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CLINICAL RESEARCH Cardiovascular Risk

A Meta-Analysis Reporting Effects of

Angiotensin-Converting Enzyme Inhibitors andAngiotensin 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;61:13142) 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

(HF) (2). The results of the HOPE study, in which asubstantial reduction of major CV events (CV death,myocardial infarction [MI], and stroke) was reported, wereconfirmed in the PROGRESS (Perindopril pROtectionaGainst REcurrent Stroke Study) (3) and EUROPA(EURopean trial On reduction of cardiac events withPerindopril in stable coronary Artery disease) (4) trial butnot in other trials comparing ACE-Is with placebo inpatients at high CV risk (512). However, a meta-analysis by Dagenais et al. (13), collecting 3 majorrandomized placebo-controlled studies on ACE-Is in

patients without HF, showed favorable effects of ACE-Ison CV events.

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 fromServier, Amgen, and Philips; speakers honoraria from Medtronic and St. Jude; andhas participated in Trial Steering Committees with Amgen. All other authors havereported 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.

Journal of the American College of Cardiology Vol. 61, No. 2, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2012.10.011

wnloaded From: http://content.onlinejacc.org/ on 03/27/2014


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The rationale for ACE-I ther-apy in patients without HF rel-ies on the effects of vascularangiotensin II or bradykinin/prostaglandin on the progressionof atherosclerosis (14). However,

it is well known that duringACE-I therapy, angiotensin IIsynthesis may shift to alternativeACE-independen t enzymaticpathways, which could reduce theefficacy of therapy (15). The unfa-vorable effects of angiotensin II onatherosclerosis progression are me-diated through stimulation of an-giotensin II receptor 1. Angioten-

sin receptor blockers (ARBs) prevent angiotensin II receptor 1stimulation without direct effects on bradykinin/prostaglandin,

which improves their adverse effect profile. Although ARBsreduce diabetic retinopathy and nephropathy (1618), and CVmorbidity and mortality in patients with HF (19), their effectsin patients without HF are less certain because major clinicaltrials comparing ARBs with placebo reported conflicting re-sults (2029).

The aim of the current study was to assess, in a meta-analysis, the effects of ACE-I and ARB therapy on thecomposite outcome of CV death, MI, and stroke as well ason all-cause death, new-onset HF, and new-onset diabetesmellitus (DM) in high-risk patients without HF.

Methods

Data sources and searches. MEDLINE, Cochrane Data-base, ISI Web of Sciences, and SCOPUS were searched forarticles with no language restrictions until June 2012. Studieswere identified by the following headings: angiotensin receptorblocker, 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 fromcolleagues to identify additional eligible studies.

Study selection. This study was designed according to thePRISMA (Preferred Reporting Items for Systematic re-views and Meta-Analyses) statement (30,31). Only ran-domized, double-blind, clinical trials comparing either anARB or an ACE-I with placebo, excluding patients withsystolic 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 reviewersindependently selected potentially eligible trials. Discrepancieswere resolved by discussion and consensus. Two reviewersindependently read the full text of retained studies, which were

checked to avoid inclusion of data published in duplicate. Dataon baseline characteristics, presence of DM, hypertension,

coronary artery disease, and pre-specified outcomes, includingall-cause and CV death, MI, stroke, new-onset HF, andnew-onset DM, were abstracted. The first objective of thestudy was to assess the effect of treatments on the compositeoutcome (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 HFand new-onset DM were also explored.

The quality of each trial was evaluated by giving a score foreach study using the Detsky method (32)(Table 1). Of 25,661articles identified by the initial search, 43 were retrieved formore detailed evaluation, and 25 (corresponding to 26 trials)were included in the study (Fig. 1). Included trials andpopulation details are listed inTables 1to3.Thirteen trialscompared ACE-Is with placebo (1,312,33,34), and 13 trialscompared ARBs with placebo (17,18,2029). Characteristicsof patient populations enrolled in ACE-I and ARB trials werecompared by using the Student ttest for unpaired samples orthe chi-square test, as appropriate.

To assess the level of risk of patients included in trials, theincidence rate (IR; expressed as events per 1,000 patient-years)of each outcome analyzed was calculated for the placebopatients enrolled in ACE-I trials and for the placebo patientsenrolled in ARB trials, by using the following formula: IR(number of placebo patients with event 1,000)/(number ofplacebo patients years of follow-up) (35).Data synthesis and analysis.OUTCOME META-ANALYSIS.Odds ratios (ORs) of the effect of randomized treatmentswere calculated by using the metan routine (STATA version11.0, StataCorp, College Station, Texas). ORs and 95%confidence intervals (CIs) for each outcome were separatelycalculated for each trial, with grouped data, by using theintention-to-treat principle (36,37). The choice to use ORswas driven by the retrospective design of the meta-analysis,based on published studies that vary in design, subjectspopulation, treatment regimens, primary outcome measures,and quality (38,39). Overall estimates of effect were calcu-lated with a random effects model (40). The assumption ofhomogeneity between the treatment effects in different trialswas tested with the Q and I2 statistics. Pooled ORs werelogarithmically transformed and weighted for the inverse of

variance. The significance level for the overall estimates ofeffect and for meta-regression analyses was set at p 0.05.Only a single, first event could contribute to each outcomemeasure.

