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C L I N I C A L F E AT U R E S
Not All Angiotensin-Converting Enzyme Inhibitors
Are Equal: Focus on Ramipril and Perindopril
DOI:
James J. DiNicolantonio,
PharmD 1,4
Carl J. Lavie, MD 2,3
James H. O’Keefe, MD 4
Wegmans Pharmacy, Ithaca, NY; 2John
Ochsner Heart and Vascular Institute,
Ochsner Clinical School/University of
Queensland School of Medicine, New
Orleans, LA; 3Pennington Biomedical
Research Center, Baton Rouge, LA;
4
Mid America Heart Institute at
Saint Luke’s Hospital, University of
Missouri–Kansas City, Kansas City, MO
1
Abstract: Angiotensin-converting enzyme (ACE) inhibitors are a heterogeneous class,
varying in pharmacologic properties, which have different therapeutic impacts on patient
bradykinin availability. Among the ACE inhibitor class, the agent perindopril, in particular, has
pleiotropic effects that are not equally shared by other ACE inhibitors, including bradykinin
site selectivity and subsequent enhancement of nitric oxide and inhibition of endothelial cell
apoptosis. Moreover, there is a large amount of evidence to suggest that perindopril therapy
may reduce cardiovascular event rates in patients, yet perindopril is rarely prescribed in the
impressive outcomes data. Our review compares the pharmacologic and trial data among perindopril, ramipril, and other ACE inhibitors. In patients with or at high risk for coronary heart
disease who do not have heart failure, or in patients with heart failure with preserved ejection
fraction, perindopril should be among the preferred treatment agents in the ACE inhibitor class.
Ramipril has an impressive track record of improving cardiovascular outcomes, too, and should
be considered a preferred agent among the ACE inhibitor class.
Keywords: angiotensin-converting enzyme inhibitor; bradykinin; heart failure; cardiovascular
disease; ramipril; perindopril
Introduction
Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality rates in patients with systolic heart failure (HF) and in those who
have recently experienced an acute myocardial infarction (AMI). Additionally, ACE
inhibitors are effective agents for treating patients with hypertension, and current data
suggest that they are more effective therapeutic agents for reducing rates of morbidity
and mortality due to cardiovascular (CV) events compared with the use of angiotensin
receptor blockers.1,2 Thus, ACE inhibitors should be prescribed frequently, as there
mortality rates.1,2 However, not all ACE inhibitors appear to be equally effective for
improving patient CV outcomes.
Pharmacokinetic/Pharmacodynamic Data
The ACE inhibitors, as a drug class, differ considerably in their clinical properties from
Correspondence: James J. DiNicolantonio,
PharmD,
500 South Meadow St.,
Ithaca, NY 14850.
Tel: 607-277-5750
Fax: 607-277-5890
E-mail: jjdinicol@gmail.com
ramipril and perindopril, appear to have superior therapeutic qualities compared with
most other currently available ACE inhibitors. Perindopril has been shown to have a
longer duration of therapeutic action and thus offers full 24-hour blood pressure (BP)
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DiNicolantonio et al
and local inhibition of the renin-angiotensin-aldosterone
system in tissues such as the heart, brain, kidneys, adrenal
glands, and blood vessels, as well as a greater selectivity for
bradykinin binding sites compared with other ACE inhibitors (Table 1; Figure 1, 2). Moreover, unlike enalapril, no
titration is needed with perindopril treatment to provide the
patient with maximal antihypertensive effect.9 Additionally,
enalapril,9,10 which can lead to underperfusion of target organs
and subsequent negative consequences.10 When initiating a
patient on ACE inhibitor therapy, perindopril seems to be
the safer choice compared to enalapril, especially in patients
relying on hemodynamics to maintain tissue perfusion, such
as patients who have HF. The lower risk for hypotension with
perindopril versus enalapril in patients with HF may also be
clinically relevant in those who are at risk for hypotension,
such as individuals who have experienced an AMI, those in
circulatory failure or shock, those with chronic kidney disease, or in patients with a propensity for orthostasis/presyncope/syncope (ie,dehydration, Parkinson’s disease, chronic
diabetes, those on low-sodium diets, carbohydrate-restricted
diets, or those taking medications that can precipitate orthostasis).10 However, further trials are required in these patient
populations testing perindopril versus other ACE-inhibitors
to know for certain.
Treatment with perindopril has been shown to more
strongly inhibit endothelial cell apoptosis compared with most
other ACE inhibitors (enalapril, quinapril, and trandolapril;
P ! 0.001), vs ramipril (P =
difference in favor of perindopril) (Figure 3).11 Treatment
Table 1. Advantages of Perindopril Therapy Compared With
Other ACE Inhibitors
3,4
Greater tissue and plasma ACE inhibition3–6
Longer duration of action. Perindopril provides complete 24-hour
blood pressure control. Enalapril should be dosed twice daily, whereas
perindopril only needs to be dosed once daily.6
No titration needed to achieve maximum effective dose7
Despite greater selectivity for bradykinin binding sites compared with
other ACE inhibitors, perindopril has a very low rate of discontinuation
due to ACE inhibitor–induced cough (∼2% in EUROPA and
PROGRESS)8,21,22
9,10
10
Greater inhibition of endothelial cell apoptosis compared with other
ACE inhibitors11
III compared with enalapril12
Associated with lower mortality rates in patients with acute myocardial
infarction compared with other ACE inhibitors13
more than trandolapril, quinapril, ramipril, and enalapril; P ! 0.05
vs trandolapril and ramipril; P ! 0.02 vs enalapril, respectively)14
Better reduction in resistin levels in patients with stable coronary artery
disease compared with enalapril17
effects compared with enalapril18
Brain ACE inhibition, which was not shown with quinapril56
Abbreviations: ACE, angiotensin-converting enzyme; EUROPA, European Trial on
Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease;
PROGRESS, Perindopril Protection Against Recurrent Stroke Study.
