BP ACE Comparison

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Postgraouate Meolclne, volume 125, |ssue 4, [uly 2013, |SSN 0032-5481, e-|SSN 1941-9260 1
ResearcbSHARL
: www.researcb-sbare.com Permlsslons: permlsslons@postgraomeo.com Reprlnts: reprlnts@postgraomeo.com

Not All Anglotensln-Convertlng Lnzyme |nblbltors
Are Lqual: Focus on Ramlprll ano Perlnooprll
[ames [. DlNlcolantonlo,
PbarmD
1,4

Carl [. Lavle, MD
2,3

[ames H. O'Keete, MD
4
1
Wegmans Pbarmacy, |tbaca, NY,
2
[obn
Ocbsner Heart ano vascular |nstltute,
Ocbsner Cllnlcal Scbool/Unlverslty ot
Queenslano Scbool ot Meolclne, New
Orleans, LA,
3
Pennlngton 8lomeolcal
Researcb Center, 8aton Rouge, LA,
4
Mlo Amerlca Heart |nstltute at
Salnt Luke's Hospltal, Unlverslty ot
MlssourlKansas Clty, Kansas Clty, MO
Corresponoence: [ames [. DlNlcolantonlo,
PbarmD,
500 Soutb Meaoow St.,
|tbaca, NY 14850.
Tel: 607-277-5750
Fa: 607-277-5890
L-mall: jjolnlcol@gmall.com
DOl:
Abstract: Angiotensin-converting enzyme (ACE) inhibitors are a heterogeneous class,
varying in pharmacologic properties, which have diIIerent therapeutic impacts on patient
profles, including lipophilicity, tissueACE binding, duration oI action, halI-liIe, and increased
bradykinin availability. Among the ACE inhibitor class, the agent perindopril, in particular, has
pleiotropic eIIects that are not equally shared by other ACE inhibitors, including bradykinin
site selectivity and subsequent enhancement oI nitric oxide and inhibition oI endothelial cell
apoptosis. Moreover, there is a large amount oI evidence to suggest that perindopril therapy
may reduce cardiovascular event rates in patients, yet perindopril is rarely prescribed in the
United States. Ramipril is another ACE inhibitor with both a Iavorable clinical profle and
impressive outcomes data. Our review compares the pharmacologic and trial data among per-
indopril, ramipril, and other ACE inhibitors. In patients with or at high risk Ior coronary heart
disease who do not have heart Iailure, or in patients with heart Iailure with preserved ejection
Iraction, perindopril should be among the preIerred treatment agents in the ACE inhibitor class.
Ramipril has an impressive track record oI improving cardiovascular outcomes, too, and should
be considered a preIerred agent among the ACE inhibitor class.
Keywords: angiotensin-converting enzyme inhibitor; bradykinin; heart Iailure; cardiovascular
disease; ramipril; perindopril
lntroduction
Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbid-
ity and mortality rates in patients with systolic heart Iailure (HF) and in those who
have recently experienced an acute myocardial inIarction (AMI). Additionally, ACE
inhibitors are eIIective agents Ior treating patients with hypertension, and current data
suggest that they are more eIIective therapeutic agents Ior reducing rates oI morbidity
and mortality due to cardiovascular (CV) events compared with the use oI angiotensin
receptor blockers.
1,2
Thus, ACE inhibitors should be prescribed Irequently, as there
is strong evidence oI their therapeutic beneft in reducing patient CV morbidity and
mortality rates.
1,2
However, not all ACE inhibitors appear to be equally eIIective Ior
improving patient CV outcomes.
Pharnacokinetic/Pharnacodynanic Data
The ACE inhibitors, as a drug class, diIIer considerably in their clinical properties Irom
other agents used to treat patients with hypertension. Specifcally, two ACE inhibitors,
ramipril and perindopril, appear to have superior therapeutic qualities compared with
most other currently available ACE inhibitors.
38
Perindopril has been shown to have a
longer duration oI therapeutic action and thus oIIers Iull 24-hour blood pressure (BP)
control. Perindopril also exhibits higher lipophilicity (stronger tissueACE binding),
DiNicolantonio_proof2
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2 Postgraouate Meolclne, volume 125, |ssue 4, [uly 2013, |SSN 0032-5481, e-|SSN 1941-9260
ResearcbSHARL

