JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 71, NO.

13, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE

REVIEW TOPIC OF THE WEEK

Angiotensin-Converting Enzyme
Inhibitors in Hypertension
To Use or Not to Use?

Franz H. Messerli, MD,a,b Sripal Bangalore, MD, MHA,c Chirag Bavishi, MD, MPH,d Stefano F. Rimoldi, MDa

ABSTRACT

Most guidelines for the management of patients with cardiovascular disease recommend angiotensin-converting enzyme
(ACE) inhibitors as first-choice therapy, whereas angiotensin receptor blockers (ARBs) are merely considered an
alternative for ACE inhibitor–intolerant patients. The aim of this review was to compare outcomes and adverse events
between ACE inhibitors and ARBs in patients. In patients with hypertension and hypertension with compelling indications,
we found no difference in efficacy between ARBs and ACE inhibitors with regard to the surrogate endpoint of blood
pressure and outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and
end-stage renal disease. However, ACE inhibitors remain associated with cough and a very low risk of angioedema and
fatalities. Overall withdrawal rates because of adverse events are lower with ARBs than with ACE inhibitors. Given the
equal outcome efficacy but fewer adverse events with ARBs, risk-to-benefit analysis in aggregate indicates that at present
there is little, if any, reason to use ACE inhibitors for the treatment of hypertension or its compelling indications.
(J Am Coll Cardiol 2018;71:1474–82) © 2018 by the American College of Cardiology Foundation.

The human understanding, once it has adopted

opinions, either because they were already
accepted and believed, or because it likes them,
draws everything else to support and agree with
E ver since captopril, the first angiotensin-
them. And though it may meet a greater number
and weight of contrary instances,
it will, with great and harmful prejudice, ignore
or condemn or exclude them by
introducing some distinction, in order that the
authority of those earlier assumptions may
remain intact and unharmed.
—Francis Bacon, Novum Organum, 1620 (1)
converting enzyme (ACE) inhibitor, became
available in 1981, this drug class has been
extensively used in a variety of cardiovascular (CV)
diseases. Losartan, the first angiotensin receptor
blocker (ARB), was launched in 1995, more than a
dozen years after the introduction of the ACE inhibitor
captopril. Both ACE inhibitors and ARBs are commonly
used in patients with hypertension, heart failure, cor-
onary artery disease, diabetes, and chronic kidney dis-
ease (CKD). However, many American and European
guidelines for the management of patients with CV

Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Cardiology and Clinical Research, University Hospital, Bern, Switzerland; bDivision of Cardiology, Mount
Sinai Medical Center, Icahn School of Medicine, New York, New York; cThe Leon H. Charney Division of Cardiology, NYU School of
Medicine, New York, New York; and the dDivision of Cardiology, Mount Sinai St. Luke’s & Mount Sinai West Hospitals, New York,
New York. Dr. Messerli has served as a consultant or advisor for Daiichi-Sankyo, Pfizer, Abbott Vascular, Servier, Medtronic,
WebMD, Menarini, Ipca, Hikma, American College of Cardiology, Relypsa, and Sandoz. Dr. Bangalore has received grants from
Abbott Vascular and the National Heart, Lung, and Blood Institute; has been on the advisory boards of Abbott Vascular, Amgen,
Menarini, Daiichi-Sankyo, Boehringer Ingelheim, Pfizer, The Medicines Company, and AstraZeneca; has been a consultant for
Merck and Abbott Vascular; and has served as a consultant or advisor for Gilead. Dr. Rimoldi has had consultant or advisory
relationships with Servier, Menarini, and Takeda; and has been on the speakers bureau for Menarini and Servier. Dr. Bavishi has
reported that he has no relationships relevant to the contents of this paper to disclose. Stanley Franklin, MD, served as Guest
Editor for this paper.