with trandolapril and quinapril vs baseline; P ! 0.001 with
perindopril and ramipril vs baseline) (Figure 4, 5).14 An
to improve myocardial tolerance to reperfusion injury15 and
transforming growth factor and collagen III compared with
enalapril therapy.12 Treatment with perindopril or ramipril
have been associated with a lower incidence of mortality
in patients with AMI compared with other ACE inhibitor
therapies (eg, enalapril, fosinopril, captopril, quinapril, and
lisinopril).13
expression in the aorta seen with perindopril treatment
(P ! 0.001) compared with other ACE inhibitor therapies
(P =
P ! 0.05 vs ramipril; P ! 0.01 vs
quinapril; P !
in the aorta (P =
P ! 0.05 vs trandolapril and
ramipril; P !
expression in cardiac myocytes (P ! 0.05 with enalapril and
quinapril vs baseline; P ! 0.01 with ramipril vs baseline;
P ! 0.001 with perindopril and trandolapril vs baseline); and
P ! 0.05 with enalapril vs baseline; P ! 0.01
2
β
pic responses, thus providing a cardioprotective effect against
excess catecholamine stimulation.16 Moreover, compared
with enalapril treatment, perindopril therapy produces
greater reductions in resistin levels in patients with stable
coronary heart disease (CHD)17
(decreased C-reactive protein), anti-atherosclerotic (reduced
monocyte chemo-attractant protein-1), antioxidant (lowered
oxidized low-density lipoprotein), antithrombotic (lowered
activator inhibitor-1) effects (Table 1). Pleiotropic effects
were shown to occur in normotensive patients with stable
CHD, and were not related to reductions in BP (either from
baseline or compared with BP changes seen in patients treated
with enalapril). In summary, treatment with perindopril
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DiNicolantonio_proof2
ACE Inhibitor Advantage: Focus on Ramipril and Perindopril
Figure 1.
with treatment with other ACE inhibitors.
The greater
pleiotropic effects of perindopril therapy may be due to
bradykinin sites on angiotensin converting enzyme compared
with other ACE inhibitor therapy.
to occur by several distinct mechanisms, which include
improved patient bradykinin availability (vasodilation,
effect, increased anti-remodeling effect, preservation of
endothelial function, anti-adhesion of monocytes (anti-
5
atherosclerotic effect), and inhibiting the conversion of
angiotensin I to angiotensin II (thereby reducing vasoconstriction, hypertrophy, adhesion of monocytes, plasminogen
activator inhibitor-1 and thrombogenesis, free radical oxygen
production, and endothelial dysfunction) (Figure 6). However, inhibition of angiotensin II receives more attention
than improvement in bradykinin availability as the primary
mechanism of action of ACE inhibitors. Despite this, the
angiotensin I, suggesting that the ACE pathway primarily
functions to degrade bradykinin. To inhibit both angiotensin
I conversion to angiotensin II and inhibit the degradation of
C-terminals) is required.19 However, angiotensin I can be
Figure 2. Relative selectivity of tested ACEIs for bradykinin vs angiotensin I binding sites. P ! 0.001 by ANOVA for repeated measures; **P ! 0.001 vs ramiprilat, quinaprilat,
trandolaprilat, and enalaprilat; *P ! 0.01 vs enalaprilat8
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DiNicolantonio et al
domains, whereas bradykinin inactivation requires the activity
of both terminal sites.19 Moreover, ACE inhibitors generally
angiotensin I, which suggests that ACE inhibitors function
primarily to inhibit bradykinin degradation and secondarily
inhibit the production of angiotensin II. This is further supported by the fact that patient angiotensin II levels generally
return to baseline, or are greater than baseline, after prolonged
ACE inhibitor use, as angiotensin II can be formed through
other non-ACE pathways (eg, cathepsin, tonin).5
The selectivity for bradykinin sites of the ACE inhibitors,
in descending order, is perindopril (P ! 0.001 vs the latter
4 named ACE inhibitors), ramipril (P ! 0.01 vs enalapril),
quinapril, trandolapril, and enalapril. Perindopril has the
greater selectivity for bradykinin sites on ACE (ratio, 1.44),
whereas enalapril has the poorest selectivity (ratio, 1.00);
binding sites compared with enalapril. Thus, compared to 4
other ACE inhibitors, perindopril has the greatest selectivity
for bradykinin sites on ACE.
Bradykinin has been shown to exert potent anti-apoptotic
actions on both the endothelium and cardiac myocytes, which
could account for the greater anti-apoptotic actions of perindopril treatment compared with use of other ACE inhibitors.11
dykinin levels (+
P ! 0.05 vs placebo) and a reduction
in angiotensin II levels (−
P ! 0.05 vs placebo).20 The
increase in bradykinin with perindopril therapy most likely
P ! 0.05) increase in protein expresP!
activity, as the addition of a bradykinin B2 receptor antagonist
P ! 0.05) and
P ! 0.05).20
in the rate of apoptosis (P ! 0.05), which was, in part, mediated by the activation of the bradykinin B2 receptors, as the
apoptosis rate was increased with the addition of a bradykinin
B2 receptor antagonist (P !
