Journal of the American College of Cardiology Vol. 61, No.

2, 2013
© 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2012.10.011

CLINICAL RESEARCH Cardiovascular Risk

A Meta-Analysis Reporting Effects of

Angiotensin-Converting Enzyme Inhibitors and
Angiotensin Receptor Blockers in
Patients Without Heart Failure

Gianluigi Savarese, MD,* Pierluigi Costanzo, MD,*† John George Franklin Cleland, MD,†
Enrico Vassallo, MD,* Donatella Ruggiero, MD,* Giuseppe Rosano, MD, PHD,‡
Pasquale Perrone-Filardi, MD, PHD*

Naples and Rome, Italy; and Cottingham, United Kingdom

Objectives The goal of the study was to assess the effects of angiotensin-converting enzyme inhibitors (ACE-Is) and angio-
tensin receptor blockers (ARBs) on the composite of cardiovascular (CV) death, myocardial infarction (MI), and
stroke, and on all-cause death, new-onset heart failure (HF), and new-onset diabetes mellitus (DM) in high-risk
patients without HF.

Background ACE-Is reduce CV events in high-risk patients without HF whereas the effects of ARBs are less certain.

Methods Twenty-six randomized trials comparing ARBs or ACE-Is versus placebo in 108,212 patients without HF were col-
lected in a meta-analysis and analyzed for the risk of the composite outcome, all-cause death, new-onset HF,
and new-onset DM.

Results ACE-Is significantly reduced the risk of the composite outcome (odds ratio [OR]: 0.830 [95% confidence interval
(CI): 0.744 to 0.927]; p ⫽ 0.001), MI (OR: 0.811 [95% CI: 0.748 to 0.879]; p ⬍ 0.001), stroke (OR: 0.796 [95%
CI: 0.682 to 0.928]; p ⬍ 0.004), all-cause death (OR: 0.908 [95% CI: 0.845 to 0.975]; p ⫽ 0.008), new-onset HF
(OR: 0.789 [95% CI: 0.686 to 0.908]; p ⫽ 0.001), and new-onset DM (OR: 0.851 [95% CI: 0.749 to 0.965]; p ⬍
0.012). ARBs significantly reduced the risk of the composite outcome (OR: 0.920 [95% CI: 0.869 to 0.975], p ⫽
0.005), stroke (OR: 0.900 [95% CI: 0.830 to 0.977], p ⫽ 0.011), and new-onset DM (OR: 0.855 [95% CI: 0.798
to 0.915]; p ⬍ 0.001).

Conclusions In patients at high CV risk without HF, ACE-Is and ARBs reduced the risk of the composite outcome of CV death,
MI, and stroke. ACE-Is also reduced the risk of all-cause death, new-onset HF, and new-onset DM. Thus, ARBs
represent a valuable option to reduce CV mortality and morbidity in patients in whom ACE-Is cannot be used. (J Am Coll
Cardiol 2013;61:131–42) © 2013 by the American College of Cardiology Foundation