Manuscript received November 9, 2017; revised manuscript received January 7, 2018, accepted January 18, 2018.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.01.058

JACC VOL. 71, NO. 13, 2018
APRIL 3, 2018:1474–82
disease recommended ACE inhibitors as a first-choice
therapy, whereas ARBs were merely considered alter-
native therapy for ACE inhibitor–intolerant patients.
In the following review, we compare the efficacy and
safety of the 2 drug classes (which are now mostly
generic) for the treatment of hypertension and hyper-
tension associated with what has been called compel-
ling indications.
MECHANISM OF ACTION
The mechanism of action of ACE inhibitors and ARBs
is both similar and different. Although both classes of
drugs act on the renin-angiotensin-aldosterone sys-
tem, ACE inhibitors inhibit the formation of angio-
tensin II and consequently the downstream effects
through the angiotensin II type 1 (AT1) receptor
(vasoconstriction, cell growth, sodium and water
retention, sympathetic activation) and the angio-
tensin II type 2 (AT2) receptor. One disadvantage of
ACE inhibitors is that the presence of non-ACE path-
ways results in continued low-level production of
angiotensin II despite the inhibition of ACE
(Figures 1A and 1B). However, the nonselective inhi-
bition of angiotensin receptors has been shown to be
beneficial because the effect of angiotensin II through
the AT2 receptor may result in incremental vasodila-
tion and antiproliferative activity. Other investigators
maintain that the purported beneficial effects of ACE
inhibitors over ARBs are caused by their action to
inhibit the breakdown of bradykinin and thereby in-
crease circulating bradykinin levels. Although bra-
dykinin is implicated in the pathogenesis of ACE
inhibitor–induced cough and angioedema, it has also
been shown to mediate vasodilation incrementally
(2). Additionally, bradykinin levels release nitric ox-
ide as well as increase synthesis of vasoactive pros-
taglandins (3,4). In contrast, ARBs were specifically
designed to displace angiotensin II from the AT1 re-
ceptor. By facilitating stimulation of the AT2 receptor,
ARBs may additionally trigger vasodilation and
natriuresis. However, this ARB-associated autocrine
cascade with bradykinin, nitric oxide, and vasoactive
prostaglandins is clinically considerably less impor-
tant than that occurring with ACE inhibitors (4).
SURROGATE ENDPOINT: BLOOD PRESSURE
REDUCTION. No clinically meaningful difference in
antihypertensive efficacy has been shown between
the classes of renin-angiotensin system blockers (5).
In fact, meta-analyses of clinical trials suggest
numerically greater reductions in office systolic and
diastolic blood pressure (BP) with ARBs when
compared with ACE inhibitors (Figure 2) (6–8). When
using ambulatory BP measurements, the BP-lowering
Messerli et al. 1475
Angiotensin-Converting Enzyme Inhibitors in Hypertension
efficacy of ARBs is similar or numerically ABBREVIATIONS
higher than that of ACE inhibitors (Figure 3) AND ACRONYMS
(9). Although within the same class the BP-
ACE = angiotensin-converting
lowering efficacy of various ARBs and ACE enzyme
inhibitors differs, recent randomized trials
ARB = angiotensin receptor
have shown superior efficacy (office systolic blocker
BP reduction of 20.6 mm Hg vs. 12.2 mm Hg; BP = blood pressure
p < 0.001) with azilsartan compared with CI = confidence interval
ramipril (10). Similar superior reduction in
CKD = chronic kidney disease
central systolic BP with olmesartan when
CV = cardiovascular
compared with perindopril (
13.72 mm Hg
HR = hazard ratio
vs.
10.21 mm Hg) was seen even when these
MI = myocardial Infarction
drugs were used in combination with amlo-
dipine in the SEVITENSION (Sevikar RR = relative risk
Compared to the Combination of Perindopril WDAE = withdrawal resulting
from adverse effects
Plus Amlodipine on Central Arterial Blood
Pressure in Patients With Moderate-to-Severe Hy-
pertension) study (11). Even when compared as
monotherapy in older patients, olmesartan provided
more effective and sustained 24-h BP control than did
ramipril (12). In a meta-analysis of 354 randomized
trials by Law et al. (13), dose-response analysis among
antihypertensive drug classes showed that ARBs had
numerically higher reductions in office systolic BP
compared with ACE inhibitors (Figure 4) shows that a
reduction of 10 mm Hg occurred with a standard ARB
dose, whereas the same reduction required almost
twice the standard ACE inhibitor dose.
TARGET ORGANS: LEFT VENTRICULAR
HYPERTROPHY AND PROTEINURIA
In a meta-analysis of 80 trials with 146 active treat-
ment arms and 17 placebo arms, adjusted for treat-
ment duration and change in diastolic BP, there was a
numerically better decrease in left ventricular mass
index with ARBs by 13% than with ACE inhibitors by
10%, although the difference was not statistically
significant (14). Urinary protein excretion was simi-
larly reduced by ACE inhibitors and ARBs in another
meta-analysis of 17 randomized controlled trials
including 17,951 patients (15).
COMPARISON OF OUTCOMES
PATIENTS WITHOUT HEART FAILURE. In hyperten-
sion, there is no prospective randomized controlled
trial that shows a morbidity or mortality reduction
with ACE inhibitors or ARBs against placebo. The
HOPE (Heart Outcomes Prevention Evaluation) (16)
study provided outstanding evidence of ramipril
efficacy in patients at high risk of CV events, but it
cannot truly be considered a study in hypertension
(hypertension was present in w47% of patients at
baseline). Similarly, CAMELOT (Comparison of
1476 Messerli et al. JACC VOL. 71, NO. 13, 2018