decrease in von Willebrand factor was seen in patients after 1
year of treatment with perindopril (P ! 0.001).20
Although increases in patient bradykinin levels with ACE
inhibitor treatment have generally been thought to cause the
the low rates of cough (∼
in the European Trial on Reduction of Cardiac Events With
Perindopril in Stable Coronary Artery Disease (EUROPA)
and the Perindopril Protection Against Recurrent Stroke
Study (PROGRESS), challenge the theory. A " 2-fold higher
incidence of cough seen in patients undergoing enalapril
dykinin sites vs the 4 other ACE inhibitors) compared with
Figure 3. Rate of apoptosis in rats treated for 7 days with ACEI or vehicle only (control) expressed as the percentage of annexin V-positive rat aortic endothelial cells following
lipopolysaccharide-induced apoptosis. *P ! 0.001 vs control.11,57
4
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DiNicolantonio_proof2
ACE Inhibitor Advantage: Focus on Ramipril and Perindopril
Figure 4. Endothelial nitric oxide synthase (eNOS) protein expression (A) and activity (B) in the descending aorta of rats treated with different ACEIs. (**) P ! 0.001 vs
vehicle, (°) P ! 0.001, (*)P ! 0.01 and (ˆ)P ! 0.05 each ACEI vs others. In each group of treatment, 5 animals were employed.14
study that used a de-challenge and re-challenge method
(a strict criteria to attribute cough not yet used in previous
reports), as well as cough incidences seen with enalapril
in a retrospective study of 1113 patients with arterial hypertension, highlight the need for more research into other
increased bradykinin availability.
therapy restored patient bradykinin levels to those seen
explain the low rates of cough seen in subjects taking perindopril in multiple clinical trials (ie, increased bradykinin
cough). The inhibition of bradykinin degradation seems
cardioprotection (although more research is required), and
CV endpoints and account for the low incidence of cough
in patients undergoing perindopril therapy.
A large meta-analysis of randomized placebo-controlled
trials echoed the data, with the included trials indicating
that for patients with or at risk for atherosclerotic vascular disease with a systolic BP (SBP) ! 130 mm Hg, ACE
inhibitor therapy provided a substantial and sustained
mary outcome of CV mortality, nonfatal AMI, or nonfatal
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Figure 5. eNOS synthase (eNOS) protein expression (A) and activity (B) in isolated cardiac myocytes from rats treated with different ACEIs. (**) P ! 0.001, (*) P ! 0.01,
(ˆ) P ! 0.05 vs vehicle. In each group of treatment, 5 animals were employed.14
25
In clinical practice, many physicians tend to think of ACE
inhibitors as antihypertensive medications, and, if a patient
has an SBP ! 140 mm Hg (and certainly if ! 130 mm
Hg), the patient is presumed to be “at goal,” and treatment
with an ACE inhibitor would generally not be prescribed.
However, even in patients with an SBP ! 130 mm Hg,
from the prescription of an ACE inhibitor, which may be
related to ACE-inhibitor effects on lowering the throm(especially in patients treated with perindopril compared
with enalapril).
Despite ACE inhibitors having been prescribed for decades,
there is still uncertainty as to the precise mechanism(s) under-
6
produce a reduction in patient serum ACE levels? Tissue
ACE levels? Endothelial ACE levels? Does treatment with
an ACE inhibitor produce an increase in patient bradykinin
levels? At which point is the mechanism of action exerted? At
the prodrug or drug stage (ie, perindoprilat vs perindopril)?
Angiotensin-converting enzyme is present in many body tissues (eg, heart, brain, kidneys, adrenal glands, blood vessels)
and is, for the most part, a tissue-based enzyme, with !
of ACE found in plasma.26 The ability of ACE inhibitors to
bind to tissue ACE seems to be clinically relevant, especially
in patients with acute coronary syndromes, in whom ACE
activity in the coronary vessels is 5-times higher than that
seen in the serum.27
activity has been shown in several patient models of cardiac
injury, including volume overload, the hypertrophied heart,
HF, AMI, and post-AMI remodeling, where elevated wall
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DiNicolantonio_proof2
ACE Inhibitor Advantage: Focus on Ramipril and Perindopril
Figure 6. The effects of angiotensin II inhibition and improvement in bradykinin availability.8
stretch and subsequent sarcolemmal stretching are believed
to be crucial factors for increased patient cardiac ACE activity
(Figure 7).
In the injured heart, recruited fibroblasts and macrophages also carry high ACE activity,26,30,31 with tissue ACE
amassing in human atherosclerotic plaque, preferentially
(Figure 7).
Localized ACE activity within atherosclerotic plaque may contribute to the progression of advanced
coronary lesions and subsequent atherothrombotic events.
The anti-atherosclerotic effects of the ACE inhibitors have
26,32
prostacyclin (through increased bradykinin availability and
inhibition of angiotensin II formation), leading to subsequent
decreased migration and proliferation of vascular smooth
and activation, decreased oxidative stress, and improved
endothelial function.5,33
Bradykinin B2 receptor antagonists have been shown
; thus, ACE inhibitors may preferentially
work through the inhibition of bradykinin degradation. This
premise is supported by the fact that perindopril therapy
increases patient bradykinin levels at dosages that are
lower than those required to reduce angiotensin II levels.34
Perindopril treatment has shown the greatest reductions in
15
other ACE inhibitors,14
-
levels.15 Additionally, bradykinin levels have been related
to the endothelial-dependent vasodilation seen in patients
taking quinapril.35 Considering that treatment with perindopril has shown consistent pleiotropic effects (that are not
equally produced by treatment with other ACE inhibitors),
and consistent reductions in rates of patient morbidity and
mortality in multiple trials, it may be that a high selectivity
binding, are at the cornerstone of ACE inhibitor therapeutic
In summary, not all ACE inhibitors are equal; of the
-
matory, antioxidant, anti-atherosclerotic, antithrombotic,
Perindopril therapy has consistently been shown to have the
when compared with other ACE-inhibitor treatment.
