THEMED ARTICLE y Hyper- & Hypo-tension Review

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The impact of ACE inhibition on

all-cause and cardiovascular
mortality in contemporary
hypertension trials: a review
Expert Rev. Cardiovasc. Ther. 11(6), 705–717 (2013)

Roberto Ferrari*1 and
Eric Boersma2
1Department of Cardiology and
LTTA Centre, University Hospital of
Ferrara, Italy
2Department of Cardiology,
Erasmus Medical Center,
Rotterdam, The Netherlands
*Author for
correspondence: Tel.: +39
0532 239882 Fax: +39
0532 237841 fri@unife.it
The renin–angiotensin–aldosterone system is a key therapeutic target in hypertension. The
latest meta-analysis of mortality reduction with angiotensin-converting enzyme (ACE) inhibitors
and angiotensin receptor blockers (ARBs) in hypertension features 158,998 patients from 20
contemporary hypertension trials. ACE inhibitors and ARBs significantly reduced relative risk for
all-cause mortality by 5% (p = 0.032) and cardiovascular mortality by 7% (p = 0.018) in
populations with a high prevalence of hypertension (≥66%). ACE inhibitors produced a 10%
reduction in relative risk for all-cause mortality (p = 0.004) and a trend toward a 12% reduction
in cardiovascular mortality (p = 0.051), whereas ARBs had no effect. On balance, mortality
evidence suggests that in hypertension, ACE inhibitors should be considered ahead of ARBs,
and ARBs restricted to patients intolerant of ACE inhibitors.
Keywords: ACE inhibitor • all-cause mortality • angiotensin II • ARB • bradykinin • cardiovascular mortality •
hypertension • meta-analysis

More than a quarter of the world’s population
and more than half of 60-year-olds have
hyper-tension [1], the leading cause of
premature death worldwide [101,102] .
European hypertension guidelines state that
mortality reduction should be the ultimate
goal of antihypertensive treat-ment [2], a goal
confirmed by the 2011 NICE guidelines [101].
Management of hypertension is a challenge,
particularly in patients with high cardiovascu-
lar risk. In 1509 American hypertensive patients
aged ≥30 years from the 2005–2006 National
Health and Nutrition Examination Survey,
treatment rates ranged from 58% to 75%,
depending on Framingham cardiovascular risk
score [3]. Hypertension control rates ranged
from good (>80%) in patients with low
cardiovascu-lar risk (assessed using the 10-year
Framingham risk score) to unsatisfactory
(<50%) in patients with high cardiovascular risk
[3]. Thus, inter-estingly, patients in most need of
treatment in the National Health and Nutrition
Examination Survey were the worst protected.
The renin–angiotensin–aldosterone system
(RAAS) is one of the key therapeutic targets in
patients with hypertension, as an overactive
RAAS is strongly associated with high blood
pressure (BP). The RAAS is an important reg-
ulator of hemodynamic stability and controls
circulating volume and electrolyte balance in the
human body [4]. RAAS inhibitors, which have
been used in the treatment of hypertension for the
past 30 years, include angiotensin-convert-ing
enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs) [3]. These drugs could positively
influence cardiovascular and cerebro-vascular
outcomes in hypertensive patients, as hypertension
is a known risk factor for both cardiovascular and
cerebrovascular disease [2,4].
Most individual ACE inhibitor and ARB trials in
hypertension are statistically underpowered to
detect any impact on mortality. Quantitative meta-
analyses of multiple trials can overcome this
statistical problem [5]. All of which makes the
results of our recent meta-analysis of ran-domized
controlled trial data in populations receiving
contemporary antihypertensive medi-cation
particularly relevant for determining the long-term
consequences of treatment with ACE inhibitors
and ARBs on all-cause and cardiovascular
mortality in hypertension [6]. The meta-analysis
showed several discrepancies