and local inhibition oI the renin-angiotensin-aldosterone
system in tissues such as the heart, brain, kidneys, adrenal
glands, and blood vessels, as well as a greater selectivity Ior
bradykinin binding sites compared with other ACE inhibi-
tors (Table 1; Figure 1, 2).
38
Moreover, unlike enalapril, no
titration is needed with perindopril treatment to provide the
patient with maximal antihypertensive eIIect.
9
Additionally,
perindopril has less frst-dose hypotensive compared with
enalapril,
9,10
which can lead to underperIusion oI target organs
and subsequent negative consequences.
10
When initiating a
patient on ACE inhibitor therapy, perindopril seems to be
the saIer choice compared to enalapril, especially in patients
relying on hemodynamics to maintain tissue perIusion, such
as patients who have HF. The lower risk Ior hypotension with
perindopril versus enalapril in patients with HF may also be
clinically relevant in those who are at risk Ior hypotension,
such as individuals who have experienced an AMI, those in
circulatory Iailure or shock, those with chronic kidney dis-
ease, or in patients with a propensity Ior orthostasis/presyn-
cope/syncope (ie,dehydration, Parkinson`s disease, chronic
diabetes, those on low-sodium diets, carbohydrate-restricted
diets, or those taking medications that can precipitate ortho-
stasis).
10
However, Iurther trials are required in these patient
populations testing perindopril versus other ACE-inhibitors
to know Ior 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 = not signifcant |NS|, 3.2
diIIerence in Iavor oI perindopril) (Figure 3).
11
Treatment
with perindopril has also shown greater benefcial eIIects on
transIorming growth Iactor and collagen III compared with
enalapril therapy.
12
Treatment with perindopril or ramipril
have been associated with a lower incidence oI mortality
in patients with AMI compared with other ACE inhibitor
therapies (eg, enalapril, Iosinopril, captopril, quinapril, and
lisinopril).
13
This may, in part, be explained by signifcant
increases in endothelial nitric oxide synthase (eNOS) protein
expression in the aorta seen with perindopril treatment
(P 0.001) compared with other ACE inhibitor therapies
(P = NS vs trandolapril; P 0.05 vs ramipril; P 0.01 vs
quinapril; P 0.001 vs enalapril); increases in eNOS activity
in the aorta (P = NS vs quinapril; P 0.05 vs trandolapril and
ramipril; P 0.01 vs enalapril); increases in eNOS protein
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
eNOS activity (P 0.05 with enalapril vs baseline; P 0.01
with trandolapril and quinapril vs baseline; P 0.001 with
perindopril and ramipril vs baseline) (Figure 4, 5).
14
An
improvement in patient eNOS expression has been shown
to improve myocardial tolerance to reperIusion injury
15
and
increased nitric oxide (NO) has been shown to lower the
-adrenergicmediated increase in inotropic and chronotro-
pic responses, thus providing a cardioprotective eIIect 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
and better anti-infammatory
(decreased C-reactive protein), anti-atherosclerotic (reduced
monocyte chemo-attractant protein-1), antioxidant (lowered
oxidized low-density lipoprotein), antithrombotic (lowered
fbrinogen), and profbrinolytic (increased plasminogen
activator inhibitor-1) eIIects (Table 1).
18
Pleiotropic eIIects
were shown to occur in normotensive patients with stable
CHD, and were not related to reductions in BP (either Irom
baseline or compared with BP changes seen in patients treated
with enalapril). In summary, treatment with perindopril
has anti-infammatory, antioxidant, anti-atherosclerotic,
TabIe 1. Aovantages ot Perlnooprll Tberapy Compareo Wltb
Otber ACL |nblbltors
Greater target organ speclclty
3,4
Greater tlssue ano plasma ACL lnblbltlon
36
Longer ouratlon ot actlon. Perlnooprll provloes complete 24-bour
blooo pressure control. Lnalaprll sboulo be ooseo twlce oally, wbereas
perlnooprll only neeos to be ooseo once oally.
6
No tltratlon neeoeo to acbleve malmum ettectlve oose
7
Desplte greater selectlvlty tor braoyklnln blnolng sltes compareo wltb
otber ACL lnblbltors, perlnooprll bas a very low rate ot olscontlnuatlon
oue to ACL lnblbltorlnouceo cougb (2 ln LUROPA ano
PROGRLSS)
8,21,22
Less rst-oose bypotenslon
9,10
|mprovement ln coronary Now reserve ln lscbemlc patlents
10
Greater lnblbltlon ot enootbellal cell apoptosls compareo wltb otber
ACL lnblbltors
11
Greater beneclal ettects on transtormlng growtb tactor ano collagen
||| compareo wltb enalaprll
12
Assoclateo wltb lower mortallty rates ln patlents wltb acute myocarolal
lntarctlon compareo wltb otber ACL lnblbltors
13
Slgnlcantly lncreases enootbellal nltrlc oloe syntbase proteln
epresslon ano actlvlty ln tbe aorta ano ln carolac myocytes (slgnlcantly
more tban tranoolaprll, qulnaprll, ramlprll, ano enalaprll, ! 0.05
vs tranoolaprll ano ramlprll, ! 0.02 vs enalaprll, respectlvely)
14
8etter reouctlon ln reslstln levels ln patlents wltb stable coronary artery
olsease compareo wltb enalaprll
17
8etter antl-lnNammatory, antloloant, antltbrombotlc, ano probrlnolytlc
ettects compareo wltb enalaprll
18
8raln ACL lnblbltlon, wblcb was not sbown wltb qulnaprll
56
Abbreviations: ACL, anglotensln-convertlng enzyme, LUROPA, Luropean Trlal on
Reouctlon ot Carolac Lvents Wltb Perlnooprll ln Stable Coronary Artery Dlsease,
PROGRLSS, Perlnooprll Protectlon Agalnst Recurrent Stroke Stuoy.
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ResearcbSHARL

antithrombotic, anti-apoptotic, antifbrotic, NO-stimulating,
and profbrinolytic properties that are not equally exhibited
with treatment with other ACE inhibitors.
1114,17,18
The greater
pleiotropic eIIects oI perindopril therapy may be due to
stronger tissueACE binding and/or greater selectivity Ior
bradykinin sites on angiotensin converting enzyme compared
with other ACE inhibitor therapy.
3,5,8
The benefts oI inhibiting ACE are generally regarded
to occur by several distinct mechanisms, which include
improved patient bradykinin availability (vasodilation,
through enhanced NO production), increased tissue plasmi-
nogen activator, increased fbrinolysis, improved antioxidant
eIIect, increased anti-remodeling eIIect, preservation oI
endothelial Iunction, anti-adhesion oI monocytes (anti-
atherosclerotic eIIect), and inhibiting the conversion oI
angiotensin I to angiotensin II (thereby reducing vasocon-
striction, hypertrophy, adhesion oI monocytes, plasminogen
activator inhibitor-1 and thrombogenesis, Iree radical oxygen
production, and endothelial dysIunction) (Figure 6).
8
How-
ever, inhibition oI angiotensin II receives more attention
than improvement in bradykinin availability as the primary
mechanism oI action oI ACE inhibitors. Despite this, the
binding aIfnity oI bradykinin Ior ACE is higher than that oI
angiotensin I,
8
suggesting that the ACE pathway primarily
Iunctions to degrade bradykinin.
8
To inhibit both angiotensin
I conversion to angiotensin II and inhibit the degradation oI
bradykinin, blockade oI both the ACE active sites (the N- and
C-terminals) is required.
19
However, angiotensin I can be
Figure 1. Tlssue atnlty ot varlous ACL|s: DD50, ACL| concentratlon requlreo tor 50 olsplacement ot bouno raolollgano.
5
Figure 2. Relatlve selectlvlty ot testeo ACL|s tor braoyklnln vs anglotensln | blnolng sltes. ! 0.001 by ANOvA tor repeateo measures, **! 0.001 vs ramlprllat, qulnaprllat,
tranoolaprllat, ano enalaprllat, *! 0.01 vs enalaprllat
8
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ResearcbSHARL

