserved
LV systolic function, and that it is possible to prevent such
remodelling with perindopril 8 mg/day. Most randomized controlled
trials of ACE inhibitors in patients with HF have focused on
patients with LV systolic dysfunction, however the PEP-CHF study
has shown that, although prognosis associated with LV diastolic
dysfunction may be more benign than that associated with systolic
dysfunction, elderly patients with LV diastolic dysfunction
may benefit from treatment with perindopril.
PREAMI
In total, 1252 patients aged 65 years with LVEF 40% and recent acute MI were randomized to perindopril (8 mg/day) or placebo for 12 months. Compared with placebo, perindopril provided a 38% RRR (P < 0.001) in the composite primary endpoint of death, hospitalization for HF, or LV remodelling (defined as a 8% increase in LV end-diastolic volume). This reduction in the primary endpoint was attributed to the significant benefit of perindopril on LV remodelling, which occurred in 27.7% of perindopril vs. 51.2% of placebo recipients (P < 0.001). The effect of perindopril on remodelling occurred despite widespread use of ß-blockers.
PEP-CHF
In the PEP-CHF study, 850 patients 70 years and treated with diuretics for a clinical diagnosis of chronic HF due to LV diastolic dysfunction, excluding substantial LV systolic dysfunction, were randomized to perindopril 4 mg/day or placebo. The event rate was much lower than expected, which substantially reduced the power of the study to show a difference in the primary endpoint, which was neutral (composite of all-cause mortality or unplanned HF-related hospitalization with a minimum follow-up of 1 year). Nevertheless, perindopril had a strong tendency to reduce the primary endpoint during the first year of follow-up (RRR 31%; P = 0.055), and a significant reduction in the hospitalization for HF was reported (RRR 37%; P = 0.033). This was also the case for cardiovascular death or unplanned HF-related hospitalization (RRR 38%; P = 0.018). In addition, patients assigned to perindopril had a greater 6 min corridor walk distance (P = 0.011) and improved New York Heart Association (NYHA) classification (P < 0.03) relative to placebo recipients.
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Tolerability
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Perindopril is generally a well-tolerated ACE inhibitor. As
with all ACE inhibitors, the side effect most commonly reported
with perindopril is a dry cough, believed to be, at least partly,
mediated by bradykinin. In large practice-based studies involving
patients with hypertension, cough occurred in 8–9% of
patients, leading to withdrawal in 3–4%.
14,15 Safety data
from the PROGRESS and EUROPA studies reported similar low withdrawal
rates associated with cough in patients receiving perindopril
(2.2 and 2.7%, respectively).
19,20 During the PROGRESS and EUROPA
studies, only 2.1 and 1.0% of patients, respectively, withdrew
from treatment because of hypotension.
19,20
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Ongoing research and development
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Although the presence of diabetes portends a worse clinical
outcome in patients with established cardiovascular disease,
further analysis of the PROGRESS and EUROPA data has found that
reductions in the relative risk of the primary study endpoints
obtained with perindopril-based therapy were maintained in diabetic
patients.
35,36 Because the cardiovascular event rate in diabetic
patients is higher than the general CAD population, any relative
reduction in events will translate into a greater absolute reduction.
On the basis of the PROGRESS data, for example, it was calculated
that, in order to avoid one stroke, 16 patients (95% CI 9–111)
with diabetes would need to be treated for 5 years compared
with 34 patients (95% CI 21–83) without diabetes. Following
on from these substudies, ADVANCE is an ongoing study specifically
aiming to determine the effects of perindopril plus the glucose-friendly
diuretic indapamide vs. placebo (BP control arm) and intensive
vs. standard glucose control (glucose control arm) on morbidity/mortality
primary endpoints among patients with diabetes.
37 The first
primary endpoint is the macrovascular composite of non-fatal
stroke, non-fatal MI, or cardiovascular death. In line with
previous studies in which perindopril has been observed to protect
progression of diabetic nephropathy and retinopathy,
38–40 ADVANCE’s second primary endpoint is the microvascular
composite of new or worsening nephropathy, or retinopathy. The
ADVANCE trial design is illustrated in
Figure 4. Perindopril
and indapamide were chosen as the most appropriate ACE inhibitor
and diuretic for ADVANCE because they are drugs with excellent
efficacy and safety profiles that bring with them all the advantages
of combining an ACE inhibitor and a glucose-friendly diuretic.
41
The currently available
tert-butylamine salt of perindopril
has a shelf life of about 2 years in countries with a temperate
climate and requires special packaging in countries with high
temperatures and relative humidity.
42 In order to improve the
overall stability and shelf life of the product, a new arginine
salt of perindopril has recently been developed. At doses of
5–10 mg, perindopril arginine is bioequivalent to perindopril
tert-butylamine 4–8 mg, but is 50% more stable and has
a shelf life of 3 years.