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 Review Ferrari & Boersma
between the two classes of drugs as well as between
individual compounds within one of these classes.
The aim of this article is to review the impact of RAAS
inhibi-tors on mortality reduction in hypertensive patients and
to explore the differences between ACE inhibitors and ARBs
in terms of clinical and pathophysiological effects.
Meta-analysis of contemporary trials in hypertension:
all-cause & cardiovascular mortality
Each meta-analysis is influenced by the methodology used, and
the methods of our meta-analysis are described in detail in the
main results paper that appeared in the European Heart Journal
[6] . Briefly, a systematic search of PubMed (Ovid
MEDLINE®) and ADIS Clinical Trials Insight (ISI Web of
Science) using a wide range of keywords, such as
‘antihypertensive agents’, ‘angi-otensin-converting enzyme
inhibitors’, ‘hypertension’ and ‘mor-tality’, identified
prospective randomized controlled ACE inhibi-tor and ARB
morbidity–mortality trials published in English between 2000
and 2011 [6]. Post-hoc analyses and subanalyses were excluded,
as well as trials in specific populations selected for criteria other
than hypertension (heart failure, acute myocar-dial infarction
[MI], stroke and so forth). For each trial, patient population,
treatments, protocol and end points were critically and
independently evaluated by two investigators. Of the publi-
cations identified, 20 were included in the meta-analysis. These
20 trials were included based on the following: >66% of patients
having hypertension according to individual trial hypertension
definitions; incidence of all-cause mortality being sufficiently
high (n > 10); RAAS inhibitors not being used simultaneously in
both arms; a relatively high number of participants (n > 100) and
trials lasting ≥1 year.
The end points were all-cause mortality and cardiovascular
mortality [6]. All-cause mortality data were available for all 20
trials [7–25] and cardiovascular mortality data were available for
16 trials [7–14,16,20–25]. Our analysis was based on incidence of
all-cause and cardiovascular mortality. For the active treatment
and control arms, estimates of the incidences of all-cause mor-
tality and cardiovascular mortality were calculated. Estimates of
absolute and relative reductions in the incidence of end points in
the active treatment arm were also determined. Reported hazard
ratios (HRs) and confidence intervals or standard errors were
used to determine estimates of relative treatment effects. HR data
were available for 17 trials and calculated using incidence rates
for three.
Trial characteristics are presented in Table 1 [7–25]. In total,
158,998 patients were randomized to active (n = 71; 401) or
control treatment (n = 87; 597). Most patients were hyper
tensive (91%), mean baseline systolic BP was 153 mmHg
(range: 135–182 mmHg), mean age was 67 years (range: 59–
84 years) and 58% of participants were male [6].
The authors noted a significant reduction in the relative risk (RR)
of all-cause mortality of 5% (HR = 0.95; 95% CI: 0.91–1.00; p =
0.032) with RAAS inhibitors [6]. A substantial part of this mor-tality
reduction was due to the effect of ACE inhibitors, which pro-duced a
significant 10% reduction in the RR of all-cause mortality
706
(HR = 0.90; 95% CI: 0.84–0.97; p = 0.004) (Figures 1 & 2). No sig-
nificant reduction in the RR of all-cause mortality could be dem-
onstrated with ARBs (HR = 0.99; 95% CI: 0.94–1.04; p = 0.68).
The treatment–effect difference between ACE inhibitors and
ARBs was significant (p = 0.036 for interaction).
Pooled analysis of RAAS inhibitor trials also demonstrated a
significant reduction in the RR of cardiovascular mortality, by
7% (HR = 0.93; 95% CI: 0.88–0.99; p = 0.018) (Figure 3) [6]. Of the
13 ARB trials eligible for all-cause mortality analysis, four trials
did not report cardiovascular mortality data. A pooled analysis of
the rest (nine trials featuring 73,100 patients) showed that ARBs
had no effect on cardiovascular mortality (HR = 0.96; 95% CI:
0.90–1.01; p = 0.14). As with all-cause mortality, car-diovascular
mortality reduction with RAAS inhibitors was domi-nated by the
effect of ACE inhibitors. With ACE inhibitors (seven trials
featuring 76,615 patients), there was a clear trend toward a RR
reduction in cardiovascular mortality of 12% (HR = 0.88; 95%
CI: 0.77–1.00; p = 0.051) (Figure 4).
Trial variation, in terms of hypertensive population, dosage
and BP target, was a limiting factor. Other limitations included
the unavailability of information about comorbidities and
therapy, the use of estimated follow-up times and the disparity in
follow-up length of some trials. More importantly, our results
were based on good-quality data from randomized controlled
trials in a large number of patients (n = 158,998) and thus may be
considered reliable overall [6].
ACE inhibitors versus ARBs: clinical evidence
The results the authors obtained and reported above indicate that
ACE inhibitors and ARBs have different effects on mortality
reduction in hypertension, although they both act on the RAAS
and may appear similar at first glance; ACE inhibitors and ARBs
share many of the same clinical benefits, such as BP reduction,
stroke reduction and improvement of heart failure symptoms [26]
and both are used to treat cardiovascular risk factors in different
types of cardiovascular disease [27]. All this raises the question, if
ACE inhibitors and ARBs have so many clinical benefits in com-
mon, why are there differences in the way they reduce mortality
in hypertension?
If one looks beyond hypertension, this is not the first report of
differences in mortality reduction between ACE inhibitors and
ARBs. In a meta-analysis of MI in 11 randomized controlled ARB
trials versus active treatment or placebo in 55,050 patients [28], nine
trials had excess rates of MI, which reached significance in two trials
(one trial vs placebo and one trial vs active treatment [amlodipine]).
ARBs significantly increased the risk of MI by 8% (95% CI: 1–16; p
= 0.03) and had no effect on all-cause mortality (odds ratio = 1.01;
95% CI: 0.96–1.06; p = 0.80). A parallel anal-ysis of 150,943
patients in 42 ACE inhibitor trials showed that ACE inhibitors
significantly reduced all-cause mortality, cardio-vascular death and
MI by 9% (95% CI: 0.86–0.95), 12% (95% CI: 0.82–0.95) and 14%
(95% CI: 0.82–0.90) versus placebo and all active comparators,
including ARBs (all p < 0.001) [28].
This lack of mortality reduction with ARBs was further -
underlined by Bangalore et al. in 2011 in a systematic review of
Expert Rev. Cardiovasc. Ther. 11(6), (2013)
 ACE inhibition & mortality in contemporary hypertension trials Review