Angiotensin-Converting Enzyme Inhibitors in Hypertension APRIL 3, 2018:1474–82

cohort of 40,625 patients (91% with hypertension)

F I G U R E 1 Mechanism of Action of ACE Inhibitors and ARBs
(ACE inhibitors 67.9% and ARBs 32.1%), the incidence
of the primary outcome, a composite of CV mortality,
A ACE-Inhibitors (ACE-I) nonfatal myocardial infarction (MI), nonfatal stroke,
or hospitalization for CV reasons, was lower in
Angiotensinogen
patients taking ARBs compared with patients taking
ACE inhibitors (29.2% vs. 33.4%; adjusted hazard
ratio [HR]: 0.90; 95% confidence interval [CI]: 0.86 to
Inactive peptide Angiotensin I
ACE-I
0.95; p < 0.001) during the 4-year follow-up. Similar
results were observed for CV mortality (6.9% vs.
ACE 8.2%; HR: 0.83; 95% CI: 0.75 to 0.93; p ¼ 0.001) and
all-cause mortality (11.6% vs. 12.6%; HR: 0.89; 95% CI:
Bradykinin ↑ Angiotensin II ↓
0.82 to 0.97; p ¼ 0.005). In a Cochrane meta-analysis
of 9 randomized trials and 11,007 participants with
primary hypertension (20), no differences between
• Nitric oxide ↑
• Fibrinolysis ↑ ACE inhibitors and ARBs were seen for all-cause
• Thrombocyte activity ↓ mortality (relative risk [RR]: 0.98; 95% CI: 0.88 to
AT1 AT2 1.10), total CV events (RR: 1.07; 95% CI: 0.96 to 1.19),
or CV mortality (RR: 0.98; 95% CI: 0.85 to 1.13).
Moreover, in our comprehensive meta-analysis of 106
B Angiotensin-Receptor Blockers (ARBs)
randomized trials with 254,301 patients without heart
failure, evidence from placebo-controlled trials
Angiotensinogen
(restricted to trials after 2000), active controlled
trials, and head-to-head randomized trials suggested

Inactive peptide Angiotensin I

that ARBs were as efficacious and safe as ACE
inhibitors (21) (Figure 4, Central Illustration). Simi-
larly, in a network meta-analysis of randomized trials
ACE
of patients at high CV risk but without heart failure,
Bradykinin Angiotensin II ARBs were similar to ACE inhibitors in preventing the
composite endpoint of CV death, MI, and stroke (RR:
ARB1