SENSITIVITY ANALYSIS. To explore the influence of poten-tial effect modifiers on outcomes, a meta-regression analysiswas performed with the metareg command (41)(STATAversion 11.0) to test demographic characteristics of thestudy population, body mass index, percentage of patientswith coronary artery disease, percentage of patients withDM, 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, andquality of trials (32). For all meta-regression analyses, a

Abbreviations

and Acronyms

ACE-I angiotensin-

converting enzyme inhibitor

ARB angiotensin

receptor blocker

CI confidence interval

CV cardiovascular

DM diabetes mellitus

HF heart failure

IR incidence rate

MI myocardial infarction

OR odds ratio

132 Savarese et al. JACC Vol. 61, No. 2, 2013

Effects of ACE-Is and ARBs on Clinical Events January 15, 2013:13142



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random effects model was used to take into account themean of a distribution of effects across studies. In fact, arandom effects model more appropriately provides widerCIs for the regression coefficients than a fixed effect analysis,if residual heterogeneity exists (42). The weight used foreach 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 restrictedmaximum likelihood method was used to take into accountthe occurrence of residual heterogeneity not explained bythe potential effect modifiers (42). To verify the consistencyof the results, individual meta-analyses were performed forsingle 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 logof the OR as the dependent variable and the inverse of thetotal sample size as the independent variable. This is amodified Macaskills test, which gives more balanced type Ierror rates in the tail probability areas compared with otherpublication bias tests (43).

Results

Characteristics of included trials. Baseline characteristicsof the 26 trials included in the meta-analysis are shown inTables 1through3.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 11years, and 35% were women. Mean age was 58.3 8.3 yearsin ACE-I trials and 57.7 13.1 years in ARB trials (p NS); 26% of patients enrolled in ACE-I trials were womencompared with 44% in ARB trials (p 0.05). Length offollow-up was not different between ACE-I (3.66 0.90years) and ARB (3.69 1.32 years) (pNS) trials. Placebopatients enrolled in ACE-I trials compared with placebopatients 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 1,000patient-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 consideredseparately, the 10% reduction of CV death did not achievestatistical 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

risk of MI by 17.7% (OR: 0.811 [95% CI: 0.748 to 0.879],comparison p 0.001, heterogeneity p 0.438) (OnlineFig. 2)and of stroke by 19.6% (OR: 0.796 [95% CI: 0.682to 0.928], comparison p 0.004, heterogeneity p 0.115)(Online Fig. 3). In addition, ACE-Is reduced the risk ofall-cause death by 8.3% (OR: 0.908 [95% CI: 0.845 to0.975], 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). Significantheterogeneity among trials was found for the compositeoutcome but not for all other outcomes explored in theanalysis.

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, heterogeneityp 0.012) (Online Fig. 1), whereas the 9.5% reduction ofMI 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 significantlyreduced 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 onthe risk of all-cause death (OR: 1.006 [95% CI: 0.941 to1.075], comparison p 0.866, heterogeneity p 0.368)(Fig. 2B) and of new-onset HF (OR: 0.892 [95% CI: 0.761to 1.046], comparison p 0.159, heterogeneity p 0.188)(Online Fig. 4). ARBs significantly reduced the risk ofnew-onset DM by 10.6% (OR: 0.855 [95% CI: 0.798 to0.915], comparison p 0.001, heterogeneity p 0.819)(Online Fig. 5). Significant heterogeneity among trials wasfound only for CV death. ORs for the effects of ACE-Is andARBs are reported inFigure 3.

Sensitivity analysis. Results were confirmed when poten-tial effect modifiers were introduced as covariates in themeta-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 thecomposite 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 inTable 4.

133JACC Vol. 61, No. 2, 2013 Savarese et al.