37 ARB studies in 147,020 patients with Table 1. The 20 trials analyzed in the meta-analysis.
hypertension, heart failure, stroke, acute
MI, coronary artery disease or new-onset Agent Control Trial Year n Ref.
diabetes mellitus [29]. The review found ACE inhibitors
that ARBs were not associated with any Enalapril Diuretic ANBP-2 2003 6083 [7]
reduction in the RR of all-cause mortality (hydrochlorothiazide)
(RR = 1.00; 95% CI: 0.97–1.02; p = 0.75) Enalapril/imidapril/ Nifedipine JMIC-B 2004 1650 [8]
or cardiovascular mortality (RR = 0.99; lisinopril
95% CI: 0.94–1.04; p = 0.73) compared Lisinopril Chlorthalidone or ALLHAT 2002 33,357 [9]
with controls [29]. However, the majority
amlodipine
of these data were retrospective and thus Lisinopril Diuretic or no Pilot HYVET 2003 1283 [10]
not randomized.
Two randomized controlled trials pro- treatment
Perindopril Atenolol ASCOT-BPLA 2005 19,257
spectively investigated whether there is [11]
a difference in outcome between ACE (amlodipine) (bendroflumethiazide)
inhibitors and ARBs – ONTARGET (in Perindopril Placebo ADVANCE 2007 11,140 [12]

patients with high cardiovascular risk) [30] (indapamide)

and DETAIL (in patients with diabetic Perindopril Placebo HYVET 2008 3845 [13]

nephropathy) [31]. The results of these trials (indapamide)

suggested there was no difference in out- ACE inhibitor total 76,615
come, but reductions in BP with the ARB Angiotensin receptor blockers
and ACE inhibitor were different: the ARB Candesartan Placebo SCOPE 2003 4937 [14]
telmisartan reduced BP more than ramipril
in ONTARGET and more than enalapril Candesartan Amlodipine CASE-J 2008 4703 [15]

in DETAIL. It is worth noting that in both Candesartan Non-RAAS inhibitor HIJ-CREATE 2009 2049 [16]

trials a long-acting ARB was compared Eprosartan Nitrendipine MOSES 2005 1352 [17]
with a short-acting ACE inhibitor given Irbesartan Amlodipine or IDNT 2001 1715 [18]
once daily in the morning.
placebo
The relationship between BP decrease Losartan Placebo RENAAL 2001 1513
and reduction in cardiovascular risk is [19]

not straightforward; as is the case in the Losartan Atenolol LIFE 2002 9193 [20]

ONTARGET and DETAIL trials, large (hydrochlorothiazide) (hydrochlorothiazide)

decreases in BP do not always lead to Telmisartan Placebo PRoFESS 2008 20,332 [21]

large decreases in the risk of cardiovascu- Telmisartan Placebo TRANSCEND 2008 5926 [22]
lar outcomes and mortality [14,21,22]. The Valsartan Amlodipine VALUE 2004 15,245 [23]
mean systolic BP reductions achieved with
Valsartan Non-RAAS inhibitor JIKEI HEART 2007 3081 [24]
ARBs in three randomized controlled tri-
als – 3.2 mmHg in the SCOPE study, Valsartan Non-RAAS inhibitor KYOTO HEART † 2009 3031
4 mmHg in the TRANSCEND study and Valsartan Placebo NAVIGATOR 2010 9306 [25]

3.8 mmHg in theh PRoFESS study – did Angiotensin receptor blocker total 82,383
not translate into better reduction of car- Overall total 158,998
diovascular outcomes and mortality risk
versus placebo. Several ARB meta-analyses Unpublished data.
†

have also shown that BP reduction with ACE: Angiotensin-converting enzyme; RAAS: renin–angiotensin–aldosterone system.
Data adapted with permission from [6].
ARBs, regardless of comparator, does not
reduce the risk of MI [32–34]. By contrast, there is evidence that reduction. This meta-analysis of the Blood Pressure Lowering
BP-dependent beneficial effects in the prevention of stroke and Treatment Trialists’ Collaboration also showed that ARBs had
heart failure are similar for ACE inhibitors and ARBs [35]. the opposite effect; they increased the BP-independent RR
The reverse may also be true: small decreases in BP may of coronary heart disease by 8% (95% CI: -17–39), and the
lead to important decreases in cardiovascular risk. In a meta- difference between ACE inhibitors and ARBs was significant
analysis of 26 randomized controlled trials featuring 146,838 (p = 0.002) [35].
hypertensive patients [35], ACE inhibitors caused small In view of these data, differences in BP-independent effects
decreases
in BP but induced an additional 9% BP-independent reduction between ACE inhibitors and ARBs [35], such as diminution
in the RR of coronary heart disease (95% CI; 3–14%) in addi- of oxidative stress and endothelial dysfunction, improvement
tion to the reduction in RR of coronary heart disease from BP in glucose metabolism, and inhibition and stabilization of

www.expert-reviews.com 707
 Review Ferrari & Boersma

ACE inhibitor All-cause mortality HR (95% CI) ARB All-cause mortality HR (95% CI)
(random effects model) (random effects model)

RENAAL 1.03 (0.83–1.29)

ALLHAT 1.03 (0.90–1.15) IDNT 0.92 (0.69–1.23)

LIFE 0.88 (0.77–1.01)

ANBP-2 0.90 (0.75–1.09) SCOPE 0.96 (0.81–1.14)

Pilot HYVET 0.99 (0.62–1.58) VALUE 1.04 (0.94–1.14)

MOSES 1.07 (0.73–1.57)

JMIC-B 1.32 (0.61–2.86) JIKEI HEART 1.09 (0.64–1.85)

0.89 (0.81–0.99) PRoFESS 1.03 (0.93–1.14)

ASCOT-BPLA TRANSCEND
1.05 (0.91–1.22)
ADVANCE 0.86 (0.75–0.98) CASE-J 0.85 (0.62 –1.16)

HIJ-CREATE 1.18 (0.83–1.67)