0.92; 95% CI: 0.78 to 1.08) (22). Compared with ARBs,

• Nitric oxide ↑
• Fibrinolysis ↑
• Thrombocyte activity ↓
AT1 AT2
(A) Angiotensin-converting enzyme (ACE) inhibitors block the conversion of angiotensin I
to angiotensin II, whereas (B) angiotensin receptor blockers (ARBs) block the action of
angiotensin II by preventing its binding to angiotensin II type 1 (AT1) but not type 2 (AT2)
receptors.
Amlodipine vs. Enalapril to Limit Occurrences of
Thrombosis) (17), in which enalapril was not better
than placebo, was not designed as a hypertension
trial (mean systolic BP at baseline of 129 mm Hg). In
ALLHAT (Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial) (18), there
were no differences in the primary endpoint among
lisinopril, chlorthalidone, and amlodipine, but the
trial had no placebo arm.
In the propensity score–adjusted REACH (Reduc-
tion of Atherothrombosis for Continued Health) (19)
there was no evidence of statistical superiority for
ACE inhibitors in preventing incident risk of all-cause
death, CV death, MI, stroke, new-onset diabetes
mellitus, and new-onset heart failure (22). Thus, the
data in aggregate attest to equal efficacy of ARBs and
ACE inhibitors in reducing outcomes in patients with
hypertension or in patients at high risk of CV events.
COMPELLING INDICATIONS. P a t i e n t s w i t h c o r o n a r y
a r t e r y d i s e a s e . In patients with coronary artery
disease and preserved left ventricular systolic func-
tion, the superiority of ACE inhibitors over ARBs re-
mains to be proven. In fact, in the CAMELOT (17) trial
of patients with coronary artery disease, enalapril
was inferior to amlodipine and not better than pla-
cebo. We also found that only indirect comparisons
formed the basis of the so-called myocardial infarc-
tion paradox (i.e., that ARBs may increase the risk of
MI). This concept ignored the wealth of solid data
from direct head-to-head trials (23), which invariably
lead us to the conclusion that ARBs reduce CV events,
including the risk of MI, as effectively as but more
safely than ACE inhibitors (24).
JACC VOL. 71, NO. 13, 2018 Messerli et al. 1477
APRIL 3, 2018:1474–82 Angiotensin-Converting Enzyme Inhibitors in Hypertension

P a t i e n t s w i t h h e a r t f a i l u r e . In contrast to hyper-
F I G U R E 2 Antihypertensive Efficacy (Placebo Subtracted) as Measured by Office
tension, in heart failure ACE inhibitors and ARBs have Blood Pressure, at Submaximal to Maximal Doses
been compared with placebo in multiple clinical tri-
als. CONSENSUS (Cooperative North Scandinavian 0
Enalapril Survival Study) (25) showed an impressive –1
31% reduction in mortality at 1 year in patients with –2

BP Reduction (mm Hg)

severe heart failure who were treated with enalapril –3
when compared with placebo. In the CHARM (Cande- –4
sartan in Heart Failure Assessment of Reduction in –5 –4.6
–5
Mortality and Morbidity) trial program, candesartan –6
–7 –6.2
was either added to ACE inhibitors (CHARM-Added)
–8 –7.7
(26) or substituted when ACE inhibitors were not
–9 –8.7
tolerated (CHARM-Alternative) (27). In both trials
–10 –9.3
candesartan reduced each of the components of the ACE Inhibitors ARBs DRIs
primary outcome significantly, as well as the total
# of Studies 92 46 6
number of hospital admissions for heart failure.
# of Patients 12954 13451 3694
A recent network meta-analysis showed that # of Drugs 14 9 11
treatment with ACE inhibitors, ARBs, beta-blockers,
Systolic Diastolic
mineralocorticoid antagonists, and angiotensin
receptor–neprilysin inhibitor and their combinations
Reductions in systolic (blue bars) and diastolic (orange bars) blood pressure (BP) for
were better than treatment with placebo in reducing
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and
all-cause mortality rates (28). In comparison with
direct renin inhibitors (DRIs) compared with other antihypertensive agents. Angiotensin
placebo, ACE inhibitor use was associated with a 16% receptor blockers showed the highest reduction in systolic and diastolic blood pressure
reduction in mortality, whereas the combination of compared with angiotensin-converting enzyme inhibitors and direct renin inhibitors. Data
ACE inhibitors, beta-blockers, and mineralocorticoid from the Cochrane meta-analyses of Musini et al. (6) and Heran et al. (7,8).