January 15, 2013:13142 Effects of ACE-Is and ARBs on Clinical Events

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Baseline CharacteristicsTable 1 Baseline Characteristics

Agent

Trial

(Ref. #) Year Treatment

Treatment

(n)

Placebo

(n)

Follow-up

(yrs)

Age

(yrs)

Women

(%)

Hypertension

(n)

DM

(n)

Dets

Qua

Sco

ARBs IRMA-2(20) 2001 Irbesartan 404 207 2.00 58 31 100 100 20

RENAAL(21) 2001 Losartan 751 762 3.40 60 37 94 100 19

IDNT(22) 2003 Irbesartan 579 567 2.60 59 32 100 100 20

Kondo et al. (23) 2003 Candesartan 203 203 2.00 65 24 44 25 17

SCOPE(24) 2003 Candesartan 2,477 2,460 3.70 76 65 53 12 18

DIRECT-PREVENT-1(17) 2008 Candesartan 711 710 4.70 30 44 0 100 19

DIRECT-PROTECT-1(17) 2008 Candesartan 951 954 4.80 32 43 0 100 19

DIRECT-PROTECT-2(18) 2008 Candesartan 951 954 4.70 57 50 62 100 19

PROFESS(26) 2008 Telmisartan 10,146 10,186 2.50 66 36 74 28 20

TRANSCEND (27) 2008 Telmisartan 2,954 2,972 4.67 67 43 76 36 20

NAVIGATOR (28) 2010 Valsartan 4,631 4,675 6.50 64 51 78 0 21

ORIENT (25) 2011 Olmesartan 282 284 3.20 59 69 94 100 17

ROADMAP (29) 2011 Olmesartan 2,232 2,215 3.20 58 54 NA 100 20



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Publication bias. Macaskills modified test did not showpublication 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, andnew-onset DM in high-risk patients without HF, mostly with

coronary or other vascular diseases. ARBs, in high-risk patientsmostly with DM or impaired glucose tolerance without HF,reduced the composite outcome and new-onset DM but didnot seem to reduce rates of all-cause death or new-onset HF.CV effects of ACE-Is in patients without HF. Ourfindings confirm and extend a previous meta-analysis ofACE-I trials reported by Dagenais et al. (13), adding anadditional 10 ACE-I trials (corresponding to 23,986 additionalpatients) (3,57,912,33,34) to HOPE (1), EUROPA (4),and PEACE (Prevention of Events with Angiotensin Con-verting Enzyme inhibition) (8) included in that previousanalysis. In particular, consistent with the study by Dagenais

et al, our analysis demonstrates that ACE-Is, comparedwith placebo, substantially reduced all-cause death by 8.3%,

CV death by 10%, MI by 17.7%, and stroke by 19.6%, aswell as new-onset HF by 20.5%. In addition, the currentanalysis reported a significant 13.7% reduction of the risk ofnew-onset DM.CV effects of ARBs in patients without HF. The effectson major clinical events of ARBs in patients without HFhave been evaluated in several trials reporting conflictingresults (17,18,2029). In the RENAAL (Reduction inENdpoints 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, andnew 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. Inthe SCOPE (Study on Cognition and Prognosis in theElderly) (24), a candesartan-based therapy in hypertensiveelderly patients failed to reduce the primary compositeoutcome of CV death, MI, and stroke, whereas it signifi-cantly decreased the risk of new-onset DM. In contrast, ina small study enrolling high-risk patients (23), candesartan,compared with placebo, significantly reduced the risk of a

composite outcome including CV death, MI, and coronaryrevascularization. Subsequently, however, high-dose cande-

Concomitant MedicationsTable 3 Concomitant Medications

Ag en t T rial (R ef . #) B et a-Block ers As pirin S tat ins Diure tics C alcium C ha nn els Bloc ke rs

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 inTable 1.





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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 bylines and those for the pooled ORs byempty diamonds. (A) Composite outcome;(B) all-cause death. ACE-I angiotensin-converting enzyme inhibitor;ARB angiotensin receptor blocker.





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sartan did not reduce CV events in patients with type 1 ortype 2 DM with no previous CV events (17,18). In theTRANSCEND (Telmisartan Randomised AssessmeNT Study

in ACEiNtoleran subjects with cardiovascular Disease) trial(27), ACE-Iintolerant patients were enrolled and assignedto either telmisartan or placebo. Although the primaryendpoint of CV death, MI, stroke, and new-onset HF wasnot significantly reduced by telmisartan, a 13% reduction inthe secondary combined endpoint, including CV death, MI,and stroke was reported (p 0.05), whereas new-onset DMwas not reduced by telmisartan. However, in the PROFESS(Prevention Regimen For Effectively Avoiding SecondStrokes) study (26), which enrolled patients with a recentstroke, telmisartan, compared with placebo, failed to reducethe 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 patientswith impaired glucose tolerance with or at high risk ofdeveloping CV disease, valsartan reduced the occurrence ofDM 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 ofEnd stage renal disease in diabetic Nephropathy Trial) (25)trial reported an increase of the prespecified secondaryendpoint of CV mortality in diabetic patients receiving

olmesartan, despite a favorable effect on the primary renalendpoint.