HYVET 0.79 (0.65–0.95) KYOTO HEART 0.76 (0.40–1.30)

NAVIGATOR 0.90 (0.77–1.05)

Overall 0.90 (0.84–0.97) Overall 0.99 (0.94–1.04)

0.50 0.75 1 1.33 2.0 0.50 0.75 1 1.33 2.0

HR (log scale) HR (log scale)

ACE inhibitor better Control better ARB better Control better
p for heterogeneity = 0.310; I2 16% p for heterogeneity = 0.631; I2 0%

Figure 1. The effect of treatment on all-cause mortality in angiotensin-converting enzyme inhibitor and angiotensin
receptor blocker hypertension trials. The effect of treatment on all-cause mortality was significant with ACE inhibitors (p =
0.004), but not with ARBs (p = 0.68).
ACE: Angiotensin-converting enzyme; ARB: Angiotensin receptor blocker; HR: Hazard ratio.
Reproduced with permission from [6].

atherosclerotic plaque, might account for some of the differ-
ences seen in mortality reduction between these two types of
RAAS inhibitor [36]. Other differences between ACE inhibi-
tors and ARBs exist, notably the way in which they act on the
RAAS, and these may also explain the differences in
mortality reduction.
ACE inhibition versus AT1 receptor blockade:
experimental evidence
ACE inhibitors, unlike ARBs, prevent ACE from converting
angiotensin I into angiotensin II (Figure 5) [37]. Angiotensin II, a
vasoconstrictor in its own right, has numerous deleterious effects
[26,36]. Angiotensin II damages vascular endothelium (increases
oxidative stress, reduces nitric oxide [NO] bioavail-ability,
increases vascular apoptosis) and vascular structure (pro-vokes
vascular remodeling, atherosclerosis, arterial stiffening). It is a
key mediator of target-organ damage, affecting the heart, brain
and kidneys. In the heart, angiotensin II causes hypertro-phy,
coronary vasoconstriction and increased QT interval; in the
brain, it increases sympathetic nervous system activity and
inflammation and negatively affects cerebral circulation and in
the kidney, it causes increased renin production, nephropathy,
albuminuria and, eventually, renal fibrosis. Angiotensin II also
modulates secretion of the hormone aldosterone, which increases
sodium reabsorption, water retention, blood volume and BP. The
resulting target-organ damage from these pathological mecha-
nisms can lead to a host of pathological outcomes, including MI,
heart failure, stroke and renal failure.
Inhibition of angiotensin II production via ACE inhibition is
therefore beneficial, improving endothelial function and reduc-
ing atherogenesis in a number of different ways. Inhibition of
angiotensin II decreases proinflammatory marker levels (TNF-α,
IL-6, monocyte chemoattractant protein 1, and PDGF) and
atherogenesis (decreases in levels of vascular cellular adhe-sion
molecule and intracellular adhesion molecule, which in turn
decrease endothelial adhesion of lymphocytes, monocytes and
eosinophils). Inhibition of angiotensin II production also inhibits
fibrosis by decreasing levels of TGF-β and PAI-1 and reduces
endothelial dysfunction by enhancing the action of NO synthase.
As angiotensin II levels decrease, levels of PAI-1 and tissue
factor decrease, which prevents thrombosis [26]. It is fair to say
that although ACE inhibitors reduce the production of

708 Expert Rev. Cardiovasc. Ther. 11(6), (2013)

 ACE inhibition & mortality in contemporary hypertension trials
All-cause mortality HR (95% CI)
ACE inhibitor trial (ACE inhibitor) n (random effects model)
42,373
ALLHAT (lisinopril)
ANBP–2 (enalapril)
Pilot HYVET (lisinopril, enalapril)
JMIC-B (lisinopril, enalapril, imidapril)
ASCOT† (perindopril)
ADVANCE† (perindopril) 34,242
HYVET† (perindopril)
All ACE inhibitor trials 76,615
Figure 2. Impact of angiotensin-converting enzyme inhibitors on all-cause mortality.
†Significant reduction in all-cause mortality in trial.
ACE: angiotensin-converting enzyme; HR: Hazard ratio.
angiotensin II, the benefits of treatment may not be sustained over
time due to so-called ‘escape’ of angiotensin II and aldoster-one [38–
41]. Angiotensin II escape results from increased plasma
concentrations of angiotensin I (due to the unopposed activity of
renin caused by the interruption of negative feedback loops), which
is eventually metabolized to angiotensin II by non-ACE enzymes,
such as chymase [42]. Aldosterone escape is the con-secutive,
progressive increase of aldosterone levels to normal or
elevated concentrations following long-term administration of
ACE inhibitors.
In addition to inhibition of angiotensin II production, ACE
inhibition also increases levels of bradykinin, one of the most
important pharmacologically active molecules involved in RAAS
inhibition and one which improves arterial function, reduces BP and
has important cardioprotective effects [43]. Essentially, bradykinin
could be said to have opposite effects to those of angi-otensin II (a
sort of local biological yin and yang), which results in vasodilation
via the release of NO [44] and other relaxing factors, such as
prostaglandins, prostacyclin and endothelium-derived
hyperpolarizing factor. Not only does the vasodilation of bradykinin
counteract the vasoconstriction of angiotensin
II but bradykinin also prevents apoptosis [36]. The benefits of
bradykinin are exclusive to ACE inhibitors, as only they stop
www.expert-reviews.com
Review
p-value
0.99 (0.89–1.10) 0.818
0.87 (0.81–0.93) <0.001
0.90 (0.84–0.97) 0.004
0.6 0.8 1.0 1.2
Favors Favors
ACE inhibitor control
the breakdown of bradykinin into inactive peptides. All these
effects are highly dependent on the capacity of ACE inhibitors to
actively inhibit local, rather than circulating, ACE.
Negative effects of angiotensin II are also reduced by ARBs,
but in a different way. ARBs stop angiotensin II binding to AT 1
receptors (Figure 5) [37], which prevents many detrimental car-
diovascular effects. Selective blockade of AT 1 receptors attenu-
ates vasoconstriction, sympathetic stimulation, oxidative stress,
release of inflammatory factors and aldosterone release. Clear
advantages of selective AT1 receptor blockade compared with
ACE inhibition are the absence of angiotensin II escape and
highly effective prevention of deleterious effects mediated by AT 1
receptor activation. The selectivity of AT 1 receptor blockade may,
however, also have negative consequences, as it leads to
compensatory increases in angiotensin II formation and con-
centration and allows free angiotensin II to bind other angio-
tensin receptors (AT2, AT 3 and AT4), leading to mixed clinical
effects. Plaque instability and thrombus formation are caused by
activation of AT2 receptors [28], as is matrix metalloprotein-ase 1-
induced fibrous cap rupture of atherosclerotic plaque [45].
Stimulation of AT2 receptors also causes hypertrophy, inflam-
mation and apoptosis, but vasodilation and decreased prolif-
eration too. Long-term treatment with ARBs is also associated
709
 Review Ferrari & Boersma