After the HOPE (Heart Outcomes Prevention Evaluation)
trial (1), angiotensin-converting enzyme inhibitors (ACE-
Is) have been recommended for reduction of cardiovascular
(CV) events in patients at high CV risk without heart failure
From *Cardiology, Federico II University, Naples, Italy; †Academic Cardiology Unit,
Hull York Medical School, University of Hull, Daisy Building, Castle Hill Hospital,
Cottingham, United Kingdom; and the ‡Clinical and Experimental Research Center,
IRCCS San Raffaele, Rome, Italy. Dr. Cleland has received research funding from
Servier, Amgen, and Philips; speakers’ honoraria from Medtronic and St. Jude; and
has participated in Trial Steering Committees with Amgen. All other authors have
reported that they have no relationships relevant to the contents of this paper to
disclose. The first two authors contributed equally to this work.
Manuscript received August 3, 2012; revised manuscript received September 28,
2012, accepted October 9, 2012.
(HF) (2). The results of the HOPE study, in which a
substantial reduction of major CV events (CV death,
myocardial infarction [MI], and stroke) was reported, were
confirmed in the PROGRESS (Perindopril pROtection
aGainst REcurrent Stroke Study) (3) and EUROPA
(EURopean trial On reduction of cardiac events with
Perindopril in stable coronary Artery disease) (4) trial but
not in other trials comparing ACE-Is with placebo in
patients at high CV risk (5–12). However, a meta-
analysis by Dagenais et al. (13), collecting 3 major
randomized placebo-controlled studies on ACE-Is in
patients without HF, showed favorable effects of ACE-Is
on CV events.
132 Savarese et al.
Effects of ACE-Is and ARBs on Clinical Events
Abbreviations The rationale for ACE-I ther-
and Acronyms apy in patients without HF rel-
ies on the effects of vascular
ACE-I ⴝ angiotensin-
converting enzyme inhibitor angiotensin II or bradykinin/
ARB ⴝ angiotensin
prostaglandin on the progression
receptor blocker of atherosclerosis (14). However,
CI ⴝ confidence interval
it is well known that during
CV ⴝ cardiovascular
ACE-I therapy, angiotensin II
synthesis may shift to alternative
DM ⴝ diabetes mellitus
ACE-independent enzymatic
HF ⴝ heart failure
pathways, which could reduce the
IR ⴝ incidence rate efficacy of therapy (15). The unfa-
MI ⴝ myocardial infarction vorable effects of angiotensin II on
OR ⴝ odds ratio atherosclerosis progression are me-
diated through stimulation of an-
giotensin II receptor 1. Angioten-
sin receptor blockers (ARBs) prevent angiotensin II receptor 1
stimulation without direct effects on bradykinin/prostaglandin,
which improves their adverse effect profile. Although ARBs
reduce diabetic retinopathy and nephropathy (16 –18), and CV
morbidity and mortality in patients with HF (19), their effects
in patients without HF are less certain because major clinical
trials comparing ARBs with placebo reported conflicting re-
sults (20 –29).
The aim of the current study was to assess, in a meta-
analysis, the effects of ACE-I and ARB therapy on the
composite outcome of CV death, MI, and stroke as well as
on all-cause death, new-onset HF, and new-onset diabetes
mellitus (DM) in high-risk patients without HF.
Methods
Data sources and searches. MEDLINE, Cochrane Data-
base, ISI Web of Sciences, and SCOPUS were searched for
articles with no language restrictions until June 2012. Studies
were identified by the following headings: angiotensin receptor
blocker, antagonist of angiotensin II receptor 1, ARB,
angiotensin-converting enzyme, ACE, randomly, random,
randomized controlled trial, and clinical trial. We used refer-
ence lists of the retrieved articles as well as information from
colleagues to identify additional eligible studies.
Study selection. This study was designed according to the
PRISMA (Preferred Reporting Items for Systematic re-
views and Meta-Analyses) statement (30,31). Only ran-
domized, double-blind, clinical trials comparing either an
ARB or an ACE-I with placebo, excluding patients with
systolic or diastolic HF and reporting clinical events (in-
cluding all-cause and CV death, MI, stroke, new-onset HF,
and new-onset DM), were considered for the analysis.
Data extraction and quality assessment. Two reviewers
independently selected potentially eligible trials. Discrepancies
were resolved by discussion and consensus. Two reviewers
independently read the full text of retained studies, which were
checked to avoid inclusion of data published in duplicate. Data
on baseline characteristics, presence of DM, hypertension,
JACC Vol. 61, No. 2, 2013
January 15, 2013:131–42
coronary artery disease, and pre-specified outcomes, including
all-cause and CV death, MI, stroke, new-onset HF, and
new-onset DM, were abstracted. The first objective of the
study was to assess the effect of treatments on the composite
outcome (CV death, MI, and stroke) and on all-cause death.
In addition, the effects of treatments on the risk of each
component of the composite outcome and on new-onset HF
and new-onset DM were also explored.
The quality of each trial was evaluated by giving a score for
each study using the Detsky method (32) (Table 1). Of 25,661
articles identified by the initial search, 43 were retrieved for
more detailed evaluation, and 25 (corresponding to 26 trials)
were included in the study (Fig. 1). Included trials and
population details are listed in Tables 1 to 3. Thirteen trials
compared ACE-Is with placebo (1,3–12,33,34), and 13 trials
compared ARBs with placebo (17,18,20 –29). Characteristics
of patient populations enrolled in ACE-I and ARB trials were
compared by using the Student t test for unpaired samples or
the chi-square test, as appropriate.
To assess the level of risk of patients included in trials, the
incidence rate (IR; expressed as events per 1,000 patient-years)
of each outcome analyzed was calculated for the placebo
patients enrolled in ACE-I trials and for the placebo patients
enrolled in ARB trials, by using the following formula: IR ⫽
(number of placebo patients with event ⫻ 1,000)/(number of
placebo patients ⫻ years of follow-up) (35).
Data synthesis and analysis. OUTCOME META-ANALYSIS.
Odds ratios (ORs) of the effect of randomized treatments
were calculated by using the metan routine (STATA version
11.0, StataCorp, College Station, Texas). ORs and 95%
confidence intervals (CIs) for each outcome were separately
calculated for each trial, with grouped data, by using the
intention-to-treat principle (36,37). The choice to use ORs
was driven by the retrospective design of the meta-analysis,
based on published studies that vary in design, subjects’
population, treatment regimens, primary outcome measures,
and quality (38,39). Overall estimates of effect were calcu-
lated with a random effects model (40). The assumption of
homogeneity between the treatment effects in different trials