converted to angiotensin II through either N- or C-terminal
domains, whereas bradykinin inactivation requires the activity
oI both terminal sites.
19
Moreover, ACE inhibitors generally
have a higher aIfnity Ior the bradykinin sites compared with
angiotensin I, which suggests that ACE inhibitors Iunction
primarily to inhibit bradykinin degradation and secondarily
inhibit the production oI angiotensin II.
8
This is Iurther sup-
ported by the Iact that patient angiotensin II levels generally
return to baseline, or are greater than baseline, aIter prolonged
ACE inhibitor use, as angiotensin II can be Iormed through
other non-ACE pathways (eg, cathepsin, tonin).
5
The selectivity Ior bradykinin sites oI 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.
8
Perindopril has the
greater selectivity Ior bradykinin sites on ACE (ratio, 1.44),
whereas enalapril has the poorest selectivity (ratio, 1.00);
perindopril has a 50 greater aIfnity Ior the bradykinin
binding sites compared with enalapril.
8
Thus, compared to 4
other ACE inhibitors, perindopril has the greatest selectivity
Ior bradykinin sites on ACE.
8
Bradykinin has been shown to exert potent anti-apoptotic
actions on both the endothelium and cardiac myocytes, which
could account Ior the greater anti-apoptotic actions oI perin-
dopril treatment compared with use oI other ACE inhibitors.
11

In the PerindoprilThrombosis, Infammation, Endothelial
DysIunction and Neurohormonal Activation (PERTINENT)
trial, 1 year oI perindopril therapy, 8 mg daily, in patients
with CHD, resulted in a signifcant increase in patient bra-
dykinin levels (+17; P 0.05 vs placebo) and a reduction
in angiotensin II levels (27; P 0.05 vs placebo).
20
The
increase in bradykinin with perindopril therapy most likely
contributed to the 19 (P 0.05) increase in protein expres-
sion oI eNOS and the 27 (P 0.05) increase in eNOS
activity, as the addition oI a bradykinin B
2
receptor antagonist
nullifed these benefcial eIIects. Furthermore, there was a sta-
tistically signifcant correlation in the PERTINENT study data
between bradykinin levels and eNOS activity (P 0.05) and
bradykinin levels and eNOS protein expression (P 0.05).
20

Moreover, treatment with perindopril caused a 31 reduction
in the rate oI apoptosis (P 0.05), which was, in part, medi-
ated by the activation oI the bradykinin B
2
receptors, as the
apoptosis rate was increased with the addition oI a bradykinin
B
2
receptor antagonist (P 0.01). Additionally, a signifcant
decrease in von Willebrand Iactor was seen in patients aIter 1
year oI treatment with perindopril (P 0.001).
20
Although increases in patient bradykinin levels with ACE
inhibitor treatment have generally been thought to cause the
ACE inhibitorinduced cough that many patients develop,
the low rates oI cough (2) seen with perindopril therapy
in the European Trial on Reduction oI Cardiac Events With
Perindopril in Stable Coronary Artery Disease (EUROPA)
and the Perindopril Protection Against Recurrent Stroke
Study (PROGRESS), challenge the theory. A 2-Iold higher
incidence oI cough seen in patients undergoing enalapril
therapy (22, which has the poorest selectivity Ior the bra-
dykinin sites vs the 4 other ACE inhibitors) compared with
perindopril treatment (11) in a randomized double-blind
Figure 3. Rate ot apoptosls ln rats treateo tor 7 oays wltb ACL| or veblcle only (control) epresseo as tbe percentage ot anneln v-posltlve rat aortlc enootbellal cells tollowlng
llpopolysaccbarloe-lnouceo apoptosls. *! 0.001 vs control.
11,57
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ResearcbSHARL

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
(7; a 3-Iold increase in cough incidence vs perindopril),
captopril (5.1), perindopril (2.2), and lisinopril (2.6)
in a retrospective study oI 1113 patients with arterial hyper-
tension, highlight the need Ior more research into other
possible causes oI ACE inhibitorinduced cough besides
increased bradykinin availability.
2124
Notably, perindopril
therapy restored patient bradykinin levels to those seen
in healthy controls in the PERTINENT trial, which may
explain the low rates oI cough seen in subjects taking per-
indopril in multiple clinical trials (ie, increased bradykinin
may actually decrease incidence oI ACE inhibitorinduced
cough). The inhibition oI bradykinin degradation seems
to be the principal mechanism oI ACE inhibitorinduced
cardioprotection (although more research is required), and
may be the mechanism underlying signifcant reduction oI
CV endpoints and account Ior the low incidence oI cough
in patients undergoing perindopril therapy.
A large meta-analysis oI randomized placebo-controlled
trials echoed the data, with the included trials indicating
that Ior patients with or at risk Ior atherosclerotic vascu-
lar disease with a systolic BP (SBP) 130 mm Hg, ACE
inhibitor therapy provided a substantial and sustained
beneft, and showed signifcant reduction in rate oI the pri-
mary outcome oI CV mortality, nonIatal AMI, or nonIatal
stroke by 16 (95 CI, 1023) and a signifcant (11)
Figure 4. Lnootbellal nltrlc oloe syntbase (eNOS) proteln epresslon (A) ano actlvlty (B) ln tbe oescenolng aorta ot rats treateo wltb oltterent ACL|s. (**) ! 0.001 vs
veblcle, () ! 0.001, (*)! 0.01 ano (`)! 0.05 eacb ACL| vs otbers. |n eacb group ot treatment, 5 anlmals were employeo.
14
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reduction in all-cause mortality rate (95 CI, 418).
25

In clinical practice, many physicians tend to think oI ACE
inhibitors as antihypertensive medications, and, iI a patient
has an SBP 140 mm Hg (and certainly iI 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,
those patients with or at risk oI vascular disease beneft
Irom the prescription oI an ACE inhibitor, which may be
related to ACE-inhibitor eIIects on lowering the throm-
botic cascade and enhancing the profbrolytic balance
(especially in patients treated with perindopril compared
with enalapril).
18
Despite ACE inhibitors having been prescribed Ior decades,
there is still uncertainty as to the precise mechanism(s) under-
lying the benefts oI this class oI therapeutic agents. Do they
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 oI action exerted? At
the prodrug or drug stage (ie, perindoprilat vs perindopril)?
Angiotensin-converting enzyme is present in many body tis-
sues (eg, heart, brain, kidneys, adrenal glands, blood vessels)
and is, Ior the most part, a tissue-based enzyme, with 10
oI ACE Iound in plasma.
26
The ability oI 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
In Iact, signifcant myocardial ACE
activity has been shown in several patient models oI cardiac
injury, including volume overload, the hypertrophied heart,
HF, AMI, and post-AMI remodeling, where elevated wall
Figure 5. eNOS syntbase (eNOS) proteln epresslon (A) ano actlvlty (B) ln lsolateo carolac myocytes trom rats treateo wltb oltterent ACL|s. (**) ! 0.001, (*) ! 0.01,
(`) ! 0.05 vs veblcle. |n eacb group ot treatment, 5 anlmals were employeo.
14
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ResearcbSHARL