antagonists was associated with a 56% reduction in

mortality compared with placebo (28). ACE inhibitor–
Estimated glomerular filtration rate declined less
based therapy was superior to placebo for all-cause
with ramipril compared with telmisartan (
2.82 
mortality, whereas ARB-based therapy was not.
However, the data on ACE inhibitors versus placebo 17.2 ml/min/1.73 m2 vs.
4.12  17.4 ml/min/1.73 m2 ;

used 4 times more patient-years as their basis than p < 0.0001), although the rates of renal impairment

did the data on ARBs (23,293.2 vs. 5,880.3 patient-

years). Moreover, in the same meta-analysis, there F I G U R E 3 Antihypertensive Efficacy as Measured by Ambulatory Blood
was no difference between ACE inhibitors and ARBs Pressure Monitoring

for all-cause mortality (RR: 0.94; 95% CI: 0.68 to

1.29). Packer and McMurray (29) attributed the ACE Beta Calcium
HCTZ Inhibitors ARBs Blockers Antagonists
heightened efficacy of ACE inhibitors to endogenous 0
compensatory vasoactive peptides that are operative
Reduction in BP (mm Hg)

in ACE inhibitors but not in ARBs. This action could –5

result in what these investigators called “broadening
the benefits of inhibitors of the renin-angiotensin
–10 N = 14
system in patients with heart failure by potentiation
of endogenous vasoactive peptides” (29). Of note,
this effect seems to be much more pronounced with –15 N=3
N=5
valsartan and sacubitril than with ACE inhibitors and N=5
may be particularly helpful in treatment of residual –20 N=7
hypertension in heart failure (30).
SBP DBP
P a t i e n t s w i t h c h r o n i c k i d n e y d i s e a s e . In >17,000
patients at high vascular risk from ONTARGET
Data from 19 trials and 1,400 patients that evaluated ambulatory blood
(ONgoing Telmisartan Alone and in Combination
pressure (BP) reduction with hydrochlorothiazide (HCTZ) when compared
With Ramipril Global Endpoint Trial), the effect of with other agents. ACE ¼ angiotensin-converting enzyme; ARBs ¼ angiotensin
telmisartan on major renal outcomes (composite of receptor blockers; DBP ¼ diastolic blood pressure; SBP ¼ systolic blood
dialysis, doubling of serum creatinine, and pressure. Adapted with permission from Messerli et al. (9).
death) was similar to that of ramipril (31).
1478 Messerli et al.
Angiotensin-Converting Enzyme Inhibitors in Hypertension
F I G U R E 4 Average Reductions in Systolic Blood Pressure Between ACE Inhibitors and ARBs
(Adjusted for the Change in the Placebo Group, With 95% Confidence Intervals)
ACE Inhibitors
20
Decrease in Systolic Blood Pressure (Treated – Placebo) (mm Hg)
10
0 ARBs with respect to all-cause mortality, CV mortal-
1/8 1/4 1/2 1 2 4 8
ARBs
20
10
0 stroke. In the multicenter PROFeSS (Prevention
1/8 1/4 1/2 1 2 4 8
Dose as Proportion of Standard Dose
The doses were a proportion of standard (designated 1). ACE ¼ angiotensin-converting
enzyme; ARBs ¼ angiotensin receptor blockers. Adapted with permission from Law et al.
(13) (BMJ Publishing Group, Ltd.).
(10.2% vs. 10.6%) and renal failure requiring dialysis
(0.6% vs. 0.6%) were similar between the 2 groups. In
a Bayesian network meta-analysis of 119 randomized
controlled trials with 564,768 people with CKD, both
ACE inhibitors and ARBs reduced the risk for kidney
failure and CV events (32). These investigators
reported that ACE inhibitors also reduced the risk for
all-cause mortality and were possibly superior to
ARBs for kidney failure, CV death, and all-cause
mortality in patients with CKD. However, a closer
look at their data clearly showed that the differences
between ARBs and ACE inhibitors were not statisti-
cally significant. In the REACH cohort, ARBs were
superior to ACE inhibitors in reducing the primary
outcome even in patients with an estimated glomer-
ular filtration rate >30 ml/min/1.73 m 2 (19). In a recent
study of 14,117 patients with pre-dialysis stage 5 CKD
(33), ACE inhibitors users were associated with higher
JACC VOL. 71, NO. 13, 2018
APRIL 3, 2018:1474–82
mortality rates than in ARBs users. This finding was
true in all patients (HR: 1.17; 95% CI: 1.07 to 1.27;
p ¼ 0.03) and in a subgroup of diabetic patients (HR:
1.32; 95% CI: 1.18 to 1.48; p ¼ 0.03) (33).
P a t i e n t s w i t h d i a b e t e s . In a prospective, multi-
center, double-blind, 5-year study of 250 subjects
with type 2 diabetes and early nephropathy, Barnett
et al. (34) found telmisartan not inferior to enalapril
in providing long-term renoprotection. In addition,
the effects of the 2 agents on the secondary endpoints
were not significantly different after 5 years. Simi-
larly, in a network meta-analysis of 71 trials with
103,120 diabetic participants, no significant differ-
ences were documented between ACE inhibitors and
ity, MI, stroke, angina pectoris, hospitalization for
heart failure, end-stage renal disease, or doubling of
serum creatinine levels (35). In the REACH cohort
ARBs were superior to ACE inhibitors in reducing the
primary outcome regardless of diabetes history (19).
Patients with cerebrovascular disease. In TRANSCEND
(Telmisartan Randomised AssessmeNt Study in ACE
iNtolerant Subjects with cardiovascular Disease) (36),
telmisartan in patients unable to tolerate ACE
inhibitors had no significant effect on the primary
outcome. However, this drug modestly reduced the
risk of the composite outcome of CV death, MI, or
Regimen For Effectively Avoiding Second Strokes)
trial (37) involving 20,332 patients, therapy with
telmisartan initiated soon after an ischemic stroke
and continued for 2.5 years did not significantly lower
the rate of recurrent stroke, major CV events, or dia-
betes. Most meta-analyses, as well as REACH cohort
data, showed no difference in stroke rates between
ARBs and ACE inhibitors in head-to-head compari-
sons. In our recent meta-analysis in older patients
(>65 years old) with predominantly systolic hyper-
tension, ACE inhibitors reduced CV outcomes
compared with placebo, but the drugs notably failed
to prevent stroke (38).
SAFETY AND ADVERSE EVENTS. ACE inhibitors are
well tolerated in general, with a dry, irritating cough
being their most common adverse effect. However,
when compared with ARBs, ACE inhibitors have
several-fold higher incidence of side effects at most
doses (13), with a dry, irritating cough being the most
common. In our meta-analysis of 125 studies
including 198,130 patients, the pooled weighted
incidence of cough for enalapril was found to be
11.48% (95% CI: 9.54% to 13.41%) (39). The pooled
weighted withdrawal rate resulting from cough for
enalapril was 2.57% (95% CI: 2.40% to 2.74%). How-
ever, the prevalence of cough in Asian patients is
JACC VOL. 71, NO. 13, 2018 Messerli et al. 1479
APRIL 3, 2018:1474–82 Angiotensin-Converting Enzyme Inhibitors in Hypertension