The pleiotropic properties of perindopril may translate
into improved clinical, hemodynamic, and CV endpoint
reductions for patients compared with other ACE inhibitor
therapy. In fact, there is a plethora of evidence showing that
treatment with perindopril results in reductions in CV event
rates. In a 4-year follow-up of 29 463 patients, a perindopril-
P=
P=
P !
P=
P = 0.015).36 Results were consistent among all subgroups.
The authors concluded that there was strong evidence to
indicate that a perindopril-based regimen improved survival
and reduced major CV event rates across a broad spectrum of
patients with vascular disease. Other ACE inhibitors cannot
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Figure 7. Myocardial tissue ACE.26
Trandolapril
as those of perindopril.
In the PEACE trial, treatment of patients with trandolapril
Patients With or at High Risk
of CHD
Perindopril and Ramipril
(AMI, or coronary revascularization in patients with stable
CHD without a history of HF or LV systolic dysfunction).39
Perindopril, in the EUROPA study, and ramipril, in the Heart
Outcomes Prevention Evaluation (HOPE) trial, are the only
ACE inhibitors that have data showing their therapeutic
association with the prevention of CV events and lower CV
mortality rates in patients with or at high risk for CHD, who
have normal left ventricular (LV) function.21,37 Additionally,
treatment with ramipril in a randomized placebo-controlled
trial of 2000 patients, post-AMI, with HF, reduced the all-cause
P = 0.002) and the adverse CV event
37
P=
In patients with or at high risk for
CHD, the only evidence-based preventive ACE inhibitor therapeutic agents are perindopril and ramipril.21,37 Unfortunately,
many clinicians prescribe other ACE inhibitors (eg, lisinopril,
enalapril, or benazepril) in this setting. However, the belief in a
“class effect” is not supported by randomized controlled trials
using ACE inhibitor treatments. For example, use of trandolapril in the Prevention of Events With Angiotensin-Converting
Enzyme Inhibition (PEACE) trial, and quinapril in the Quinapril Ischemic Event Trial (QUIET) did not show reductions
in the primary outcome, whereas ramipril and perindopril, used
8
as being caused by the high use of optimal medical therapy.
However, in the EUROPA, HOPE, and PEACE trials, rates
of use of antiplatelet agents, statins, and β-blockers were
Thus, the background
medical therapy was similar between EUROPA and PEACE,
whereas HOPE had lower percentages of all 3 background
21,37,39
clinical CV practice in treating patients. Perindopril is the
only ACE inhibitor that was powered to show therapeutic
reductions in CV endpoints in patients with or at high risk
for CHD (in patients without HF) on optimal background
medical therapy.21,37
Additionally, Dagenais et al41
group analysis evaluating patients on lipid-lowering agents,
β-blockers, and antiplatelet drugs (alone or in combination).
Therefore, even patients on optimal background medical
Dagenais et al41 also conducted a subgroup analysis of lowrisk patients in the HOPE and EUROPA trials, who also
showed large reductions in the composite endpoint of CV
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DiNicolantonio_proof2
ACE Inhibitor Advantage: Focus on Ramipril and Perindopril
Figure 8. Primary outcomes from the four major ACEI trials.38
mortality, nonfatal AMI, or stroke, when patients were treated
with either perindopril or ramipril therapy.41 The high percentage of patients on optimal medical background therapy
and/or the low-risk patient populations in the PEACE trial do
not explain the therapeutic failure of trandolapril to prevent
or reduce patient vascular events, as opposed to the success
with perindopril and ramipril treatment in similar trials.
While a head-to-head comparison trial is required to
determine with certainty the inferiority of trandolapril treatment and other ACE inhibitor therapy compared with perindopril and ramipril, a class effect should not be assumed to
be true. For example, in the cases of pioglitazone compared
with rosiglitazone, or hydrochlorothiazide compared with
chlorthalidone, therapeutic agents within the same class
have been shown to have markedly different clinical and CV
effects. Considering that no trial data exist for trandolapril
treatment demonstrating a reduction in CV endpoints in
patients with or at risk for CHD (without HF), we believe
that trandolapril should not be prescribed preferentially over
ramipril or perindopril. If we are to practice evidence-based
medicine, ramipril or perindopril should be the preferred ACE
inhibitor for treating this high-risk patient population.21,37,39
Quinapril
The QUIET study was a randomized, blinded, multicenter,
36-month trial (mean duration of follow-up, 27 months) that
compared treatment with quinapril 20 mg with placebo in
1750 patients with CHD without systolic LV dysfunction.40
There was no difference in rates of ischemic events between
patients taking quinapril therapy compared with those
P = 0.60), or in the incidence of patients who experienced
angiographic progression of coronary disease (P = 0.71).