and platelets, producing vasodilation

Cardiovascular mortality HR (95% CI) and impairing thrombosis [47]. Levels of
(random effects model) angiotensin-(I–VII) are increased mark-
Trial HR (95% CI) edly by long-term treatment with ACE
LIFE 0.87 (0.72–1.05) inhibitors and ARBs.
In summary, ACE inhibitors prevent
ACE from converting angiotensin I into
ALLHAT 1.02 (0.93–1.12)
angiotensin II, a vasoconstrictor respon-
ANBP-2 0.99 (0.72–1.35)
sible for many harmful effects and a key
SCOPE 0.94 (0.75–1.18) mediator of target-organ damage. ACE
Pilot HYVET 1.00 (0.60–1.67) inhibitors also prevent the breakdown of
JMIC-B 1.04 (0.34–3.23) bradykinin, a peptide with vasculo- and
cardio-protective effects that reduces
VALUE 1.01 (0.86–1.18)
BP. Selective blockade of AT1 receptors
ASCOT-BPLA 0.76 (0.65–0.90)
by ARBs prevents many negative car-
diovascular effects, but may also cause
JIKEI HEART 1.03 (0.41–2.60) unintended clinical effects, both posi-
ADVANCE 0.82 (0.68–0.98)
tive and negative, related to the selectiv-
ity of AT receptor blockade. Together,
HYVET 0.77 (0.60–1.01)
these processes may explain the distinct
PRoFESS 0.94 (0.87–1.01) impacts of these agents on all-cause and
TRANSCEND 1.03 (0.85–1.24) cardiovascular mortality.