was tested with the Q and I2 statistics. Pooled ORs were
logarithmically transformed and weighted for the inverse of
variance. The significance level for the overall estimates of
effect and for meta-regression analyses was set at p ⱕ 0.05.
Only a single, first event could contribute to each outcome
measure.
SENSITIVITY ANALYSIS. To explore the influence of poten-
tial effect modifiers on outcomes, a meta-regression analysis
was performed with the metareg command (41) (STATA
version 11.0) to test demographic characteristics of the
study population, body mass index, percentage of patients
with coronary artery disease, percentage of patients with
DM, percentage of patients with hypertension, blood pres-
sure values and blood pressure differences from start to end
of each study, current therapy, length of follow-up, and
quality of trials (32). For all meta-regression analyses, a
JACC Vol. 61, No. 2, 2013
January 15, 2013:131–42
random effects model was used to take into account the
mean of a distribution of effects across studies. In fact, a
random effects model more appropriately provides wider
CIs for the regression coefficients than a fixed effect analysis,
if residual heterogeneity exists (42). The weight used for
each trial was the inverse of the sum of the within-trial
variance and the residual between trial variance, to corre-
spond to a random effects analysis. To estimate the additive
(between-study) component of variance tau-2, the restricted
maximum likelihood method was used to take into account
the occurrence of residual heterogeneity not explained by
the potential effect modifiers (42). To verify the consistency
of the results, individual meta-analyses were performed for
single drugs (candesartan, olmesartan, telmisartan, irbesar-
tan, perindopril, ramipril, and enalapril) against each out-
come when a drug was used in at least 2 trials.
PUBLICATION BIAS. To evaluate potential publication bias,
a weighted linear regression was used, with the natural log
of the OR as the dependent variable and the inverse of the
total sample size as the independent variable. This is a
modified Macaskill’s test, which gives more balanced type I
error rates in the tail probability areas compared with other
publication bias tests (43).
Results
Characteristics of included trials. Baseline characteristics
of the 26 trials included in the meta-analysis are shown in
Tables 1 through 3. Of 108,212 patients, a total of 53,791
were enrolled in ACE-I trials and 54,421 in ARB trials.
Duration of follow-up ranged from 2 to 6.5 years (3.68 ⫾
1.11 years). The overall mean age of subjects was 58 ⫾ 11
years, and 35% were women. Mean age was 58.3 ⫾ 8.3 years
in ACE-I trials and 57.7 ⫾ 13.1 years in ARB trials (p ⫽
NS); 26% of patients enrolled in ACE-I trials were women
compared with 44% in ARB trials (p ⬍ 0.05). Length of
follow-up was not different between ACE-I (3.66 ⫾ 0.90
years) and ARB (3.69 ⫾ 1.32 years) (p ⫽ NS) trials. Placebo
patients enrolled in ACE-I trials compared with placebo
patients enrolled in ARB trials showed nonsignificant dif-
ferences in the IR of composite outcome (27 vs. 25 events
per 1,000 patient-years; p ⫽ 0.608) as well as all-cause death
(21 vs. 19 events per 1,000 patient-years; p ⫽ 0.898),
new-onset HF (7 vs. 6 events per 1,000 patient-years; p ⫽
0.784), and new-onset DM (15 vs. 24 events per 1,000
patient-years; p ⫽ 0.176).
Outcomes analysis. EFFECTS OF ACE-Is. ACE-Is signifi-
cantly reduced the risk of the composite outcome by 14.9%
compared with placebo (OR: 0.830 [95% CI: 0.744 to 0.927];
comparison p ⫽ 0.001, heterogeneity p ⫽ 0.002) (Fig. 2A).
When components of the composite outcome were considered
separately, the 10% reduction of CV death did not achieve
statistical significance (OR: 0.896 [95% CI: 0.783 to 1.026],
comparison p ⫽ 0.112, heterogeneity p ⫽ 0.087)
(Online Fig. 1), whereas ACE-Is significantly reduced the
Savarese et al. 133
Effects of ACE-Is and ARBs on Clinical Events
risk of MI by 17.7% (OR: 0.811 [95% CI: 0.748 to 0.879],
comparison p ⬍ 0.001, heterogeneity p ⫽ 0.438) (Online
Fig. 2) and of stroke by 19.6% (OR: 0.796 [95% CI: 0.682
to 0.928], comparison p ⫽ 0.004, heterogeneity p ⫽ 0.115)
(Online Fig. 3). In addition, ACE-Is reduced the risk of
all-cause death by 8.3% (OR: 0.908 [95% CI: 0.845 to
0.975], comparison p ⫽ 0.008, heterogeneity p ⫽ 0.368)
(Fig. 2B), new-onset HF by 20.5% (OR: 0.789 [95% CI:
0.686 to 0.908], comparison p ⫽ 0.001, heterogeneity p ⫽
0.252) (Online Fig. 4), and new-onset DM by 13.7% (OR:
0.851 [95% CI: 0.749 to 0.965], comparison p ⫽ 0.012,
heterogeneity p ⫽ 0.069) (Online Fig. 5). Significant
heterogeneity among trials was found for the composite
outcome but not for all other outcomes explored in the
analysis.
EFFECTS OF ARBS. ARBs significantly reduced the risk of
the composite outcome by 7.0% compared with placebo
(OR: 0.920 [95% CI: 0.869 to 0.975], comparison p ⫽
0.005, heterogeneity p ⫽ 0.686) (Fig. 2A). When compo-
nents of the composite outcome were analyzed separately,
ARBs did not reduce the risk of CV death (OR: 1.033 [95%
CI: 0.847 to 1.260], comparison p ⫽ 0.748, heterogeneity
p ⫽ 0.012) (Online Fig. 1), whereas the 9.5% reduction of
MI risk approximated statistical significance (OR: 0.903
[95% CI: 0.803 to 1.015], comparison p ⫽ 0.086, hetero-
geneity p ⫽ 0.420 (Online Fig. 2). ARBs significantly
reduced the risk of stroke by 9.1% (OR: 0.900 [95% CI:
0.830 to 0.977], comparison p ⫽ 0.011, heterogeneity p ⫽
0.469) (Online Fig. 3). No significant effect was found on
the risk of all-cause death (OR: 1.006 [95% CI: 0.941 to
1.075], comparison p ⫽ 0.866, heterogeneity p ⫽ 0.368)
(Fig. 2B) and of new-onset HF (OR: 0.892 [95% CI: 0.761
to 1.046], comparison p ⫽ 0.159, heterogeneity p ⫽ 0.188)
(Online Fig. 4). ARBs significantly reduced the risk of
new-onset DM by 10.6% (OR: 0.855 [95% CI: 0.798 to
0.915], comparison p ⬍ 0.001, heterogeneity p ⫽ 0.819)
(Online Fig. 5). Significant heterogeneity among trials was
found only for CV death. ORs for the effects of ACE-Is and
ARBs are reported in Figure 3.
Sensitivity analysis. Results were confirmed when poten-
tial effect modifiers were introduced as covariates in the
meta-regression analysis (Online Table 1). Moreover, sim-
ilarly to the overall results, telmisartan (OR: 0.915 [95% CI:
0.853 to 0.982], p ⫽ 0.013), perindopril (OR: 0.768 [95%
CI: 0.679 to 0.869], p ⬍ 0.001), and enalapril (OR: 0.580
[95% CI: 0.370 to 0.908], p ⫽ 0.017) reduced the risk of the
composite outcome, whereas olmesartan (OR: 1.063 [95%
CI: 0.748 to 1.509], p ⫽ 0.733), candesartan (OR: 0.728
[95% CI: 0.357 to 1.482], p ⫽ 0.381), irbesartan (OR:
0.949 [95% CI: 0.597 to 1.508], p ⫽ 0.824), and ramipril
(OR: 0.861 [95% CI: 0.661 to 1.122], p ⫽ 0.268) did not
(Online Fig. 6). Results for other outcomes are reported in
Table 4.
 134
Baseline
Table 1 Characteristics