The rates of CV mortality, overall mortality, and nonfatal
AMI were similar between patients treated with quinapril
P=
Furthermore, the development of new coronary lesions was
similar in incidence for both patient groups (P = 0.35). However, treatment with quinapril did reduce patient incidence
of angioplasty for new (previously un-intervened) vessels
(P =
of coronary atherosclerosis. However, the study authors did
note that the absence of a demonstrable effect with quinapril
therapy may have been due to several limitations in study
design, including: 1) the QUIET study would have needed
potentially underpowered to show a reduction in major CV
endpoints; 2) the subjectivity in the decision to proceed with
management increased the number of non-major outcomes,
which may have masked detection of the effect of quinapril
therapy on major CV outcomes; and 3) the dose of quinapril
may have been low (20 mg) compared with 40 mg daily,
endothelial reactivity in the Trial on Reversing Endothelial
42
Despite these limitations, there was
less reduction in patient BP with perindopril treatment in the
EUROPA trial and ramipril therapy in the HOPE study compared with quinapril use in QUIET and trandolapril therapy
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Table 2. Comparing Patient Population Characteristics of the
HOPE, EUROPA, and PEACE Trials21,37,39
Parameter
HOPE
N = 9,297
EUROPA
N = 12,218
PEACE
N = 8,290
Age, y, mean
Diabetes, %
Prior CABG surgery/PCI, %
SBP/DBP, mm Hg, mean
Prior MI, %
On antiplatelet therapy, %
On β-blocker therapy, %
On statin therapy, %
66
38
40
139/79
53
76
40
29
60
12
55
137/82
65
92
62
58
64
17
72
133/78
55
90
60
70
Abbreviations: CABG, coronary artery bypass graft; EUROPA, European Trial on
Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease;
HOPE, Heart Outcomes Prevention Evaluation; MI, myocardial infarction; PEACE,
Prevention of Events with Angiotensin Converting Enzyme Inhibition; PCI, percutaneous
coronary intervention.
in the PEACE study (Figure 9). Suggesting that quinapril’s
being too low is unlikely, despite the fact that there are no
reports, to our knowledge, comparing rates of central BP
P = 0.16). However, there was
ment compared with placebo, which just missed statistical
P = 0.11).43
There are a few explanations that may explain the results
of the CAMELOT trial. For example, the placebo group was
actually treated with ACE inhibitors and calcium channel
43
; thus, active
therapy drop-ins into the placebo group could have muted
is not fully apparent when these patient drop-ins occurred or
whether they were clinically meaningful (ie, if most occurred
late in the trial, it may not have caused a clinically meaningful effect); however, this limitation should not be overlooked
nor over-interpreted. Another possible explanation for the
placebo could be due to a higher rate of patients discontinuing
3-year follow-up in QUIET may have been too short a time
reaching a maximum target dose in the enalapril group
duration of 5 years, requiring 1 to 2 years of treatment with
ramipril before the AMI/stroke/death Kaplan-Meier curves
began to separate compared with placebo.37
The Comparison of Amlodipine Versus Enalapril to
Limit Occurrences of Thrombosis (CAMELOT) study was
a randomized, double-blind, multicenter, 24-month trial that
compared amlodipine or enalapril with placebo in approximately 2000 patients with angiographically documented
CHD ("
stolic BP ! 100 mm Hg (Table 3).43 Patients were randomized
to receive amlodipine 10 mg, enalapril 20 mg, or placebo.
Compared with placebo, amlodipine therapy reduced nonfatal
43
Although enalapril treatment failed to reduce CV event rates
in patients with CHD, some explanations could potentially
clarify this failure. Despite these limitations, treatment
with enalapril was not shown to reduce CV event rates in
patients with CHD who did not have HF, and thus should not
be readily prescribed in this patient population, especially
considering that treatment with ramipril and perindopril
have proven to be therapeutically effective ACE inhibitors
in this setting.21,37,43
Although differences in patient populations and duration of follow-up among trials may explain why treatment
with trandolapril, quinapril, and enalapril failed to show a
compared with placebo, it is also plausible that these 3 ACE
P=
reduced the rate of resuscitated cardiac arrests compared with
P = 0.04). Moreover, amlodipine treatment reduced the primary endpoint compared with enalapril
P = 0.10). However, this was mainly driven by
a reduction in patient hospitalizations for episodes of angina
P = 0.003), and a trend toward
fewer episodes of revascularization in patients undergoing
perindopril and ramipril treatment.
Patients With HF and Systolic
Dysfunction
an ACE inhibitor within 30 days after hospital discharge,
enalapril and captopril therapy were associated with higher
patient mortality rates compared with ramipril treatment
P = 0.09). While there was a trend for a reduction in CV event
10
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DiNicolantonio_proof2
ACE Inhibitor Advantage: Focus on Ramipril and Perindopril
Figure 9. Blood pressure reduction from baseline values in four major ACEI trials.38
perindopril was associated with an equivalent reduction
In patients with HF, treatment with enalapril
or captopril has been associated with a higher rate of patient
mortality compared with ramipril or perindopril therapy.
A limitation does exist for the aforementioned data, as it was
observational, and thus cannot prove causality, although it is
vs 2.12 ± 0.07; P =
±
±
P = 0.395) compared with baseline values.
44
inhibitor therapies.
Masuelli et al45 indicated that patients switched from
functional class (P !
LV end-diastolic diameter (P = 0.001) and LV mass index
(P !
P ! 0.001).
While these improvements may, in part, be explained by
not be explained by reductions in patient BP measurements
(111 ±
± 1.3 mm Hg vs 112 ±
± 1.0 mm Hg;
P value not reported), norepinephrine levels (414 ± 30 pg/mL
vs 361 ± 35 pg/mL; P =
± 17
± 12 pg/mL; P = 0.53), or endothelin-1
levels (2.5 ± 0.4 pg/mL vs 2.2 ± 0.9 pg/mL; P = 0.39), as
treatments.46
A study by Kasama et al47 showed that patients with HF
ments in total defect score (39 ± 10 to 34 ± 9; P ! 0.01), H/M
ratio (1.62 ± 0.27 to 1.76 ± 0.29; P !
±
±
P!