stretch and subsequent sarcolemmal stretching are believed
to be crucial Iactors Ior increased patient cardiac ACE activity
(Figure 7).
2830
In the injured heart, recruited Iibroblasts and mac-
rophages also carry high ACE activity,
26,30,31
with tissue ACE
amassing in human atherosclerotic plaque, preIerentially
in areas oI infammation and macrophage accumulation
(Figure 7).
26,32
Localized ACE activity within atheroscle-
rotic plaque may contribute to the progression oI advanced
coronary lesions and subsequent atherothrombotic events.
The anti-atherosclerotic eIIects oI the ACE inhibitors have
been presumed to be due to the enhancement oI NO and
prostacyclin (through increased bradykinin availability and
inhibition oI angiotensin II Iormation), leading to subsequent
decreased migration and proliIeration oI vascular smooth
muscle cells, decreased infammatory cell accumulation
and activation, decreased oxidative stress, and improved
endothelial Iunction.
5,33
Bradykinin B
2
receptor antagonists have been shown
to counteract the benefcial eIIects oI ACE inhibition on
eNOS activity
15
; thus, ACE inhibitors may preIerentially
work through the inhibition oI bradykinin degradation. This
premise is supported by the Iact 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
patient eNOS activity and protein expression compared with
other ACE inhibitors,
14
with statistically signifcant correla-
tions between eNOS improvement and increased bradykinin
levels.
15
Additionally, bradykinin levels have been related
to the endothelial-dependent vasodilation seen in patients
taking quinapril.
35
Considering that treatment with perin-
dopril has shown consistent pleiotropic eIIects (that are not
equally produced by treatment with other ACE inhibitors),
and consistent reductions in rates oI patient morbidity and
mortality in multiple trials, it may be that a high selectivity
Ior the bradykinin sites on ACE, as well as robust tissueACE
binding, are at the cornerstone oI ACE inhibitor therapeutic
benefts (especially with perindopril use).
In summary, not all ACE inhibitors are equal; oI the
many agents in the drug class, each has signifcant diI-
Ierences in bradykinin selectivity, enhancement oI eNOS
activity and protein expression (NO stimulation), tissue
penetration/tissueACE binding, and varying anti-infam-
matory, antioxidant, anti-atherosclerotic, antithrombotic,
anti-apoptotic, antifbrotic, and profbrinolytic properties.
Perindopril therapy has consistently been shown to have the
most benefcial eIIects on the aIorementioned parameters
when compared with other ACE-inhibitor treatment.
1116,18
The pleiotropic properties oI perindopril may translate
into improved clinical, hemodynamic, and CV endpoint
reductions Ior patients compared with other ACE inhibitor
therapy. In Iact, there is a plethora oI evidence showing that
treatment with perindopril results in reductions in CV event
rates. In a 4-year Iollow-up oI 29 463 patients, a perindopril-
based regimen produced a signifcant reduction in rates oI
patient all-cause mortality (hazard ratio |HR|, 0.89; 95
CI, 0.820.96; P = 0.006), CV mortality (HR, 0.85; 95
CI, 0.760.95; P = 0.004), nonIatal AMI (HR, 0.80; 95
CI, 0.710.90; P 0.001), stroke (HR, 0.82; 95 CI,
0.740.92; P = 0.002), and HF (HR, 0.84; 95 CI, 0.720.96;
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 oI
patients with vascular disease. Other ACE inhibitors cannot
ACE inhibition
Angiotensin II Bradykinin
Vasoconstriction Vasodilation
Adhesion of monocytes Antiadhesion of monocytes
SMC growth, proliferation, and migration ncreased eNOS expression
ncreased PA-1 and thrombogenesis ncreased t-PA and fibrinolysis
Matrix degradation Antiremodeling effect
Oxygen free radical production Antioxidant effect
Endothelial dysfunction Preserved endothelial function
The decrease in angiotensin levels prevents a number of deleterious cardiovascular
effects, while the increase in bradykinin has cardioprotective consequences. eNOS,
endothelial nitric oxide synthase; PA-1, plasminogen activator inhibitor-1; SMC, smooth
muscle cell; t-PA, tissue plasminogen activator.
Figure 6. Tbe ettects ot anglotensln || lnblbltlon ano lmprovement ln braoyklnln avallablllty.
8
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ResearcbSHARL

be assumed to possess the same benefcial therapeutic eIIects
as those oI perindopril.
Patients With or at High Risk
of CHD
Perlnooprll ano Ramlprll
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 oI CV events and lower CV
mortality rates in patients with or at high risk Ior CHD, who
have normal leIt ventricular (LV) Iunction.
21,37
Additionally,
treatment with ramipril in a randomized placebo-controlled
trial oI 2000 patients, post-AMI, with HF, reduced the all-cause
mortality rate by 27 (P = 0.002) and the adverse CV event
rate by 19 (P = 0.008).
37
In patients with or at high risk Ior
CHD, the only evidence-based preventive ACE inhibitor thera-
peutic agents are perindopril and ramipril.
21,37
UnIortunately,
many clinicians prescribe other ACE inhibitors (eg, lisinopril,
enalapril, or benazepril) in this setting. However, the belieI in a
'class eIIect is not supported by randomized controlled trials
using ACE inhibitor treatments. For example, use oI trandola-
pril in the Prevention oI Events With Angiotensin-Converting
Enzyme Inhibition (PEACE) trial, and quinapril in the Qui-
napril Ischemic Event Trial (QUIET) did not show reductions
in the primary outcome, whereas ramipril and perindopril, used
in similar patient populations, have demonstrated signifcant
reductions in major CV endpoints (Figure 8).
3840
Tranoolaprll
In the PEACE trial, treatment oI patients with trandolapril
Iailed to provide beneft in terms oI mortality Irom CV causes
(AMI, or coronary revascularization in patients with stable
CHD without a history oI HF or LV systolic dysIunction).
39