Mortality reduction with ACE

HIJ-CREATE 1.14 (0.66–1.95) inhibitors: are they all the same?
KYOTO HEART 0.66 (0.30–1.60) Further examination of the all-cause and
NAVIGATOR 1.09 (0.85–1.40) cardiovascular mortality reduction with
ACE inhibitors in our meta-analysis of
Overall 0.93 (0.88–0.99) RAAS inhibition in hypertension [6]
found that perindopril trials had a consid-
0.50 0.75 1 1.33 2.0 erable bearing on these results. The largest
HR (log scale) reductions in the RR of all-cause mortal-
Favors RAAS inhibitor Favors control ity (-13%) occurred in trials featuring
the ACE inhibitor perindopril (pooled
HR = 0.87; 95% CI: 0.81–0.93; p < 0.001)
Figure 3. Random-effects model comparison of cardiovascular mortality (Figure 2) [11–13].
reduction in angiotensin-converting enzyme inhibitor and angiotensin receptor When the trend in cardiovascular mor-
blocker trials. tality risk reduction exhibited by ACE
ARB: angiotensin receptor blocker; HR: Hazard ratio; RAAS: Renin–angiotensin– inhibitors (HR = 0.88; 95% CI: 0.77–1.00;
aldosterone system.
Adapted with permission from [6]. p = 0.051) was examined in more detail, it
also appeared to be driven by perindopril.
With perindopril-based trials, there was
with aldosterone escape, which is principally modulated via an a significant 22% reduction in cardiovascular mortality (three
AT2-dependent mechanism [39–41]. The effect of AT3 receptor trials – ASCOT-BPLA, ADVANCE and HYVET – featuring
stimulation is largely unknown and stimulation of AT4 recep- 34,242 patients [11–13]; HR = 0.78; 95% CI: 0.70–0.87; p <
0.001),
tors may promote thrombosis via release of PAI-1, an important but no cardiovascular mortality reduction with other ACE inhibi-
inhibitor of fibrinolysis (Figure 5) [37]. tors (four trials featuring 42,373 patients [7–10]; HR = 1.02;
RAAS inhibitors can also affect parts of the RAAS other 95% CI: 0.92–1.11; p = 0.75) (Figure 4).
than the ACE/angiotensin II/AT1 axis, which is the best known Examination of the characteristics of this molecule shows
axis of the RAAS. Harmful effects caused by activation of that perindopril has a long duration of antihypertensive action
ACE/angiotensin II/AT1 can be counterbalanced by beneficial (trough–peak ratio, 75–100%) [48,49] and has been found to
have
effects of a less well-known RAAS axis, the ACE2/angiotensin- an effect on key parameters of BP, such as brachial BP, cen-
(I–VII)/Mas axis [46]. ACE2, a homologue of ACE, converts tral BP, pressure wave reflection, BP variability and 24-h and
angiotensin II into angiotensin-(I–VII), a heptapeptide that nighttime BP [11,50–52]. Perindopril is lipophilic and is able to
binds to Mas receptors in the cell wall of endothelial cells penetrate tissue [53] and therefore, has a long-lasting effect on
710 Expert Rev. Cardiovasc. Ther. 11(6), (2013)
 ACE inhibition & mortality in contemporary hypertension trials
Cardiovascular mortality HR (95% CI)
ACE inhibitor trial (ACE inhibitor) n (random effects model)
ALLHAT (lisinopril)
ANBP-2 (enalapril)
42,373
Pilot HYVET (lisinopril, enalapril)
JMIC-B (lisinopril, enalapril, imidapril)
ASCOT† (perindopril)
ADVANCE† (perindopril) 34,242
HYVET (perindopril)
All ACE inhibitor trials 76,615
Figure 4. Impact of angiotensin-converting enzyme inhibitors on cardiovascular mortality.
†Significant reduction in cardiovascular mortality in trial.
ACE: angiotensin-converting enzyme; HR: Hazard ratio.
tissue ACE. After administration, a maximum level of
inhibition is seen after approximately 8 h. After 24 h, levels
remain high, at more than 70% of maximum [54]. This 24-h
effect has also been corroborated clinically in hypertensive
patients in general practice [55].
The efficacy of perindopril has been confirmed in a wide range
of hypertensive patients. In a 12-week open-label study of
13,220 American hypertensive patients ≥18 years of age in a
real-world setting, perindopril was shown to be effective in men
and women, patients young (aged <65 years) and old (aged ≥65
years) and patients of all ethnic backgrounds [55]. Mean resting
BP fell sig-nificantly from 157/95 mmHg at baseline to 139/84
mmHg at week 12 (p < 0.001) with perindopril (dose uptitrated
to full dose at week 6 for better BP control, at the physician’s
discre-tion). Perindopril was well tolerated and safe in high-risk
patients, as well as all other hypertensive subgroups [56]. More
recently, a Canadian prospective, observational, multicenter
study inves-tigated the antihypertensive efficacy of full-dose
perindopril in a range of hypertensive patients and found it to be
an effective therapeutic approach [57].
Perindopril has a strong affinity for bradykinin-binding
sites and can restore bradykinin levels, leading to improved
www.expert-reviews.com
Review
p-value
1.02 (0.92–1.11) 0.747
0.78 (0.70–0.87) <0.001
0.88 (0.77–1.00) 0.051
0.6 0.8 1.0 1.2
Favors Favors
ACE inhibitor control
endothelial function, neovascularization, arterial stiffness
reduc-tion and regression of atherosclerosis [58]. In the
PERTINENT trial [59], a substudy of the EUROPA trial, in
which half the coronary heart disease patients had
hypertension, perindopril was able to restore the disrupted
balance between bradykinin and angiotensin II; perindopril
decreased angiotensin II by 27% and increased bradykinin by
17% after 1 year (p < 0.05 vs baseline). This substudy also
showed that perindopril reduced endothelial apoptosis by 31%
(p < 0.05 vs placebo) in coronary artery disease patients
[59,60].
Vascular remodeling in hypertensive patients can also be reduced
with this ACE inhibitor; perindopril was able to reduce arterial
stiffness, a marker of vascular remodeling, in 2187 patients aged 18–
79 years with mild to moderate essential hypertension
[61] . Treatment with perindopril reduced carotid–femoral
pulse wave velocity significantly after 2 months (10.7 ± 2.2
m/s) and after 6 months (10.5 ± 2.1 m/s) versus baseline (11.6
± 2.6 m/s; all p < 0.001 vs baseline levels).
Interestingly, the effect of different dosages (4 vs 8 mg) of per-
indopril on carotid stiffness, a BP-independent effect, has been
investigated in hypertensive patients with Type 2 diabetes [62].
After 6 months, results showed that dose-dependent BP reduction
711
 Review Ferrari & Boersma

Angiotensin I

Inactive peptide
ACE

ARB ACE inhibitor

Bradykinin
Angiotensin II

NO PGI2 EDHF

AT3
AT AT AT4 B2
1 2

Vasoconstriction Plaque Unknown Thrombosis Vasodilation

SNS instability
Oxidative stress Thrombus Vasodilation
Inflammation formation Tissue protection
Aldosterone Fibrous cap

rupture Apoptosis
Hypertrophy
Inflammation
Apoptosis
Vasodilation
Proliferation

Figure 5. The renin–angiotensin–aldosterone system.