The current meta-analysis demonstrates that ARBssignificantly 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 orglucose-intolerant patients without HF enrolled in ran-domized clinical trials. However, no significant effectscould be found on the risk of all-cause death, MI, andnew-onset HF.

To our knowledge, no previous meta-analysis investi-gated the effects of ARBs compared with placebo, on top ofconcomitant therapy, in patients without HF. In fact, ina previous meta-analysis by Baker et al. (44), only theTRANSCEND (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-analysisof randomized clinical trials of renin-angiotensin-aldosterone system inhibitors. Compared with the currentanalysis, only hypertension trials were included in the studyby van Vark et al. (35), and only CV and all-cause deathwere analyzed. The study demonstrated a significant benefiton all-cause and CV death, significantly associated withblood pressure reduction and almost entirely driven byACE-I effects, but it could not assess the effects of ARBs onhigh-risk, nonhypertensive patients. Finally, McAlister etal. (46)reported a meta-analysis of ACE-Is and ARBs in

normotensive atherosclerotic patients showing a favorableeffect on major clinical outcomes. In this study, however,

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 inFigure 2.





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ACE-I and ARB trials were grouped into the same analysis,and no distinction was made between ACE-I and ARBtrials. In addition, trials also enrolling patients with HFwere included. Thus, the CV effects of ARBs in high-risk

patients without HF were not adequately investigated inprevious meta-analyses.Study limitations. First, we used summary rather thanindividual patient data. In addition, the characteristics ofpopulations enrolled in ACE-I and ARB trials weredifferent. ACE-I trials were mostly conducted in patientswith coronary or other vascular atherosclerotic disease,and ARB trials were mostly conducted in patients withDM or impaired glucose intolerance. Although the levelof risk in the placebo arms of the ACE-I and ARB trialswas not significantly different for any outcome analyzed,

and the characteristics of study populations did notinfluence the findings of the study in sensitivity analyses,the differences between ACE-I and ARB populationsencourage caution regarding the generalizability of theresults. In addition, inherent limitations of meta-regression analysis should be considered when interpret-ing the results of sensitivity analysis (47). Thus, this studydoes not represent a direct comparison between ACE-Isand ARBs that can only be adequately assessed in ad hoctrials. In fact, the ONTARGET (ONgoing TelmisartanAlone 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 ofthe 2 treatments on top of concomitant CV therapy. Asubstantial number of patients discontinued ARBs inclinical trials, and this action may have attenuated theeffect of therapy by an intention-to-treat analysis. Inaddition, a potentially greater benefit from ARBs inparticular subgroups of patients, such as those with organdamage, cannot be excluded from the current analysis.Finally, the current study considered ACE-Is and ARBsas 2 classes of drugs, although both include several agents

with different pharmacokinetic and pharmacodynamicsproperties.

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 ofCV death, MI, and stroke as well the risk of new-onsetDM. Thus, ARBs represent a viable option for high-riskpatients 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:[email protected]

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OR Estimate of Each Outcome for Each Drug Treatment Group Compared With PlaceboTable 4 OR Estimate of Each Outcome for Each Drug Treatment Group Compared With Placebo

Myocardial Infarction Cardiovascular Death Stroke

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

Candesartan 1.161 0.7861.715 0.452 0.552 0.1362.235 0.405 NA NA NA

Olmesartan 0.610 0.3661.020 0.059 4.181 1.70310.263 0.002 0.999 0.5121.951 0.008

Telmisartan 0.893 0.7071.128 0.343 0.930 0.7711.121 0.447 0.925 0.8451.012 0.091

Irbesartan 0.873 0.5811.312 0.514 NA NA NA NA NA NA

Perindopril 0.724 0.5980.877 0.001 0.881 0.7671.012 0.073 0.801 0.5871.093 0.162

Ramipril 0.807 0.7160.910 0.000 0.840 0.6041.169 0.302 0.856 0.5801.265 0.436

Enalapril 0.564 0.3131.016 0.056 1.064 0.2584.379 0.932 0.451 0.1641.235 0.121

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

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ContinuedTable 4 Continued

All-Cause Mortality Heart Failure New-Onset Diabetes Mellitus

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

0.960 0.8161.131 0.627 NA NA NA NA NA NA

1.288 0.7192.308 0.394 NA NA NA NA NA NA

1.036 0.9491.130 0.434 1.043 0.8731.246 0.643 0.884 0.7771.006 0.061

NA NA NA NA NA NA NA NA NA

0.915 0.8211.020 0.110 0.686 0.5640.834 0.000 NA NA NA

0.907 0.7571.085 0.286 0.918 0.6931.215 0.548 0.784 0.5651.087 0.144

0.933 0.4631.879 0.846 NA NA NA NA NA NA





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Key Words:ACE-I yangiotensin-converting enzyme inhibitor yangiotensin receptor blocker yARB yclinical events.

APPENDIX

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