Effects of ACE-Is and ARBs on Clinical Events

Savarese et al.
Baseline Characteristics

Detsky
Trial Treatment Placebo Follow-up Age Women Hypertension DM Quality CAD
Agent (Ref. #) Year Treatment (n) (n) (yrs) (yrs) (%) (%) (%) Score (%) Study Population Specifics
ARBs IRMA-2 (20) 2001 Irbesartan 404 207 2.00 58 31 100 100 20 8 Hypertensive patients with
type 2 DM and
microalbuminuria
RENAAL (21) 2001 Losartan 751 762 3.40 60 37 94 100 19 21 Patients with a history of
stroke or transient
ischemic attack
IDNT (22) 2003 Irbesartan 579 567 2.60 59 32 100 100 20 28 Patients with type 2 DM
nephropathy and
hypertension
Kondo et al. (23) 2003 Candesartan 203 203 2.00 65 24 44 25 17 100 Patients with history of
coronary intervention
and no significant
coronary stenosis on
follow-up
SCOPE (24) 2003 Candesartan 2,477 2,460 3.70 76 65 53 12 18 5 Elderly patients with
hypertension and MMSE
test score ⬎24
DIRECT-PREVENT-1 (17) 2008 Candesartan 711 710 4.70 30 44 0 100 19 0 Patients with normotensive,
normoalbuminuric type 1
DM without retinopathy
DIRECT-PROTECT-1 (17) 2008 Candesartan 951 954 4.80 32 43 0 100 19 0 Patients with normotensive,
normoalbuminuric type 1
DM with retinopathy
DIRECT-PROTECT-2 (18) 2008 Candesartan 951 954 4.70 57 50 62 100 19 0 Normoalbuminuric,
normotensive, or treated
hypertensive people with
type 2 DM and
retinopathy
PROFESS (26) 2008 Telmisartan 10,146 10,186 2.50 66 36 74 28 20 NA Patients with a recent
ischemic stroke
TRANSCEND (27) 2008 Telmisartan 2,954 2,972 4.67 67 43 76 36 20 75 High-risk patients intolerant
to ACE-Is
NAVIGATOR (28) 2010 Valsartan 4,631 4,675 6.50 64 51 78 0 21 28 Patients with impaired
glucose tolerance and
established CV disease
or CV risk factors