± 155 pg/
mL to 141 ± 90 pg/mL; P ! 0.0005 vs baseline; P ! 0.05
± 30 mL to
161 ± 30 mL; P ! 0.05), and LV end-systolic volume
(122 ± 35 mL to 105 ± 36 mL; P ! 0.05). Patients random-
trials that enrolled patients with systolic HF indicated greater
were not explained by enhanced BP-lowering effects.46,47
In a study by Tsutamoto et al,46 patients with ischemic HF
P value not reported),
P = 0.013), plasma brain natri±
±
pg/mL; P = 0.042), heart-to-mediastinum (H/M) ratio
(2.0 ± 0.07 vs 2.15 ± 0.07; P = 0.013), and washout rate (WR)
±
±
P = 0.030) with perindopril
therapy compared with baseline values. Patients who received
tional class (P
±
±
P=
± 26 pg/
mL vs 169.3 ± 33 pg/mL; P = 0.36), H/M ratio (2.09 ± 0.07
P value not reported), LV end-systolic volume (120 vs
111 mL; P
P value
P
(P !
enalapril therapy was less robust (P ! 0.05).47
Perindopril is a unique ACE inhibitor that offers therapeutic improvements for patients with systolic dysfunction
in hemodynamic, functional, and neurohumoral parameters
dopril therapy cannot be explained by reductions in patient
reduction (P =
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DiNicolantonio et al
Table 3. Clinical Trials of ACE Inhibitors in Patients With CHD
ACE Inhibitor Trial
Results
Perindopril
Positive
20% relative risk reduction on the
primary endpoint (CV death, MI, or
cardiac arrest) (95% CI 9–29, P = 0.0003)
with perindopril versus placebo.
Positive
22% reduction in the primary outcome
(MI, stroke or CV death) (relative risk
0.78: 95% CI: 0.70–0.86, P ! 0.001).
Negative
No difference in the primary endpoint
(CV death, nonfatal MI, CABG, PCI)
between trandolapril (21.9%) and placebo
(22.5%) (HR 0.96, 95% CI: 0.88–1.08,
P = 0.43).
Negative
The rates of CV mortality, overall
mortality, and nonfatal AMI were similar
between patients treated with quinapril
and those given placebo (1.4% vs
1.5%; 3.1% vs 3.2%; and 4.1% vs 4.6%,
respectively; P = NS
for each endpoint).
Negative
Ramipril
EUROPA21
HOPE37
Trandolapril
PEACE39
Quinapril
QUIET40
Enalapril
CAMELOT43
enalapril versus placebo (20.2% vs 23.1%),
(HR, 0.85; 95% CI, 0.67–1.07; P = 0.16).
Abbreviations: ACE, angiotensin-converting enzyme; CHD, coronary heart disease;
CAMELOT, Comparison of Amlodipine Versus Enalapril to Limit Occurrences of
Thrombosis; EUROPEAN, European Trial on Reduction of Cardiac Events With
Perindopril in Stable Coronary Artery Disease; HOPE, Heart Outcomes Prevention
Evaluation; PEACE, Prevention of Events with Angiotensin Converting Enzyme Inhibition;
QUIET, Quinapril Ischemic Event Trial.
experienced hypotension that required withdrawal of
enalapril.
mal medical therapy, especially if patients with less severe
HF were studied. While there have been no studies, to our
knowledge, of the effect of perindopril therapy on morbidity
and mortality rates in patients with systolic HF, it could be
hypothesized that treatment with perindopril would provide
equivalent if not superior reductions in major CV endpoints
compared with enalapril treatment based on the 3 aforementioned trials in this setting.
Patients With HF and Preserved EF
EF.49 In the Perindopril in Elderly People With Chronic HF
(PEP-HF) trial, perindopril treatment was associated with
at 1 year, a reduction in composite of all-cause mortality
and unplanned HF hospitalization rates (relative risk
P = 0.055),
P=
(P ! 0.030) and 6-minute walking distance (P = 0.011).49
After 1 year trial duration, “drop-in” perindopril treatment
was allowed into the placebo-treated group, which resulted
tion for all-cause mortality and hospitalization rates in
patients with HF and preserved EF,49 which has not been
shown with treatment other ACE inhibitors.
Patient Outcomes Post-AMI
inhibitor within 30 days of hospital discharge after an AMI,
enalapril, fosinopril, captopril, quinapril, and lisinopril
treatment were associated with higher patient mortality rate
perindopril had a mortality rate similar to that of patients
13
The study
year after an AMI were less with enalapril, fosinopril,
captopril, quinapril, or lisinopril treatment compared with
ramipril therapy, and that treatment with perindopril was
13
Limitations
to be noted about the study include the fact that it was
observational and retrospective in design, and, thus, could
not prove causality; however, the results offer real-world
evidence consistent with data from trials using ramipril and
perindopril to treat patients with and at high risk for CHD.
ST-segment elevation AMI in a prospective multicenter
registry from Germany to compare the effect of ramipril
Perindopril is the only ACE inhibitor with evidence-based
patient in-hospital mortality rate. In a multivariate analysis,
12
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ACE Inhibitor Advantage: Focus on Ramipril and Perindopril
treatment with ACE inhibitors was associated with lower
patient in-hospital mortality and major CV event rates, but
treatment with other ACE inhibitors. However, patient HF
assessed in this study).50
Perindopril
The Perindopril and Remodeling in Elderly With Acute
Myocardial Infarction (PREAMI) trial was a 12-month,
double-blind, randomized, parallel-group, multicenter trial
that enrolled 1252 patients (aged # 65 years) with preserved
51
The primary endpoint (patient mortality, hospitalization for
P ! 0.001),
which was mainly driven by a reduction in LV remodeling
on placebo; P ! 0.001). Moreover, the mean increase in
with perindopril treatment compared with placebo treatment
(0.7 mL vs 4.0 mL; P ! 0.001, respectively). A subanalysis
of EUROPA in the PREAMI-like population (# 65 years,
LVEF #
P = 0.03) for the primary EUROPA
endpoint after 3 years of perindopril treatment. In summary,
with a recent AMI, despite patients having a normal EF
51
Enalapril
ized, double-blind, placebo-controlled, parallel-group trial
that compared treatment with enalapril with placebo in
6090 patients with AMI. Enalapril therapy, started within
24 hours of AMI, increased patient mortality risk compared
P = 0.26).