C ENTR AL I LL U STRA T I O N Efficacy and Safety of ACE Inhibitors and ARBs From Head-to-Head Studies and
Compared With Placebo Trials

Outcomes Trials RR (95% CI)

Efficacy Head-to-Head Studies

Cardiovascular mortality 5 1.00 (0.89-1.12)

Myocardial infarction 5 1.07 (0.94-1.22)

Stroke 4 0.92 (0.80-1.06)

End-stage renal disease 2 0.88 (0.63-1.22)

Safety

Drug withdrawal 8 0.72 (0.65-0.81)

Favors ARBs Favors ACEIs

Active Treatment Against Placebo

ACEIs withdrawal 55 0.85 (0.67-1.07)

ARBs withdrawal 26 0.68 (0.54-0.87)

Favors Active Treatment Favors Placebo

0.5 1 1.5

Messerli, F.H. et al. J Am Coll Cardiol. 2018;71(13):1474–82.

Compared with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) showed similar efficacy in terms of cardiovascular mortality,
myocardial infarction, stroke, and end-stage renal disease, with significantly lower drug withdrawal rates. When compared with placebo, angiotensin receptor blockers
and not angiotensin-converting enzyme inhibitors showed significantly lower rates of withdrawal. CI ¼ confidence interval; RR ¼ relative risk. Data from the
meta-analyses of Bangalore et al. (23) and Heran et al. (7,8).