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January 15, 2013:131–42
ORIENT (25) 2011 Olmesartan 282 284 3.20 59 69 94 100 17 8 Type 2 DM patients with
overt nephropathy
ROADMAP (29) 2011 Olmesartan 2,232 2,215 3.20 58 54 NA 100 20 31 Patients with type 2 DM

Continued on the next page

 January 15, 2013:131–42
JACC Vol. 61, No. 2, 2013
Continued
Table 1 Continued

Detsky
Trial Treatment Placebo Follow-up Age Women Hypertension DM Quality CAD
Agent (Ref. #) Year Treatment (n) (n) (yrs) (yrs) (%) (%) (%) Score (%) Study Population Specifics
ACE-Is Lewis et al. (33) 1993 Captopril 207 202 3.00 35 47 76 100 16 NA Patients with diabetic
nephropathy
AIPRI (34) 1996 Benazepril 300 283 3.00 51 28 82 NA 16 NA Patients with renal
insufficiency
HOPE (1) 2000 Ramipril 4,645 4,652 5.00 66 27 47 39 20 80 High-risk patients with
evidence of vascular
disease or DM plus 1
other CV risk factor
PART-2 (5) 2000 Ramipril 308 309 4.70 61 18 NA 9 18 100 Patients with coronary or
other occlusive arterial
disease
SCAT (6) 2000 Enalapril 229 231 3.98 62 11 36 11 17 100 Patients with CAD
PROGRESS (3) 2001 Perindopril 3,051 3,054 4.00 64 30 48 13 19 8 Patients with previous
stroke or transient
ischemic attack
QUIET (7) 2001 Quinapril 878 872 3.00 58 18 47 16 18 100 Patients with CAD
EUROPA (4) 2003 Perindopril 6,110 6,108 4.20 60 15 27 12 20 100 Patients with stable CAD
PEACE (8) 2004 Trandolapril 4,158 4,132 4.80 64 18 46 17 20 100 Patients with stable CAD
CAMELOT (9) 2004 Enalapril 673 655 2.00 58 28 60 19 19 100 Patients with documented
CAD
DIABHYCAR (10) 2004 Ramipril 2,443 2,469 4.00 65 30 56 100 18 6 Type 2 DM patients with
persistent
microalbuminuria or
proteinuria

Effects of ACE-Is and ARBs on Clinical Events

DREAM (11) 2006 Ramipril 2,623 2,646 3.00 55 59 44 0 18 NA Patients without CV disease
but with impaired fasting
glucose levels or
impaired glucose
tolerance
IMAGINE (12) 2007 Quinapril 1,280 1,273 2.95 61 13 47 9 21 100 Low-risk patients early after
coronary artery bypass
surgery

ACE-I ⫽ angiotensin-converting enzyme inhibitor; AIPRI ⫽ Angiotensin-converting-enzyme Inhibition in Progressive Renal Insufficiency; ARB ⫽ angiotensin receptor blocker; CAD ⫽ coronary artery disease; CAMELOT ⫽ Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis; CV ⫽ cardiovascular; DIABHYCAR ⫽ type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril; DIRECT ⫽ DIabetic REtinopathy Candesartan Trials; DM ⫽ diabetes mellitus; DREAM ⫽ Diabetes REduction Assessment with ramipril and

Savarese et al.
rosiglitazone Medication; EUROPA ⫽ in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease; HOPE ⫽ Heart Outcomes Prevention Evaluation; PART-2 ⫽ Prevention of Atheroslerosis with Ramipril Trial; IDNT ⫽ Irbesartan Diabetic
Nephropathy Trial; IMAGINE ⫽ Ischemia Management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme; IRMA-2 ⫽ IRbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients; MMSE ⫽ MiniMental State Examination; NA ⫽ not
available; NAVIGATOR ⫽ Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research; ORIENT ⫽ Olmesartan Reducing Incidence of End stage renal disease in diabetic Nephropathy Trial; PEACE ⫽ Prevention of Events with Angiotensin Converting Enzyme
inhibition; PRoFESS ⫽ Prevention Regimen For Effectively Avoiding Second Strokes; PROGRESS ⫽ Perindopril pROtection aGainst REcurrent Stroke Study; QUIET ⫽ QUinapril Ischemic Event Trial; RENAAL ⫽ Reduction in ENdpoints with the Angiotensin Antagonist Losartan;
ROADMAP ⫽ Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention; SCAT ⫽ Simvastatin/enalapril Coronary Atheroslerosis Trial; SCOPE ⫽ Study on Cognition and Prognosis in the Elderly; TRASCEND ⫽ Telmisartan Randomised AssessmeNT Study in
ACEiNtoleran subjects with cardiovascular Disease.