Angiotensin II, which is formed from angiotensin I by ACE, acts on different angiotensin receptors (ATs) to produce a variety of effects
on the heart, vasculature and kidneys. ACE inhibitors block the formation of angiotensin II by ACE. In addition, they block the
degradation of bradykinin, the accumulation of which is associated with beneficial vasodilatory and tissue-protecting effects. ARBs
block the AT1 receptor, allowing selective stimulation of AT2, AT3 and AT4 receptors, leading to mixed clinical effects.
ACE: Angiotensin-converting enzyme; ARB: Angiotensin receptor blocker; B 2: Bradykinin B2 receptor; EDHF: Endothelium-derived
hyperpolarizing factor; NO: Nitric oxide; PGI2: Prostacyclin; SNS: Sympathetic nervous system.
Adapted with permission from [37].

and BP-independent carotid stiffness reduction were greater
with full-dose perindopril.
In the perindopril trials, it should be noted that another
antihypertensive medication with a proven ability to reduce
morbidity and mortality (amlodipine in ASCOT-BPLA and
indapamide in ADVANCE and HYVET) was used alongside
perindopril [11–13]. Nevertheless, perindopril was clearly the
antihypertensive drug most prescribed when these three trials
were combined and all-cause mortality was reduced
regardless of the drug coprescribed. In ADVANCE,
perindopril was pre-scribed at baseline to all patients in the
active arm, while 73% had perindopril added to indapamide
in HYVET. Perindopril was also added in ASCOT-BPLA to
amlodipine in 68% of patients.
The between-arm differences in BP reduction in ASCOT-BPLA
(amlodipine ± perindopril vs atenolol ± bendroflumethiazide),
ADVANCE (fixed-dose combination perindopril/indapamide vs
placebo [including ongoing cardiovascular therapy]) and HYVET
(indapamide ± perindopril vs placebo) were
-2.7/-1.9 mmHg after 5.5 years (median), -5.6/-2.2 mmHg after
4.3 years (mean) and -15.0/-6.1 mmHg after 2 years. Statistical
adjustment for BP differences between study arms could not be
carried out because these data were not systematically published.
There have, however, been many hypertension trials with ARBs
in which the differences in BP reduction between arms were
superior to those observed in ASCOT-BPLA, but did not lead to
further reductions in mortality [14,21,22]. Baseline BP was shown
to have no influence on mortality after adjustment.
The recent retraction of the KYOTO HEART study from the
European Heart Journal in February 2013 does not affect the
con-clusions of this meta-analysis. The patients in KYOTO
HEART represented a small proportion of the ARB and total
populations in the meta-analysis (3.7% [3031/82,383] of the
ARB population and 1.9% [3031/158,998] of the total
population). Reanalysis of the results without KYOTO HEART
also showed there was a significant 10% reduction in the relative
risk of all-cause mortal-ity (p = 0.004) with ACE inhibitors, and
no mortality reduction with ARBs (p = 0.729) [103].