The lack oI CV beneft in the PEACE trial may be argued
as being caused by the high use oI optimal medical therapy.
However, in the EUROPA, HOPE, and PEACE trials, rates
oI use oI antiplatelet agents, statins, and -blockers were
92, 58, and 62; 76, 29, and 40; and 90, 70,
and 60, respectively (Table 2).
21,37,39
Thus, the background
medical therapy was similar between EUROPA and PEACE,
whereas HOPE had lower percentages oI all 3 background
medications, making HOPE somewhat unrefective oI current
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
Ior CHD (in patients without HF) on optimal background
medical therapy.
21,37
Additionally, Dagenais et al
41
indicated a signifcant
patient beneft with perindopril or ramipril therapy in a sub-
group analysis evaluating patients on lipid-lowering agents,
-blockers, and antiplatelet drugs (alone or in combination).
ThereIore, even patients on optimal background medical
therapy seem to beneft Irom ramipril and perindopril therapy.
Dagenais et al
41
also conducted a subgroup analysis oI low-
risk patients in the HOPE and EUROPA trials, who also
showed large reductions in the composite endpoint oI CV
Figure 7. Myocarolal tlssue ACL.
26
!"# %&'()(*+, !-./&*/012 3+456 +& 7/8(9,(: /&- ;1,(&-+9,(:
ResearcbSHARL

mortality, nonIatal AMI, or stroke, when patients were treated
with either perindopril or ramipril therapy.
41
The high per-
centage oI patients on optimal medical background therapy
and/or the low-risk patient populations in the PEACE trial do
not explain the therapeutic Iailure oI 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 inIeriority oI trandolapril treat-
ment and other ACE inhibitor therapy compared with perin-
dopril and ramipril, a class eIIect should not be assumed to
be true. For example, in the cases oI pioglitazone compared
with rosiglitazone, or hydrochlorothiazide compared with
chlorthalidone, therapeutic agents within the same class
have been shown to have markedly diIIerent clinical and CV
eIIects. Considering that no trial data exist Ior trandolapril
treatment demonstrating a reduction in CV endpoints in
patients with or at risk Ior CHD (without HF), we believe
that trandolapril should not be prescribed preIerentially over
ramipril or perindopril. II we are to practice evidence-based
medicine, ramipril or perindopril should be the preIerred ACE
inhibitor Ior treating this high-risk patient population.
21,37,39
Qulnaprll
The QUIET study was a randomized, blinded, multicenter,
36-month trial (mean duration oI Iollow-up, 27 months) that
compared treatment with quinapril 20 mg with placebo in
1750 patients with CHD without systolic LV dysIunction.
40

There was no diIIerence in rates oI ischemic events between
patients taking quinapril therapy compared with those
taking placebo (relative risk |RR|, 1.04; 95 CI, 0.891.22;
P = 0.60), or in the incidence oI patients who experienced
angiographic progression oI coronary disease (P = 0.71).
The rates oI CV mortality, overall mortality, and nonIatal
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 Ior each endpoint).
Furthermore, the development oI new coronary lesions was
similar in incidence Ior both patient groups (P = 0.35). How-
ever, treatment with quinapril did reduce patient incidence
oI angioplasty Ior new (previously un-intervened) vessels
(P = 0.018). While quinapril 20 mg was well tolerated, it did
not signifcantly improve clinical outcomes or the progression
oI coronary atherosclerosis. However, the study authors did
note that the absence oI a demonstrable eIIect with quinapril
therapy may have been due to several limitations in study
design, including: 1) the QUIET study would have needed
to enroll 20 000 patients in order to detect a 25 reduction
in rate oI major CV events with a 95 CI; thus, the trial was
potentially underpowered to show a reduction in major CV
endpoints; 2) the subjectivity in the decision to proceed with
angioplasty and the variability in postcatheter intervention
management increased the number oI non-major outcomes,
which may have masked detection oI the eIIect oI quinapril
therapy on major CV outcomes; and 3) the dose oI quinapril
may have been low (20 mg) compared with 40 mg daily,
which was shown to signifcantly improve coronary artery
endothelial reactivity in the Trial on Reversing Endothelial
DysIunction (TREND).
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 com-
pared with quinapril use in QUIET and trandolapril therapy
Figure 8. Prlmary outcomes trom tbe tour major ACL| trlals.
38
!"#"$%&'()%("% +) '&
ResearcbSHARL

in the PEACE study (Figure 9). Suggesting that quinapril`s
lack oI CV beneft in QUIET was due to the medication dose
being too low is unlikely, despite the Iact that there are no
reports, to our knowledge, comparing rates oI central BP
lowering with these agents or among these trials. Notably, the
3-year Iollow-up in QUIET may have been too short a time
period to detect a beneft, as the HOPE trial had a mean trial
duration oI 5 years, requiring 1 to 2 years oI treatment with
ramipril beIore the AMI/stroke/death Kaplan-Meier curves
began to separate compared with placebo.
37
The Comparison oI Amlodipine Versus Enalapril to
Limit Occurrences oI Thrombosis (CAMELOT) study was
a randomized, double-blind, multicenter, 24-month trial that
compared amlodipine or enalapril with placebo in approxi-
mately 2000 patients with angiographically documented
CHD ( 20 stenosis by coronary angiography) and a dia-
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 nonIatal
AMI rate by 26, stroke or transient ischemic attack rate
by 50 (number oI patients needed to treat to prevent one
event, 16), and CV event rate (16.6 vs 23.1; HR 0.69,
95 CI, 0.540.88; P = 0.003). Amlodipine also signifcantly
reduced the rate oI resuscitated cardiac arrests compared with
placebo (0 vs 0.6; P = 0.04). Moreover, amlodipine treat-
ment reduced the primary endpoint compared with enalapril
therapy, just missing statistical signifcance (HR, 0.81; 95
CI, 0.631.04; P = 0.10). However, this was mainly driven by
a reduction in patient hospitalizations Ior episodes oI angina
(HR, 0.59; 95 CI, 0.420.84; P = 0.003), and a trend toward
Iewer episodes oI revascularization in patients undergoing
intervention at baseline (HR, 0.66; 95 CI, 0.401.06;
P = 0.09). While there was a trend Ior a reduction in CV event
rate with enalapril therapy compared with placebo (20.2 vs
23.1), the diIIerence did not reach statistical signifcance
(HR, 0.85; 95 CI, 0.671.07; P = 0.16). However, there was
a 45 reduction in rate oI nonIatal AMI with enalapril treat-
ment compared with placebo, which just missed statistical
signifcance (HR, 0.55; 95 CI, 0.261.15; P = 0.11).
43
There are a Iew explanations that may explain the results
oI the CAMELOT trial. For example, the placebo group was
actually treated with ACE inhibitors and calcium channel
blockers (12.8 and 12.1, respectively)
43
; thus, active
therapy drop-ins into the placebo group could have muted
the beneft oI treatment with either amlodipine or enalapril. It
is not Iully apparent when these patient drop-ins occurred or
whether they were clinically meaningIul (ie, iI most occurred
late in the trial, it may not have caused a clinically meaning-
Iul eIIect); however, this limitation should not be overlooked
nor over-interpreted. Another possible explanation Ior the
lack oI CV beneft with enalapril treatment compared with
placebo could be due to a higher rate oI patients discontinuing
treatment in the enalapril group (35.1) compared with the
amlodipine group (29.3), or the Iewer number oI patients
reaching a maximum target dose in the enalapril group
(84.3) compared with the amlodipine group (86.7).
43