135
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Effects of ACE-Is and ARBs on Clinical Events January 15, 2013:131–42

Figure 1 Flow Chart Showing the Progress Through the Stages of the Meta-Analysis

RCT ⫽ randomized controlled trial.

Blood
TablePressure
2 Blood Levels at Baseline
Pressure Levels and End of Follow-up
at Baseline and End of Follow-up

Trial Blood Pressure Baseline, Blood Pressure Baseline, Blood Pressure End Follow-up, Blood Pressure End Follow-up,
Agent (Ref. #) T (mm Hg) C (mm Hg) T (mm Hg) C (mm Hg)
ARBs
IRMA-2 (20) 137/81 136/80 126/74 129/76
RENAAL (21) 166/90 166/90 145/80 148/82
IDNT (22) 144/84 144/84 NA NA
Kondo et al. (23) 141/82 141/82 NA NA
SCOPE 24 117/74 117/73 NA NA
DIRECT-PREVENT-1 (17) 129/76 128/76 127/75 126/76
DIRECT-PROTECT-1 (17) 139/82 140/83 133/78 136/80
DIRECT-PROTECT-2 (18) 142/78 141/77 132/72 137/74
PROFESS (26) 152/82 153/82 140/74 142/74
TRANSCEND (27) 131/77 131/78 NA NA
NAVIGATOR (28) 160/87 158/87 140/77 144/80
ORIENT (25) 153/90 153/90 142/83 144/83
ROADMAP (29) 116/72 116/72 NA NA
ACE-Is
Lewis et al. (33) 137/85 140/86 NA NA
AIPRI (34) 137/82 137/82 128/78 133/80
HOPE (1) 142/87 144/88 NA NA
PART-2 (5) 146/82 145/82 143/80 143/80
SCAT (6) 136/83 136/83 NA NA
PROGRESS (3) 123/74 123/74 NA NA
QUIET (7) 128/77 132/78 NA NA
EUROPA (4) 122/70 121/70 125/74 129/76
PEACE (8) 133/79 133/79 127/74 132/78
CAMELOT (9) 139/79 139/79 136/76 139/77
DIABHYCAR (10) 134/78 133/78 130/74 132/76
DREAM (11) 147/86 147/86 138/82 142/84
IMAGINE (12) 129/77 129/78 124/74 130/79

C ⫽ control; T ⫽ treatment; other abbreviations as in Table 1.

JACC Vol. 61, No. 2, 2013 Savarese et al. 137
January 15, 2013:131–42 Effects of ACE-Is and ARBs on Clinical Events

Concomitant
Table 3 Medications Medications
Concomitant

Agent Trial (Ref. #) Beta-Blockers Aspirin Statins Diuretics Calcium Channels Blockers
ARBs
IRMA-2 (20) NA NA NA NA NA
RENAAL (21) NA NA 9 NA NA
IDNT (22) 21 NA 47 21 24
Kondo et al. (23) 58 75 55 33 40
SCOPE (24) NA NA NA NA NA
DIRECT-PREVENT-1 (17) 5 15 14 NA NA
DIRECT-PROTECT-1 (17) 39 37 38 32 32
DIRECT-PROTECT-2 (18) 17 20 53 37 68
PROFESS (26) 18 NA NA 58 71
TRANSCEND (27) NA NA NA NA NA
NAVIGATOR (28) 47 NA NA NA 8
ORIENT (25) 15 18 18 23 NA
ROADMAP (29) NA NA NA NA NA
ACE-Is
Lewis et al. (33) NA NA NA NA NA
AIPRI (34) 62 92 58 9 31
HOPE (1) 38 NA NA 23 48
PART-2 (5) NA 19 29 NA NA
SCAT (6) 17 14 13 16 13
PROGRESS (3) 26 73 0 NA 0
QUIET (7) 48 90 NA NA 15
EUROPA (4) 63 95 83 NA 37
PEACE (8) 43 81 29 NA 25
CAMELOT (9) 40 76 29 15 47
DIABHYCAR (10) 60 91 70 13 36
DREAM (11) NA NA NA NA NA
IMAGINE (12) 77 95 83 30 9

Abbreviations as in Table 1.