42
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Conclusion
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Compared with other inhibitors of the renin–angiotensin
system, perindopril has the richest evidence to support its
use along the cardiovascular disease continuum, not only in
patients with uncomplicated hypertension, but also in patients
with established CAD or previous stroke, whether they have hypertension
even in the absence of clinical HF, as evidenced in the EUROPA
and PROGRESS studies. In addition, the ASCOT-BPLA trial has
provided evidence of the need for evolution of traditional prescribing
practices to include first-line ACE inhibition as standard practice
in hypertensive patients. It is not yet certain whether improved
outcomes observed in conjunction with perindopril in large morbidity/mortality
studies are related to a class effect of ACE inhibitors or specifically
related to specific properties of perindopril, a long-acting,
lipophilic inhibitor of tissue ACE,
per se. Worldwide recognition
and use of perindopril in clinical practice is evidence of the
success of the perindopril clinical development programme over
the past 20 years.
Conflict of interest: Professor Fox has received research grants and honoraria from Servier.
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References
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|---|
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension (2003) 42:1206–1252.[Abstract/Free Full Text]
- White HD. Should all patients with coronary disease receive angiotensin-converting-enzyme inhibitors? Lancet (2003) 352:755–757.[CrossRef]
- Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation (1998) 97:1411–1420.[Abstract/Free Full Text]
- Ferrari R, Pasanisi G, Notarstefano P, Campo G, Gardini E, Ceconi C. Specific properties and effect of perindopril in controlling the rennin–angiotensin system. Am J Hypertens (2005) 18:142S–154S.[Web of Science][Medline]
- Asmar RG, Journo HJ, Lacolley PJ, Santoni JP, Billaud E, Levy BI, Safar ME. Treatment for one year with perindopril: effect on cardiac mass and arterial compliance in essential hypertension. J Hypertens Suppl (1988) 6:S33–S39.[Medline]
- Kool MJ, Lustermans FA, Breed JG, Struyker Boudier HA, Hoeks AP, Reneman RS, Van Bortel LM. The influence of perindopril and the diuretic combination amiloride+hydrochlorothiazide on the vessel wall properties of large arteries in hypertensive patients. J Hypertens (1995) 13:839–848.[Web of Science][Medline]
- Tropeano AI, Boutouyrie P, Pannier B, Joannides R, Balkestein E, Katsahian S, Laloux B, Thuillez C, Struijker-Boudier H, Laurent S. Brachial pressure-independent reduction in carotid stiffness after long-term angiotensin-converting enzyme inhibition in diabetic hypertensives. Hypertension (2006) 48:80–86.[Abstract/Free Full Text]
- Sihm I, Schroeder AP, Aalkjaer C, Holm M, Morn B, Mulvany M, Thygesen K, Lederballe O. Normalization of structural cardiovascular changes during antihypertensive treatment with a regimen based on the ACE inhibitor perindopril. Blood Press (1995) 4:241–248.[Medline]
- Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany MJ. Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension (1995) 25:474–481.[Abstract/Free Full Text]
- Myers MG. A dose–response study of perindopril in hypertension: effects on blood pressure 6 and 24 h after dosing. Perindopril Multicentre Dose–Response Study Group. Can J Cardiol (1996) 12:1191–1196.[Web of Science][Medline]
- Morgan TO, Morgan O, Anderson A. Effect of dose on trough peak ratio of antihypertensive drugs in elderly hypertensive males. Clin Exp Pharmacol Physiol (1995) 22:778–780.[CrossRef][Web of Science][Medline]
- Ferrari R. Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril. Expert Rev Cardiovasc Ther (2005) 3:15–29.[CrossRef][Medline]
- Guo W, Turlapaty P, Shen Y, Dong V, Batchelor A, Barlow D, Lagast H. Clinical experience with perindopril in patients nonresponsive to previous antihypertensive therapy: a large US community trial. Am J Ther (2004) 11:199–205.[CrossRef][Medline]
- Julius S, Cohn JN, Neutel J, Weber M, Turlapaty P, Shen Y, Dong V, Batchelor A, Lagast H. Antihypertensive utility of perindopril in a large, general practice-based clinical trial. J Clin Hypertens (Greenwich) (2004) 6:10–17.[CrossRef][Medline]
- Poggi L, Renucci JF, Denolle T. Treatment of essential hypertension in general practice: an open-label study of 47,351 French hypertensive patients treated for one year with perindopril. Can J Cardiol (1994) 10(Suppl. D):21D–24D.[Medline]
- Ghiadoni L, Magagna A, Versari D, Kardasz I, Huang Y, Taddei S, Salvetti A. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension (2003) 41:1281–1286.[Abstract/Free Full Text]
- Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation (2001) 103:987–992.[Abstract/Free Full Text]
- London GM, Pannier B, Guerin AP, Marchais SJ, Safar ME, Cuche JL. Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease. Comparative effects of ACE inhibition and calcium channel blockade. Circulation (1994) 90:2786–2796.[Abstract/Free Full Text]
- PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet (2001) 358:1033–1041.[CrossRef][Web of Science][Medline]
- Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet (2003) 362:782–788.[CrossRef][Web of Science][Medline]
- Deckers JW, Goedhart DM, Boersma E, Briggs A, Bertrand M, Ferrari R, Remme WJ, Fox K, Simoons ML. Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk. Eur Heart J (2006) 27:796–801.[Abstract/Free Full Text]
- Bertrand ME, Remme WJ, Fox KM, Ferrari R, Simoons ML. Effects of perindopril on long-term clinical outcome of patients with coronary artery disease and preserved left ventricular function. Int J Cardiol (2007) in press.