more than 2.5 times higher than in Caucasian
patients, and withdrawal rates exceed 30% (40,41).
For this reason, many Asian physicians are no longer
prescribing ACE inhibitors. In a recent nationwide
cross-sectional survey of antihypertensive
classes in China (42), ARBs were used more than
twice as often as ACE inhibitors A much less common
adverse event of ACE inhibitor therapy is angioe-
dema, which is most prevalent in black patients of
African origin and occasionally can be fatal. In 26
trials with 74,857 patients, we found the weighted
incidence of angioedema with ACE inhibitors to be
0.30% (95% CI: 0.28% to 0.32%) (43). Angioedema
affects about 1 in 2,500 patients during the first week
of exposure (44–46). However, it can first appear
from a few hours to 8 years after an ACE inhibitor is
initiated (36). The subsequent incidence of angioe-
dema with ACE inhibitors is around 1 in 500 patients/
year (46). Banerji et al. (47) recently showed that
drug among 134,945 patients who were prescribed an ACE
inhibitor, 0.7% (n ¼ 888) developed angioedema
during the subsequent 5 years. In this study, there
was a 0.07% incidence of angioedema within 1 month
of prescription of an ACE inhibitor and a 0.23% inci-
dence during the first year. Thereafter, the annual
incidence of angioedema was relatively constant over
the subsequent 4 years (0.10% to 0.12%) (47). In the
prospective OCTAVE (Omapatrilat Cardiovascular
Treatment vs. Enalapril) study (48) of 12,557 patients,
the overall prevalence of angioedema associated with
1480 Messerli et al. JACC VOL. 71, NO. 13, 2018

Angiotensin-Converting Enzyme Inhibitors in Hypertension APRIL 3, 2018:1474–82

formulation. As of today most if not all ACE inhibitors

T A B L E 1 Characteristics of ACE Inhibitor and ARB
Outcome Trials
and ARBs are available as generic formulations; thus
acquisition cost should not tip the scale in favor of 1
ACE Inhibitor ARB
Trials Trials
class or the other. However, even among generic
Publication period 1990s 2000s formulations there are distinct cost differences
Placebo event rates* 10.5% 5.0% among formularies and from country to country.
Concomitant statin therapy Rare Common Moreover, many fixed drug combinations of both ACE
RAS blockade naive Most Rare inhibitors and ARBs with thiazides and amlodipine
Concomitant RAS blockade Rare Common are at hand in most countries, thereby allowing
Aggressive risk factor control Rare Common
simplification of the therapeutic regimen.
*Aggregate of all events/year in placebo group.
DISCUSSION
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker;
RAS ¼ renin-angiotensin system.
The foregoing data establish that in terms of efficacy
there is little, if any, difference between ACE
enalapril was 0.68%. Among all instances of angioe-
inhibitors and ARBs. This holds true for the surrogate
dema, about 20% of cases are life-threatening,
endpoint of BP, as well as for outcomes such as
affecting the larynx and upper respiratory tract (49).
stroke, coronary artery disease, and CV and all-cause
Among these, about 20% of cases are fatal unless the
mortality. Head-to-head comparison trials are the
patient is intubated (50,51). An autopsy study from
only iron-clad way to compare the efficacy and safety
Columbus, Ohio reported 7 fatalities, all in African
of 2 drug classes objectively and to test whether the
Americans, between 1998 and 2000 caused by ACE
ARB MI paradox really holds true. In patients without
inhibitor–induced angioedema (52). Because antihy-
heart failure, we found no significant difference in
pertensive efficacy is also diminished, there is no
any of the CV efficacy outcomes between ACE
good clinical reason to initiate therapy with ACE
inhibitors and ARBs, a finding that is consistent with
inhibitors in black patients.
data from recent placebo-controlled trials and from
When compared with placebo in a Cochrane meta-
active controlled trials. The perceived differences
analysis (7), the pooled estimate of withdrawal rates
between ACE inhibitors and ARBs mostly reflect the
resulting from adverse events (WDAEs) for all doses
so-called generation gap between the 2 sets of trials
resulted in a statistically nonsignificant RR of 0.85
(Table 1). Concomitant statin therapy was distinctly
(95% CI: 0.67 to 1.07) (7). In contrast, for ARBs when
less common in ACE inhibitor trials than in ARB
all doses were pooled, there was a statistically sig-
trials. For instance, in the 2 studies with the same
nificant reduction in WDAEs compared with placebo
principal investigator, statin use doubled over a
(RR: 0.68; 95% CI: 0.54 to 0.87) (8). This finding
period of 8 years: in ONTARGET it was 61%, and in
would indicate that independent of the dose, WDAEs
HOPE it was 29% (16,54). Conceivably, in patients
of ARBs are 32% lower than WDAEs of placebo. In
with heart failure the vasoactive peptides of ACE
other words, in contrast to ACE inhibitors, ARBs are
inhibitors may provide modest incremental benefits,
better tolerated than placebo. In our meta-analysis of
although the evidence for such benefits is unsub-
head-to-head randomized trials of ACE inhibitors vs.
stantiated (29).
ARBs in patients without heart failure, there was a
In terms of safety, there is no question that ARBs
lower risk of drug WDAEs with ARBs (RR: 0.72; 95%
are better tolerated than are ACE inhibitors. In head-
CI: 0.65 to 0.81) (21). Thomopoulos et al. (53) found
to-head comparisons withdrawal rates with ARBs
that, compared with placebo, ACE inhibitors, and not
were 22% lower than with ACE inhibitors (20). This
ARBs, significantly increased discontinuation rates
number can be expected to differ even more in favor
for adverse events (RR: 2.78; 95% CI: 1.37 to 5.47).
of ARBs in Asian patients. Although ACE inhibitor–
Similarly, in randomized head-to-head comparison
related cough is not dose dependent (13) and is
trials, ARBs were the only class associated with a
considered merely a nuisance adverse event, it
significantly lower risk of adverse events (RR: 0.71;
invariably triggers a telephone call to the prescribing
95% CI: 0.58 to 0.87) compared with other drug
physician or may necessitate an additional visit
classes (53).
and/or additional tests. With the prescription of an
COST AND PRACTICAL CONSIDERATIONS ARB instead of an ACE inhibitor, both events can be
avoided. The fact that in a Cochrane analysis (8)
In the past, the main argument against using ARBs withdrawal rates of ARBs were 32% lower than with
was that they were not available in a generic placebo merely reflects the fact that hypertensive CV
JACC VOL. 71, NO. 13, 2018 Messerli et al. 1481
APRIL 3, 2018:1474–82 Angiotensin-Converting Enzyme Inhibitors in Hypertension