Publication bias. Macaskill’s modified test did not show
publication bias for any outcome.
Discussion
This meta-analysis confirmed that, compared with placebo,
ACE-Is substantially reduced the composite of CV death, MI,
and stroke as well as all-cause death, new-onset HF, and
new-onset DM in high-risk patients without HF, mostly with
coronary or other vascular diseases. ARBs, in high-risk patients
mostly with DM or impaired glucose tolerance without HF,
reduced the composite outcome and new-onset DM but did
not seem to reduce rates of all-cause death or new-onset HF.
CV effects of ACE-Is in patients without HF. Our
findings confirm and extend a previous meta-analysis of
ACE-I trials reported by Dagenais et al. (13), adding an
additional 10 ACE-I trials (corresponding to 23,986 additional
patients) (3,5–7,9 –12,33,34) to HOPE (1), EUROPA (4),
and PEACE (Prevention of Events with Angiotensin Con-
verting Enzyme inhibition) (8) included in that previous
analysis. In particular, consistent with the study by Dagenais
et al, our analysis demonstrates that ACE-Is, compared
with placebo, substantially reduced all-cause death by 8.3%,
CV death by 10%, MI by 17.7%, and stroke by 19.6%, as
well as new-onset HF by 20.5%. In addition, the current
analysis reported a significant 13.7% reduction of the risk of
new-onset DM.
CV effects of ARBs in patients without HF. The effects
on major clinical events of ARBs in patients without HF
have been evaluated in several trials reporting conflicting
results (17,18,20 –29). In the RENAAL (Reduction in
ENdpoints with the Angiotensin Antagonist Losartan)
study (21), losartan, compared with placebo, failed to reduce
the secondary composite CV outcome, including CV death,
MI, stroke, coronary or peripheral revascularization, and
new HF, in diabetic patients with nephropathy. Similarly,
in high-risk diabetic patients without (20) and with (22)
overt nephropathy, irbesartan did not reduce CV events. In
the SCOPE (Study on Cognition and Prognosis in the
Elderly) (24), a candesartan-based therapy in hypertensive
elderly patients failed to reduce the primary composite
outcome of CV death, MI, and stroke, whereas it signifi-
cantly decreased the risk of new-onset DM. In contrast, in
a small study enrolling high-risk patients (23), candesartan,
compared with placebo, significantly reduced the risk of a
composite outcome including CV death, MI, and coronary
revascularization. Subsequently, however, high-dose cande-
138 Savarese et al. JACC Vol. 61, No. 2, 2013
Effects of ACE-Is and ARBs on Clinical Events January 15, 2013:131–42

Figure 2 OR of Composite Outcome and All-Cause Death

Solid squares represent odds ratio (ORs) in trials and have a size proportional to the number of events. The 95% confidence intervals (CIs) for individual trials are
denoted by lines and those for the pooled ORs by empty diamonds. (A) Composite outcome; (B) all-cause death. ACE-I ⫽ angiotensin-converting enzyme inhibitor;
ARB ⫽ angiotensin receptor blocker.
JACC Vol. 61, No. 2, 2013
January 15, 2013:131–42
Figure 3 ORs and 95% CIs for the Effects of ACE-Is and ARBs, Compared With Placebo, on Each Outcome
*Outcomes significantly reduced compared with placebo. Abbreviations as in Figure 2.
sartan did not reduce CV events in patients with type 1 or
type 2 DM with no previous CV events (17,18). In the
TRANSCEND (Telmisartan Randomised AssessmeNT Study
in ACEiNtoleran subjects with cardiovascular Disease) trial
(27), ACE-I–intolerant patients were enrolled and assigned
to either telmisartan or placebo. Although the primary
endpoint of CV death, MI, stroke, and new-onset HF was
not significantly reduced by telmisartan, a 13% reduction in
the secondary combined endpoint, including CV death, MI,
and stroke was reported (p ⫽ 0.05), whereas new-onset DM
was not reduced by telmisartan. However, in the PROFESS
(Prevention Regimen For Effectively Avoiding Second
Strokes) study (26), which enrolled patients with a recent
stroke, telmisartan, compared with placebo, failed to reduce
the recurrence of stroke, all-cause mortality, DM, or any
CV endpoint. More recently, in the NAVIGATOR (Nateg-
linide And Valsartan in Impaired Glucose Tolerance Out-
comes Research) trial (28), which enrolled stable patients
with impaired glucose tolerance with or at high risk of
developing CV disease, valsartan reduced the occurrence of
DM but failed to reduce CV morbidity or mortality. Finally,
the recently concluded ROADMAP (Randomized Olm-
esartan And Diabetes MicroAlbuminuria Prevention) (29)
trial and the ORIENT (Olmesartan Reducing Incidence of
End stage renal disease in diabetic Nephropathy Trial) (25)
trial reported an increase of the prespecified secondary
endpoint of CV mortality in diabetic patients receiving
olmesartan, despite a favorable effect on the primary renal
endpoint.
Savarese et al. 139
Effects of ACE-Is and ARBs on Clinical Events
The current meta-analysis demonstrates that ARBs
significantly reduce the composite outcome of CV death,
MI, and stroke by 7.0%, as well as stroke by 9.1% and
new-onset DM by 10.6% in high-risk, mostly diabetic or
glucose-intolerant patients without HF enrolled in ran-
domized clinical trials. However, no significant effects
could be found on the risk of all-cause death, MI, and
new-onset HF.
To our knowledge, no previous meta-analysis investi-
gated the effects of ARBs compared with placebo, on top of
concomitant therapy, in patients without HF. In fact, in
a previous meta-analysis by Baker et al. (44), only the
TRANSCEND (27) study, among ARB trials reported,
was included, whereas the meta-analysis by Bangalore et al.
(45), that mainly focused on the risk of MI in patients
receiving ARBs, reported also trials in patients with HF.
More recently, van Vark et al. (35) reported a meta-analysis
of randomized clinical trials of renin-angiotensin-
aldosterone system inhibitors. Compared with the current
analysis, only hypertension trials were included in the study
by van Vark et al. (35), and only CV and all-cause death
were analyzed. The study demonstrated a significant benefit
on all-cause and CV death, significantly associated with
blood pressure reduction and almost entirely driven by
ACE-I effects, but it could not assess the effects of ARBs on
high-risk, nonhypertensive patients. Finally, McAlister et
al. (46) reported a meta-analysis of ACE-Is and ARBs in
normotensive atherosclerotic patients showing a favorable
effect on major clinical outcomes. In this study, however,
140 Savarese et al. JACC Vol. 61, No. 2, 2013
Effects of ACE-Is and ARBs on Clinical Events January 15, 2013:131–42