Although enalapril treatment Iailed to reduce CV event rates
in patients with CHD, some explanations could potentially
clariIy this Iailure. 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 eIIective ACE inhibitors
in this setting.
21,37,43
Although diIIerences in patient populations and dura-
tion oI Iollow-up among trials may explain why treatment
with trandolapril, quinapril, and enalapril Iailed to show a
signifcant reduction in CV event rates in patients with CHD
compared with placebo, it is also plausible that these 3 ACE
inhibitors are not as therapeutically benefcial to patients as
perindopril and ramipril treatment.
Patients With HF and 5ystoIic
Dysfunction
In 43 316 patients with HF who flled prescriptions Ior
an ACE inhibitor within 30 days aIter hospital discharge,
enalapril and captopril therapy were associated with higher
patient mortality rates compared with ramipril treatment
(enalapril, 1.10 |95 CI, 1.041.16| and captopril,
1.13 |95 CI, 1.011.26|), whereas treatment with
TabIe 2. Comparlng Patlent Populatlon Cbaracterlstlcs ot tbe
HOPL, LUROPA, ano PLACL Trlals
21,37,39
Paraneter HOPE
N = 9,297
EUROPA
N = 12,218
PEACE
N = 8,290
Age, y, mean 66 60 64
Dlabetes, 38 12 17
Prlor CA8G surgery/PC|, 40 55 72
S8P/D8P, mm Hg, mean 139/79 137/82 133/78
Prlor M|, 53 65 55
On antlplatelet tberapy, 76 92 90
On -blocker tberapy, 40 62 60
On statln tberapy, 29 58 70
Abbreviations: CA8G, coronary artery bypass gratt, LUROPA, Luropean Trlal on
Reouctlon ot Carolac Lvents Wltb Perlnooprll ln Stable Coronary Artery Dlsease,
HOPL, Heart Outcomes Preventlon Lvaluatlon, M|, myocarolal lntarctlon, PLACL,
Preventlon ot Lvents wltb Anglotensln Convertlng Lnzyme |nblbltlon, PC|, percutaneous
coronary lnterventlon.
!"# %&'()(*+, !-./&*/012 3+456 +& 7/8(9,(: /&- ;1,(&-+9,(:
ResearcbSHARL

perindopril was associated with an equivalent reduction
in mortality rate compared with ramipril (1.00 |95 CI,
0.81.24|).
44
In patients with HF, treatment with enalapril
or captopril has been associated with a higher rate oI patient
mortality compared with ramipril or perindopril therapy.
A limitation does exist Ior the aIorementioned data, as it was
observational, and thus cannot prove causality, although it is
refective oI real-world outcomes seen with diIIerent ACE
inhibitor therapies.
Masuelli et al
45
indicated that patients switched Irom
enalapril therapy to perindopril treatment had signifcant
improvements in New York Heart Association (NYHA)
Iunctional class (P 0.001), with signifcant reductions in
LV end-diastolic diameter (P = 0.001) and LV mass index
(P 0.001), as well as signifcant improvements in ejection
Iraction (EF) (14.2 increase), Irom 22.4 in patients taking
enalapril to 26.1 in patients taking perindopril (P 0.001).
While these improvements may, in part, be explained by
signifcant reductions in BP with perindopril use (9/8.3 mm
Hg at 6 months and 12.4/8.5 mm Hg at 12 months), 2 other
trials that enrolled patients with systolic HF indicated greater
benefts with perindopril treatment than enalapril therapy that
were not explained by enhanced BP-lowering eIIects.
46,47
In a study by Tsutamoto et al,
46
patients with ischemic HF
or dilated congestive HF experienced signifcant improve-
ments in NYHA Iunctional class (P value not reported),
LVEF (42.6 vs 44.9; P = 0.013), plasma brain natri-
uretic peptide (BNP) levels (127.4 32 pg/mL vs 83 18
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)
(33.0 1.4 vs 30.5 1.2; P = 0.030) with perindopril
therapy compared with baseline values. Patients who received
enalapril therapy showed no improvement in NYHA Iunc-
tional class (P value not reported), LVEF (41.1 2.5 vs
44.9 2.8; P = 0.29), plasma BNP levels (148.9 26 pg/
mL vs 169.3 33 pg/mL; P = 0.36), H/M ratio (2.09 0.07
vs 2.12 0.07; P = 0.450), and WR (31.1 1.4 vs
32.1 0.07; P = 0.395) compared with baseline values.
The benefcial eIIects seen with perindopril therapy could
not be explained by reductions in patient BP measurements
(111 3.1/68 1.3 mm Hg vs 112 2.8/68 1.0 mm Hg;
P value not reported), norepinephrine levels (414 30 pg/mL
vs 361 35 pg/mL; P = 0.19), aldosterone levels (103.8 17
pg/mL vs 92.8 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
none oI these values were signifcantly diIIerent between
treatments.
46
A study by Kasama et al
47
showed that patients with HF
who received perindopril experienced signifcant improve-
ments in total deIect score (39 10 to 34 9; P 0.01), H/M
ratio (1.62 0.27 to 1.76 0.29; P 0.01), WR (50 14
to 42 14; P 0.05), plasma BNP levels (226 155 pg/
mL to 141 90 pg/mL; P 0.0005 vs baseline; P 0.05
vs enalapril), LV end-diastolic volume (180 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-
ized to treatment with enalapril did not show any signifcant
improvements in LV end-diastolic volume (182 vs 174 mL;
P value not reported), LV end-systolic volume (120 vs
111 mL; P value not reported), LVEF (34 vs 35; P value
not reported), or plasma BNP level (248 vs 209 pg/mL;
P value not reported). Perindopril treatment also signifcantly
improved patient NYHA Iunctional class at 6 months
(P 0.001), whereas patient classifcation improvement on
enalapril therapy was less robust (P 0.05).
47
Perindopril is a unique ACE inhibitor that oIIers thera-
peutic improvements Ior patients with systolic dysIunction
in hemodynamic, Iunctional, and neurohumoral parameters
compared with enalapril treatment. The benefts oI perin-
dopril therapy cannot be explained by reductions in patient
BP alone. While treatment with enalapril has shown a 40
reduction (P = 0.002) in mortality rate in NYHA Iunctional
Figure 9. 8looo pressure reouctlon trom basellne values ln tour major ACL| trlals.
38
!"#"$%&'()%("% +) '&
ResearcbSHARL