disease is not an entirely silent clinical entity. It can CONCLUSIONS

be associated with nonspecific symptoms such as
headache, fatigue, dizziness, impaired exercise
capacity, and sexual dysfunction. Hansson et al. (55)
documented in 7 randomized, double-blind,
placebo-controlled trials, in which 2,673 patients
with mild to moderate hypertension were random-
ized to the ARB irbesartan or placebo, that ARB use
was associated with a significant reduction in the
incidence of headache (p ¼ 0.003). These data
suggest that nonspecific symptoms occurring with
hypertension such as headache can be reduced by
antihypertensive treatment with a favorable adverse
effect profile.
As documented earlier, angioedema is a very rare
adverse event of ACE inhibitors. However, because 20
to 30 million patients are taking these drugs world-
wide, use of ACE inhibitors could result in several
hundred fatalities per year (46). Admittedly some of
the foregoing numbers are extrapolations, but they
still beg the question whether ACE inhibitors remain
acceptable at all, not only for the treatment of hy-
pertension but also as ingredients in polypills (56).
In patients with hypertension and hypertension with
compelling indications, there is no difference in ef-
ficacy between ARBs and ACE inhibitors with regard
to the surrogate endpoint of BP and the outcomes of
all-cause mortality, CV mortality, MI, heart failure,
stroke, and end-stage renal disease. ACE inhibitors
are associated with cough and very low risks of
angioedema and fatalities that are more prevalent in
dark-skinned people. Overall, rates of WDAEs are
significantly lower with ARBs than with ACE in-
hibitors. Because efficacy is similar but adverse
events are fewer with ARBs, risk-to-benefit analysis
in aggregate indicates that at present there is little, if
any, clinical reason to use ACE inhibitors for the
treatment of hypertension and so-called compelling
indications.
ADDRESS FOR CORRESPONDENCE: Dr. Franz H.
Messerli, Department of Cardiology, Inselspital,
Freiburgstrasse, CH-3010 Bern, Switzerland. E-mail:
messerli.f@gmail.com.

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KEY WORDS adverse events, angioedema,
angiotensin receptor blocker, blood
pressure, chronic kidney disease, coronary
heart disease, cough, diabetes, heart failure,
hypertension, left ventricular hypertrophy