- Fox KM, Bertrand ME, Remme WJ, Ferrari R, Simoons ML, Deckers JW, on behalf of the EUROPA Investigators. Efficacy of perindopril in reducing risk of cardiac events in patients with revascularized coronary artery disease. Am Heart J (2007) 153:629–635.[CrossRef][Web of Science][Medline]
- Fox K, Ferrari R, Yusuf S, Borer JS. Should angiotensin-converting enzyme-inhibitors be used to improve outcome in patients with coronary artery disease and ‘preserved’ left ventricular function? Eur Heart J (2006) 27:2154–2157.[Abstract/Free Full Text]
- Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, Daly C, De Backer G, Hjemdahl P, Lopez-Sendon J, Marco J, Morais J, Pepper J, Sechtem U, Simoons M, Thygesen K, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo J, Zamorano JL. Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology; ESC Committee for Practice Guidelines (CPG). Guidelines on the management of stable angina pectoris: executive summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J (2006) 27:1341–1381.[Free Full Text]
- Scientific Committee of the PERTINENT Sub-Study, EUROPA-PERTINENT Investigators. PERTINENT—perindopril-thrombosis, inflammation, endothelial dysfunction and neurohormonal activation trial: a sub-study of the EUROPA study. Cardiovasc Drugs Ther (2003) 17:83–91.[CrossRef][Web of Science][Medline]
- Ceconi C, Fox KM, Remme WJ, Simoons ML, Bertrand M, Parrinello G, Kluft C, Blann A, Cokkinos D, Ferrari R. EUROPA Investigators; PERTINENT Investigators and the Statistical Committee. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res (2007) 73:237–246.[Abstract/Free Full Text]
- Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J. ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet (2005) 366:895–906.[CrossRef][Web of Science][Medline]
- Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O'Rourke M, CAFE Investigators. Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation (2006) 113:1213–1225.[Abstract/Free Full Text]
- Poulter NR, Wedel H, Dahlof B, Sever PS, Beevers DG, Caulfield M, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J, Pocock S. ASCOT Investigators. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet (2005) 366:907–913.[CrossRef][Web of Science][Medline]
- Staessen JA, Birkenhager WH. Evidence that new antihypertensives are superior to older drugs. Lancet (2005) 366:869–871.[CrossRef][Web of Science][Medline]
- National Institute for Health and Clinical Excellence (NICE). Hypertension: management of hypertension in adults in primary care (partial update).
- Ferrari R. Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) Study. Arch Intern Med (2006) 166:659–666.[Abstract/Free Full Text]
- Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J (2006) 27:2338–2345.[Abstract/Free Full Text]
- Berthet K, Neal BC, Chalmers JP, MacMahon SW, Bousser MG, Colman SA, Woodward M, Perindopril Protection Against Recurrent Stroke Study Collaborative Group. Reductions in the risks of recurrent stroke in patients with and without diabetes: the PROGRESS Trial. Blood Press (2004) 13:7–13.[CrossRef][Web of Science][Medline]
- Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J (2005) 26:1369–1378.[Abstract/Free Full Text]
- Rationale and design of the ADVANCE study: a randomised trial of blood pressure lowering and intensive glucose control in high-risk individuals with type 2 diabetes mellitus. Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation. J Hypertens Suppl (2001) 19:S21–S28.[CrossRef][Medline]
- Cordonnier DJ, Pinel N, Barro C, Maynard M, Zaoui P, Halimi S, Hurault de Ligny B, Reznic Y, Simon D, Bilous RW. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group. J Am Soc Nephrol (1999) 10:1253–1263.[Abstract/Free Full Text]
- Jerums G, Allen TJ, Campbell DJ, Cooper ME, Gilbert RE, Hammond JJ, O'Brien RC, Raffaele J, Tsalamandris C, Melbourne Diabetic Nephropathy Study Group. Long-term renoprotection by perindopril or nifedipine in non-hypertensive patients with type 2 diabetes and microalbuminuria. Diabet Med (2004) 21:1192–1199.[CrossRef][Web of Science][Medline]
- Patel V, Rassam SM, Chen HC, Jones M, Kohner EM. Effect of angiotensin-converting enzyme inhibition with perindopril and beta-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects. Metabolism (1998) 47(Suppl. 1):28–33.[CrossRef][Web of Science][Medline]
- Chalmers J, Perkovic V, Joshi R, Patel A. ADVANCE: breaking new ground in type 2 diabetes. J Hypertens Suppl (2006) 24:S22–S28.[Medline]
- Telejko E. Perindopril–arginine: benefits of a new salt of the ACE inhibitor perindopril. Curr Med Res Opin (2007) 23:953–960.[CrossRef][Medline]
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M. Tendera
Introduction
Eur. Heart J. Suppl.,
September 1, 2007;
9(suppl_E):
E1 - E1.
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Abstract
Introduction