OR Estimate
Table 4 OR of Each Outcome
Estimate for Outcome
of Each Each Drug
forTreatment
Each DrugGroup Compared
Treatment GroupWith PlaceboWith Placebo
Compared

Myocardial Infarction Cardiovascular Death Stroke

Drug OR 95% CI p Value OR 95% CI p Value OR 95% CI p Value

Candesartan 1.161 0.786–1.715 0.452 0.552 0.136–2.235 0.405 NA NA NA
Olmesartan 0.610 0.366–1.020 0.059 4.181 1.703–10.263 0.002 0.999 0.512–1.951 0.008
Telmisartan 0.893 0.707–1.128 0.343 0.930 0.771–1.121 0.447 0.925 0.845–1.012 0.091
Irbesartan 0.873 0.581–1.312 0.514 NA NA NA NA NA NA
Perindopril 0.724 0.598–0.877 0.001 0.881 0.767–1.012 0.073 0.801 0.587–1.093 0.162
Ramipril 0.807 0.716–0.910 0.000 0.840 0.604–1.169 0.302 0.856 0.580–1.265 0.436
Enalapril 0.564 0.313–1.016 0.056 1.064 0.258–4.379 0.932 0.451 0.164–1.235 0.121

CI ⫽ confidence interval; OR ⫽ odds ratio; NA ⫽ not available.

Continued on the next page

ACE-I and ARB trials were grouped into the same analysis,
and no distinction was made between ACE-I and ARB
trials. In addition, trials also enrolling patients with HF
were included. Thus, the CV effects of ARBs in high-risk
patients without HF were not adequately investigated in
previous meta-analyses.
Study limitations. First, we used summary rather than
individual patient data. In addition, the characteristics of
populations enrolled in ACE-I and ARB trials were
different. ACE-I trials were mostly conducted in patients
with coronary or other vascular atherosclerotic disease,
and ARB trials were mostly conducted in patients with
DM or impaired glucose intolerance. Although the level
of risk in the placebo arms of the ACE-I and ARB trials
was not significantly different for any outcome analyzed,
and the characteristics of study populations did not
influence the findings of the study in sensitivity analyses,
the differences between ACE-I and ARB populations
encourage caution regarding the generalizability of the
results. In addition, inherent limitations of meta-
regression analysis should be considered when interpret-
ing the results of sensitivity analysis (47). Thus, this study
does not represent a direct comparison between ACE-Is
and ARBs that can only be adequately assessed in ad hoc
trials. In fact, the ONTARGET (ONgoing Telmisartan
Alone and in combination with Ramipril Global End-
point Trial) (48) study observed no significant difference
between telmisartan and ramipril on major CV outcomes,
although no placebo arm was available in that trial,
preventing a thorough evaluation of the net benefits of
the 2 treatments on top of concomitant CV therapy. A
substantial number of patients discontinued ARBs in
clinical trials, and this action may have attenuated the
effect of therapy by an intention-to-treat analysis. In
addition, a potentially greater benefit from ARBs in
particular subgroups of patients, such as those with organ
damage, cannot be excluded from the current analysis.
Finally, the current study considered ACE-Is and ARBs
as 2 classes of drugs, although both include several agents
with different pharmacokinetic and pharmacodynamics
properties.
Conclusions
In high-risk patients without HF, ACE-Is, as a class,
reduced all-cause and CV death, as well CV morbidity and
new-onset DM. ARBs reduced the composite outcome of
CV death, MI, and stroke as well the risk of new-onset
DM. Thus, ARBs represent a viable option for high-risk
patients who do not tolerate ACE-I therapy.
Reprint requests and correspondence: Dr. Pasquale Perrone-
Filardi, Cardiology, Federico II University, Via S. Pansini 5,
80131 Naples, Italy. E-mail: fpperron@unina.it
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Key Words: ACE-I y angiotensin-converting enzyme inhibitor y
angiotensin receptor blocker y ARB y clinical events.
APPENDIX
For supplementary results of the study,
please see the online version of this article.