class IV patients in the Cooperative North Scandinavian
Enalapril Survival Study (CONSENSUS), 6 oI patients
experienced hypotension that required withdrawal oI
enalapril.
48
Moreover, the results oI CONSENSUS were
published in 1987 and the population studied had severe HF
(NYHA class IV). It is uncertain iI enalapril would provide
such a robust (iI any) beneft compared with current opti-
mal medical therapy, especially iI patients with less severe
HF were studied. While there have been no studies, to our
knowledge, oI the eIIect oI perindopril therapy on morbidity
and mortality rates in patients with systolic HF, it could be
hypothesized that treatment with perindopril would provide
equivalent iI not superior reductions in major CV endpoints
compared with enalapril treatment based on the 3 aIoremen-
tioned trials in this setting.
Patients With HF and Preserved EF
Perindopril is the only ACE inhibitor with evidence-based
fndings in the population oI patients with HF and preserved
EF.
49
In the Perindopril in Elderly People With Chronic HF
(PEP-HF) trial, perindopril treatment was associated with
a borderline signifcant reduction in the primary outcome
at 1 year, a reduction in composite oI all-cause mortality
and unplanned HF hospitalization rates (relative risk
reduction |RRR|, 31; 95 CI, 0.4741.010; P = 0.055),
and a signifcant reduction in hospitalization rates Ior HF
(RRR, 37; 95 CI, 0.4080.966; P = 0.033). Signifcant
patient improvements were seen in NYHA Iunctional class
(P 0.030) and 6-minute walking distance (P = 0.011).
49

AIter 1 year trial duration, 'drop-in perindopril treatment
was allowed into the placebo-treated group, which resulted
in a waning oI beneft (groups became perindopril-treated
vs placebo-plus-perindopriltreated patients). Perindopril
therapy signifcantly reduced patient hospitalization rates
Ior HF and improved patient exercise tolerance, NYHA
Iunctional class, and showed a borderline signifcant reduc-
tion Ior 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 Outcones Post-AMl
OI 7512 patients who flled a prescription Ior an ACE
inhibitor within 30 days oI hospital discharge aIter an AMI,
enalapril, Iosinopril, captopril, quinapril, and lisinopril
treatment were associated with higher patient mortality rate
than ramipril therapy; adjusted HRs (95 CIs) Ior patients
treated with the other ACE inhibitors were: 1.47 (1.141.89),
1.71 (1.292.25), 1.56 (1.132.15), 1.58 (1.102.82), and
1.28 (0.981.67), respectively, whereas patients taking
perindopril had a mortality rate similar to that oI patients
on ramipril (0.98 |95 CI, 0.601.60|).
13
The study
authors concluded that patient survival rates in the frst
year aIter an AMI were less with enalapril, Iosinopril,
captopril, quinapril, or lisinopril treatment compared with
ramipril therapy, and that treatment with perindopril was
benefcially equivalent to ramipril treatment.
13
Limitations
to be noted about the study include the Iact that it was
observational and retrospective in design, and, thus, could
not prove causality; however, the results oIIer real-world
evidence consistent with data Irom trials using ramipril and
perindopril to treat patients with and at high risk Ior CHD.
Another study enrolled 14 608 consecutive patients with
ST-segment elevation AMI in a prospective multicenter
registry Irom Germany to compare the eIIect oI ramipril
therapy (used in 4.7 oI patients) with other ACE inhibitors
(used in 39 oI patients), and no ACE inhibitor treatment on
patient in-hospital mortality rate. In a multivariate analysis,
TabIe 3. Cllnlcal Trlals ot ACL |nblbltors ln Patlents Wltb CHD
ACE lnhibitor TriaI ResuIts
Perlnooprll LUROPA
21
Posltlve
20 relatlve rlsk reouctlon on tbe
prlmary enopolnt (Cv oeatb, M|, or
carolac arrest) (95 C| 929, ! = 0.0003)
wltb perlnooprll versus placebo.
Ramlprll HOPL
37
Posltlve
22 reouctlon ln tbe prlmary outcome
(M|, stroke or Cv oeatb) (relatlve rlsk
0.78: 95 C|: 0.700.86, ! 0.001).
Tranoolaprll PLACL
39
Negatlve
No oltterence ln tbe prlmary enopolnt
(Cv oeatb, nontatal M|, CA8G, PC|)
between tranoolaprll (21.9) ano placebo
(22.5) (HR 0.96, 95 C|: 0.881.08,
! = 0.43).
Qulnaprll QU|LT
40
Negatlve
Tbe rates ot Cv mortallty, overall
mortallty, ano nontatal AM| were slmllar
between patlents treateo wltb qulnaprll
ano tbose glven placebo (1.4 vs
1.5, 3.1 vs 3.2, ano 4.1 vs 4.6,
respectlvely, ! = NS
tor eacb enopolnt).
Lnalaprll CAMLLOT
43
Negatlve
No slgnlcant reouctlon ln Cv eventswltb
enalaprll versus placebo (20.2 vs 23.1),
(HR, 0.85, 95 C|, 0.671.07, ! = 0.16).
Abbreviations: ACL, anglotensln-convertlng enzyme, CHD, coronary beart olsease,
CAMLLOT, Comparlson ot Amloolplne versus Lnalaprll to Llmlt Occurrences ot
Tbrombosls, LUROPLAN, Luropean Trlal on Reouctlon ot Carolac Lvents Wltb
Perlnooprll ln Stable Coronary Artery Dlsease, HOPL, Heart Outcomes Preventlon
Lvaluatlon, PLACL, Preventlon ot Lvents wltb Anglotensln Convertlng Lnzyme |nblbltlon,
QU|LT, Qulnaprll |scbemlc Lvent Trlal.
!"# %&'()(*+, !-./&*/012 3+456 +& 7/8(9,(: /&- ;1,(&-+9,(:
ResearcbSHARL