The increase in mortality with enalapril treatment versus
placebo could be argued as being caused by the use of an
intravenous dosage form of enalapril, causing hypotension, which would not have been seen with oral enalapril
treatment. However, enalapril and perindopril treatment
have been shown to produce similar reductions in patient
BP when administered intravenously,52 whereas enalapril,
given orally, has caused severe hypotension, an effect that
has not been seen with orally administered perindopril.10,53
Enalapril, as an individual compound (not the intravenous
formulation) was the likely cause of the 4-fold increase in
the rate of patient hypotension when compared with placebo
P ! 0.001, respectively).
The disparate effects of enalapril treatment compared with
perindopril therapy on patients with hypotension are further
elucidated when evaluating tolerability data of these 2 ACE
inhibitors from previous trials in patients with HF, in which
indopril.
Orally administered enalapril can cause severe
hypotension at a much higher rate than treatment with oral
perindopril. If a clinician is selecting an ACE inhibitor for
a patient with AMI, perindopril and ramipril seem to be the
safer therapeutic choices.
54,55
Conclusion
Perindopril has been shown to have a longer duration
of action, higher lipophilicity, and stronger tissue ACEinhibiting properties compared with other ACE inhibitors.
Moreover, there are several clinical trials supporting the CV
patients with AMI, those with HF and preserved EF, patients
with or at high risk for CHD without HF). Thus, perindopril
for treatment of patients with HF and preserved EF and in
patients with or at high risk for CHD without HF.
Perindopril and ramipril are the only ACE inhibitors to
show a reduction in CV event rates in patients with or at
high risk for CHD with normal LV function.21,37 Therefore, in
ACE inhibitor therapy. Although ramipril has demonstrated
excellent ability to improve patient clinical outcomes, most
of the trials were completed decades ago, prior to the current era of optimal medical therapies. Only use of the ACE
inhibitor perindopril has demonstrated clear reductions in CV
endpoints in patients who have been treated in ways that are
medical therapy and at a lower baseline risk of CV events
compared with patients receiving ramipril in HOPE). Moreover, perindopril is the only ACE inhibitor with evidence for
improving morbidity and mortality rates in patients with HF
who have a preserved EF.49 Therefore, in patients with or at
high risk for CHD (without HF) and HF with preserved EF,
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DiNicolantonio_proof2
DiNicolantonio et al
inhibitor, perhaps even prior to ramipril use.
In the future, we are hopeful that perindopril will become
more widely prescribed and used, as it possesses an impressive amount of evidence supporting its ability to reduce CV
endpoints in a wide range of patient populations. Clinicians
should be aware that a clear and complete class effect does
not seem to exist with the ACE inhibitors. If we are to practice
evidence-based medicine, we should be preferentially prescribing medications that have the strongest evidence (perindopril
and ramipril) for improving long-term clinical CV outcomes.
14. Comini L, Bachetti T, Cargnoni A, et al. Therapeutic modulation of the
nitric oxide: all ace inhibitors are not equivalent. Pharmacological Res.
in the anti-ischaemic effect of trandolapril. British J Pharm. 2001;
16. du Toit EF, Genade S, Carlini S, Moolman JA, Brunner F, Lochner A.
ing mouse heart model. Euro J Pharma
17. Krysiak R, Sierant M, Marek B, Okopien B. The effect of perindopril
and enalapril on plasma resistin levels in normotensive patients with
coronary heart disease. Endokrynologia Polska
enzyme inhibitors in normotensive patients with coronary artery disease.
Pharmacol Rep
of the two active sites of somatic angiotensin-converting enzyme in
the cleavage of angiotensin I and bradykinin: insights from selective
inhibitors. Circulation Res
20. Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with perindopril
and endothelial function. Results of a substudy of the EUROPA study:
Cardiovasc Res
References
1. van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensinconverting enzyme inhibitors reduce mortality in hypertension:
a meta-analysis of randomized clinical trials of renin-angiotensinEuro Heart J.
2. Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk
of myocardial infarction: unraveling the ARB-MI paradox. Circulation.
3. Unger T, Ganten D, Lang RE. Tissue converting enzyme and
cardiovascular actions of converting enzyme inhibitors. J Cardiovasc
Pharmacol
4. Zhuo JL, Mendelsohn FA, Ohishi M. Perindopril alters vascular
angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase
expression in patients with coronary heart disease. Hypertension. 2002;
among patients with stable coronary artery disease: randomised, doubleblind, placebo-controlled, multicentre trial (the EUROPA study). Lancet.
22. PROGRESS Collaborative Group. Randomised trial of a perindoprilbased blood-pressure-lowering regimen among 6,105 individuals
with previous stroke or transient ischaemic attack. Lancet. 2001;
23. Tumanan-Mendoza BA, Dans AL, Villacin LL, et al. Dechallenge and
rechallenge method showed different incidences of cough among four
ACE-Is. J Clinic Epidem
Angiology
25. McAlister FA. Angiotensin-converting enzyme inhibitors or angiotensin
a collaborative meta-analysis of randomized trials. Euro Heart J.
5. Ferrari R. Preserving bradykinin or blocking angiotensin II: the cardiovascular dilemma. Dialogues Cardiovasc Med
Clin Exp Pharmacol Physiol Suppl
7. Farnsworth A. Angiotensin-converting enzyme inhibitors in heart
failure: target dose prescription in elderly patients. Age Ageing.
Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have
different selectivity for bradykinin binding sites of human somatic ACE.
Eur J Pharmacol
to angiotensin converting enzyme inhibition in congestive heart
failure: a placebo controlled study. Br Heart J
10. Vítovec J, Spinar J. First-dose hypotension after angiotensin-converting
enzyme (ACE) inhibitors in chronic heart failure: a comparison of
enalapril and perindopril. Slovak Investigator Group. Eur J Heart Fail.
11. Ceconi C, Francolini G, Bastianon D, Gitti GL, Comini L, Ferrari R.
Differences in the effect of angiotensin-converting enzyme inhibitors
on the rate of endothelial cell apoptosis: in vitro and in vivo studies.
Cardiovasc Drugs Ther
with enalapril in rats with dilated cardiomyopathy. J Cardiovasc Pharm.
13. Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg MJ, Rahme E.
Mortality rates in elderly patients who take different angiotensinconverting enzyme inhibitors after acute myocardial infarction: a class
effect? Ann Int Med
14
26. Dzau VJ, Bernstein K, Celermajer D, et al. Pathophysiologic and
therapeutic importance of tissue ACE: a consensus report. Cardiovasc
Drug Ther
enzyme activity in coronary artery specimens from patients with acute
coronary syndrome. Circulation
pressure overload left ventricular hypertrophy. Effects on coronary resistance,
contractility, and relaxation. J Clinic Invest
29. Pieruzzi F, Abassi ZA, Keiser HR. Expression of renin-angiotensin
system components in the heart, kidneys, and lungs of rats with experimental heart failure. Circulation
converting enzyme in remaining viable myocytes of human ventricles
after myocardial infarction. Circulation
31. Heymes C, Swynghedauw B, Chevalier B. Activation of angiotensinogen and angiotensin-converting enzyme gene expression in the left
ventricle of senescent rats. Circulation
accumulation of tissue ACE in human atherosclerotic coronary artery
disease. Circulation
33. Finta KM, Fischer MJ, Lee L, Gordon D, Pitt B, Webb RC. Ramipril prevents impaired endothelium-dependent relaxation in arteries from rabbits fed an atherogenic diet. Atherosclerosis
34. Campbell DJ, Kladis A, Duncan AM. Effects of converting enzyme
inhibitors on angiotensin and bradykinin peptides. Hypertension.
© Postgraduate Medicine, Volume 125, Issue 4, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260
ResearchSHARE®: www.research-share.com • Permissions: permissions@postgradmed.com • Reprints: reprints@postgradmed.com
DiNicolantonio_proof2
ACE Inhibitor Advantage: Focus on Ramipril and Perindopril
35. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular
effects of angiotensin-converting enzyme inhibitors in humans. Circulation
47. Kasama S, Toyama T, Kumakura H, et al. Effects of perindopril on
cardiac sympathetic nerve activity in patients with congestive heart
failure: comparison with enalapril. Euro J Nuc Med Mole Imag.
treatment effect of an ACE-inhibitor based treatment regimen in patients
with vascular disease or high risk of vascular disease: a combined
Effects of the early administration of enalapril on mortality in patients
trials. Euro Heart J
N Engl J
Med
an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. The Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med
in coronary artery disease: the ultimate ‘EUROPA’ story. Drugs.
39. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-convertingenzyme inhibition in stable coronary artery disease. N Engl J Med.
Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor
therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol
converting-enzyme inhibitors in stable vascular disease without left
ventricular systolic dysfunction or heart failure: a combined analysis
of three trials. Lancet
42. Mancini GB, Henry GC, Macaya C, et al. Angiotensin-converting
enzyme inhibition with quinapril improves endothelial vasomotor
Circulation.
on cardiovascular events in patients with coronary disease and normal
blood pressure: the CAMELOT study: a randomized controlled trial.
JAMA
44. Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H,
Tu JV. Effect of different angiotensin-converting-enzyme inhibitors on
mortality among elderly patients with congestive heart failure. CMAJ.
The perindopril in elderly people with chronic heart failure (PEP-CHF)
study. Euro Heart J
50. Wienbergen H, Schiele R, Gitt AK, et al. Impact of ramipril versus other
angiotensin-converting enzyme inhibitors on outcome of unselected
patients with ST-elevation acute myocardial infarction. Am J Cardiol.
51. 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 Int Med.
52. MacFadyen RJ, Lees KR, Reid JL. Double blind controlled study of
low dose intravenous perindoprilat or enalaprilat infusion in elderly
patients with heart failure. Brit Heart J
53. Reid JL, MacFadyen RJ, Squire IB, Lees KR. Blood pressure response
tive heart failure. Am J Cardio
54. Kjekshus J, Swedberg K. Tolerability of enalapril in congestive heart
failure. Am J Cardiol
55. Desche P, Antony I, Lerebours G, Violet I, Robert S, Weber C. Acceptability of perindopril in mild-to-moderate chronic congestive heart
failure. Results of a long-term open study in 320 patients. Am J Cardiol.
inhibition by angiotensin converting enzyme inhibitors. J Hypertens.
57. Tardif JC. Angiotensin-converting enzyme inhibitors and atherosclerotic
plaque: a key role in the cardiovascular protection of patients with
coronary artery disease. Euro Heart J
45. Masuell M, Brusca G, Pardo A, Pineiro D, Checkerdhemian S, Forcada P.
ACE inhibitors in heart failure—switching from enalapril to perindopril.
Curr Med Res Opin
on cardiac sympathetic nerve activity and brain natriuretic peptide in
patients with chronic heart failure: comparison with enalapril. Circulation
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