712 Expert Rev. Cardiovasc. Ther. 11(6), (2013)

 ACE inhibition & mortality in contemporary hypertension trials
In brief, perindopril has a long-lasting action, an effect on all
major parameters of BP and its efficacy has been confirmed in a
wide range of hypertensive patients. The combination of these and
the other beneficial effects detailed above may be responsible for the
perindopril trial results seen in our meta-analysis [6].
Conclusion
The most recent meta-analysis of mortality reduction with RAAS
inhibition in hypertension demonstrated a statistically significant
10% reduction in all-cause mortality (p = 0.004) and a trend
towards a 12% reduction in cardiovascular mortality with ACE
inhibitors (p = 0.051), while no significant mortality reduction
was observed with ARBs. Interestingly, a recent meta-analysis of
26 randomized controlled trials comparing ACE inhibitors or
ARBs versus placebo in a different population, patients at high
cardiovascular risk (n = 108, 212), confirmed this absence of
mortality reduction with ARBs, showing that they did not signifi-
cantly reduce cardiovascular or all-cause death [63]. By conclud-
ing that ARBs represent a practical treatment option for patients
intolerant to ACE inhibitors, the authors endorsed the first-line
use of ACE inhibitors.
Significant heterogeneity among ACE inhibitors was
observed in our meta-analysis; treatment with perindopril was
associated with a further significant 13% reduction in all-
cause mortality, mainly due to a 22% reduction in
cardiovascular mortality. The balance of mortality evidence
now suggests that in hyper-tension, ACE inhibitors should be
considered ahead of ARBs, and ARBs should be restricted to
patients intolerant of ACE inhibitors [64].
Expert commentary
The top preventable cause of premature death in the developed
world is hypertension and it is well known that antihypertensive
drugs reduce cardiovascular mortality [11]. Our meta-analysis of
mortality reduction with RAAS inhibition in hypertension con-
firmed this [6]; ACE inhibitors and ARBs significantly reduced
cardiovascular mortality by 7% (p = 0.018) and also all-cause
mortality by 5% (p = 0.032). In ACE inhibitor trials, there was a
statistically significant 10% reduction in all-cause mortality (p =
0.004) and a strong trend toward a 12% reduction in car-
diovascular mortality (p = 0.051). No all-cause or cardiovascu-
lar mortality reduction was observed with ARBs (p = 0.68 and
p = 0.13, respectively).
By inhibiting the RAAS in hypertensive patients with or
without coronary heart disease, ACE inhibitors reduce central
aortic BP, decrease arterial stiffness and prevent
cardiovascular events [65]. In addition, ACE inhibition is also
able to prevent the cardiac and vascular remodeling
associated with hyper-tension and thus the development of
clinical cardiovascular disease.
ACE inhibitors are effective and well tolerated in hyperten-
sion management [7–13] and recommended as first line for the
treatment of hypertension in British and American prescrib-
ing guidelines [66,101]. The latest hypertension guidelines, the
2007 guidelines of the European Society of Hypertension and
www.expert-reviews.com
Review
European Society of Cardiology [2], therefore list ACE inhibi-
tors as an appropriate first-line choice in hypertension in mon-
otherapy or combination. The usefulness of ACE inhibition is
also underlined by the fact that European guidelines favor the
use of ACE inhibitors in several conditions: heart failure, left
ventricular dysfunction, post-MI, diabetic and nondiabetic
nephropathy, left ventricular hypertrophy, carotid atheroscle-
rosis, atrial fibrillation, proteinuria, microalbuminuria and
metabolic syndrome [2].
In our meta-analysis [6], there was significant heterogeneity
among ACE inhibitors. Treatment with perindopril, in particular,
was associated with further significant all-cause and cardiovas-
cular mortality reductions (13 and 22%, respectively). Further
support for perindopril’s use comes from the European guideline
position statement on the choice of antihypertensive agents,
which cites the importance of the drugs effect on cardiovascular
risk factors and of once-a-day administration [2].
More extensive use of proven RAAS inhibition in hypertensive
patients could save numerous lives. Thanks to a range of effects on
BP, arterial stiffness and cardiovascular remodeling, ACE inhibi-tors
– perindopril in particular – are a good choice for preventing all-
cause and cardiovascular mortality in hypertension.
Five-year view
According to the latest European guidelines for the management
of arterial hypertension [2], ACE inhibitors are one of the five
major classes of antihypertensive drugs appropriate for the initia-
tion and maintenance of hypertensive treatment. Indeed, ACE
inhibition is likely to remain a central part of the management of
hypertension in the future.
The findings from our meta-analysis provide a substantial
amount of additional evidence that the effect of ACE
inhibitors and ARBs differs with respect to all-cause and
cardiovascular mortality. In the future, more evidence is likely
to emerge show-ing that the effects of different types of
agents – ACE inhibitors, ARBs and direct renin inhibitors
(DRIs) – are not the same, as will evidence showing the
existence of differences between individual ACE inhibitors,
ARBs and DRIs. Future hyperten-sion guidelines will need to
take the results of this meta-analysis into account.
Changing global demographics, seeing increased numbers
of people living longer with increasing burdens of
comorbidity, will have a major impact on global health in the
next 5 years. With these changes, the management of
hypertension will become even more vital, as increasing life
expectancy increases the preva-lence of hypertension and the
disorder becomes a more common comorbidity.
Cardiovascular health worldwide is likely to be
detrimentally affected by another of these global demographic
changes, the increasing prevalence of metabolic syndrome
and obesity. The combination of hypertension and obesity is
particularly danger-ous, as it increases cardiovascular risk by
much more than the sum of its parts. Unfortunately, metabolic
syndrome and obesity are increasing fast in large, rapidly-
developing countries such as India and China.
713
 Review Ferrari & Boersma

The number of antihypertensive fixed-dose combinations on the
market is likely to increase, as it is now acknowledged that
combination treatment rather than monotherapy is required to
control BP in most hypertensive patients. New ‘polypill’ formu-
lations containing aspirin and statins in combination with ACE
inhibitors and ARBs, calcium channel blockers and diuretics are
likely to appear in future, although many dual-agent fixed-dose
combinations already exist, for example, fixed-dose combinations of
RAAS inhibitors with calcium channel blockers or diuretics.
Lastly, a recent report from the Agency for Healthcare
Research and Quality has highlighted seven key areas for future
research into the comparative effectiveness of ACE inhibitors,
ARBs and DRIs in patients with hypertension [67]. These seven
areas in order of priority are as follows: long-term cardiovascular
and cerebrovascular events; comorbidities; demographics;
dif-ferences between randomized controlled trials and
observational studies in practice settings; new cardiovascular
or metabolic diagnoses; patient health status and differences
in medication adherence. Our meta-analysis results go some
way to achieving these goals [6].
Financial & competing interests disclosure
The authors received honoraria and research grants from Servier
and others. The authors have no other relevant affiliations or
financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Blockade of the renin–angiotensin–aldosterone system (RAAS) system is an important strategy in the contemporary
management of cardiovascular disease.
• The choice of antihypertensive agent may markedly affect clinical outcome.
• Our meta-analysis of RAAS inhibition in hypertension demonstrated that angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs) significantly reduced the relative risk of all-cause mortality by 5% (p = 0.032) and
cardiovascular mortality by 7% (p = 0.018), respectively.
• There was a statistically significant 10% reduction in the relative risk of all-cause mortality (p = 0.004) and a trend toward a
12% reduction in the relative risk of cardiovascular mortality (p = 0.051) with ACE inhibitors.
• No all-cause or cardiovascular mortality reduction was observed with ARBs (p = 0.68 and p = 0.13, respectively).
• Blood pressure (BP)-independent effects of ACE inhibitors might account for the differences seen in mortality reduction between
ACE inhibitors and ARBs.
• The relationship between BP decrease and reduction in cardiovascular risk is not straightforward, as large decreases in BP do not
always lead to large decreases in the risk of cardiovascular mortality and vice versa.
• Treatment with perindopril was associated with further significant all-cause and cardiovascular mortality reductions of 13 and
22%, respectively (both p < 0.001).
• These results provide a convincing argument for improving treatment adherence in patients with hypertension.
• Widespread use of proven antihypertensive agents could save a considerable number of lives, given the high
prevalence of hypertension.

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