treatment with ACE inhibitors was associated with lower
patient in-hospital mortality and major CV event rates, but
ramipril therapy was associated with a 46 lower patient
in-hospital mortality rate (95 CI, 0.320.90) and a 35
reduction in major CV events (95 CI, 0.460.93) than
treatment with other ACE inhibitors. However, patient HF
was not signifcantly impacted by ramipril therapy compared
with other ACE inhibitors (perindopril was not specifcally
assessed in this study).
50
Perlnooprll
The Perindopril and Remodeling in Elderly With Acute
Myocardial InIarction (PREAMI) trial was a 12-month,
double-blind, randomized, parallel-group, multicenter trial
that enrolled 1252 patients (aged 65 years) with preserved
LVEF (average LVEF, 59.1) to compare therapy with perin-
dopril 8 mg daily with placebo.
51
OI the 43 oI patients who
underwent thrombolysis, 90 did so within 6 hours oI AMI.
The primary endpoint (patient mortality, hospitalization Ior
HF, or LV remodeling) was signifcantly reduced by treatment
with perindopril (RR, 0.22; 95 CI, 0.160.28; P 0.001),
which was mainly driven by a reduction in LV remodeling
(126 patients |28| on perindopril vs 226 patients |51|
on placebo; P 0.001). Moreover, the mean increase in
patient LV end-diastolic volume was signifcantly lower
with perindopril treatment compared with placebo treatment
(0.7 mL vs 4.0 mL; P 0.001, respectively). A subanalysis
oI EUROPA in the PREAMI-like population ( 65 years,
LVEF 40 in patients with a previous AMI) indicated a
signifcant 36.1 RRR (P = 0.03) Ior the primary EUROPA
endpoint aIter 3 years oI perindopril treatment. In summary,
perindopril therapy was shown to be benefcial in patients
with a recent AMI, despite patients having a normal EF
(mean LVEF, 59.1).
51
Lnalaprll
The Cooperative New Scandinavian Enalapril Survival
Study II (CONSENSUS-II) was a multicenter, random-
ized, double-blind, placebo-controlled, parallel-group trial
that compared treatment with enalapril with placebo in
6090 patients with AMI.
48
Enalapril therapy, started within
24 hours oI AMI, increased patient mortality risk compared
with placebo (HR, 1.10; 95 CI, 0.931.29; P = 0.26).
48

The increase in mortality with enalapril treatment versus
placebo could be argued as being caused by the use oI an
intravenous dosage Iorm oI enalapril, causing hypoten-
sion, 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 eIIect that
has not been seen with orally administered perindopril.
10,53

Enalapril, as an individual compound (not the intravenous
Iormulation) was the likely cause oI the 4-Iold increase in
the rate oI patient hypotension when compared with placebo
in CONSENSUS-II (12 vs 3; P 0.001, respectively).
The disparate eIIects oI enalapril treatment compared with
perindopril therapy on patients with hypotension are Iurther
elucidated when evaluating tolerability data oI these 2 ACE
inhibitors Irom previous trials in patients with HF, in which
orthostatic/symptomatic hypotension was seen in 17 oI
enalapril users compared with 1.9 oI patients given per-
indopril.
54,55
Orally administered enalapril can cause severe
hypotension at a much higher rate than treatment with oral
perindopril. II a clinician is selecting an ACE inhibitor Ior
a patient with AMI, perindopril and ramipril seem to be the
saIer therapeutic choices.
ConcIusion
Perindopril has been shown to have a longer duration
oI action, higher lipophilicity, and stronger tissue ACE-
inhibiting properties compared with other ACE inhibitors.
Moreover, there are several clinical trials supporting the CV
beneft oI perindopril therapy in many clinical settings (eg,
patients with AMI, those with HF and preserved EF, patients
with or at high risk Ior CHD without HF). Thus, perindopril
should be strongly considered as a frst-choice ACE inhibitor
Ior treatment oI patients with HF and preserved EF and in
patients with or at high risk Ior 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 Ior CHD with normal LV Iunction.
21,37
ThereIore, in
this patient population, these 2 agents should be frst-choice
ACE inhibitor therapy. Although ramipril has demonstrated
excellent ability to improve patient clinical outcomes, most
oI the trials were completed decades ago, prior to the cur-
rent era oI optimal medical therapies. Only use oI the ACE
inhibitor perindopril has demonstrated clear reductions in CV
endpoints in patients who have been treated in ways that are
refective oI current-day intensive practice (ie, on optimal
medical therapy and at a lower baseline risk oI CV events
compared with patients receiving ramipril in HOPE). More-
over, perindopril is the only ACE inhibitor with evidence Ior
improving morbidity and mortality rates in patients with HF
who have a preserved EF.
49
ThereIore, in patients with or at
high risk Ior CHD (without HF) and HF with preserved EF,
!"#"$%&'()%("% +) '&
ResearcbSHARL

perindopril should be strongly considered as frst-choice ACE
inhibitor, perhaps even prior to ramipril use.
In the Iuture, we are hopeIul that perindopril will become
more widely prescribed and used, as it possesses an impres-
sive amount oI evidence supporting its ability to reduce CV
endpoints in a wide range oI patient populations. Clinicians
should be aware that a clear and complete class eIIect does
not seem to exist with the ACE inhibitors. II we are to practice
evidence-based medicine, we should be preIerentially prescrib-
ing medications that have the strongest evidence (perindopril
and ramipril) Ior improving long-term clinical CV outcomes.
Conict of lnterest 5tatenent
James J. DiNicolantonio, PharmD, Carl J. Lavie, MD, and
James H. O`KeeIe, MD, disclose no confict oI interest.
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