Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis

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1282 Meta-analysis

Comparison between angioten

sin-converting enzymeinhibitors and angiotensin receptor blockers on the riskof myocardial infarction, stroke and death: a meta-analysisGianpaolo Reboldia, Fabio Angelib, Claudio Cavallinib, Giorgio Gentilea,Giuseppe Manciac and Paolo Verdecchiab

Objectives To compare the effects of angiotensin II

receptor blockers and angiotensin-converting enzyme

inhibitors on the risk of myocardial infarction, stroke,

cardiovascular mortality and total mortality.

Methods We conducted a meta-analysis of randomized

comparative trials between angiotensin II receptor blockers

and angiotensin-converting enzyme inhibitors. Inclusion

criteria were publication in peer-reviewed journals indexed

in Medline, randomized comparison of angiotensin II

receptor blockers vs. angiotensin-converting enzyme

inhibitors, or angiotensin II receptor

blockers R angiotensin-converting enzyme inhibitors vs.

angiotensin-converting enzyme inhibitors, report of major

complications including myocardial infarction, stroke,

cardiovascular mortality or all-cause mortality; average

follow-up of at least 1 year in at least 200 patients.

Results Six trials fulfilled the inclusion criteria, for a total of

49 924 patients. In the pooled estimate, there were no

significant differences between angiotensin II receptor

blockers and angiotensin-converting enzyme inhibitors on

the risk of myocardial infarction (odds ratio 1.01; 95%

confidence interval 0.95–1.07; P U 0.75), cardiovascular

mortality (odds ratio 1.03; 95% confidence interval 0.98–

1.08; P U 0.23) and total mortality (odds ratio 1.03; 95%

confidence interval 0.97–1.10; P U 0.20). This was the case

also when the analysis involved only the comparison

between angiotensin-converting enzyme inhibitors and

angiotensin II receptor blockers. Overall, the risk of stroke

was slightly lower with angiotensin II receptor blockers than

angiotensin-converting enzyme inhibitors (odds ratio 0.92;

95% confidence interval 0.85–0.99; P U 0.037), the direct

opyright © Lippincott Williams & Wilkins. Unautho

0263-6352 � 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

angiotensin-converting enzyme inhibitors and angiotensin II

receptor blockers comparison showing a nonsignificant

trend in a similar direction. Statistical heterogeneity among

trials was not significant, with a low to null inconsistency

statistic, for stroke (P U 0.67), myocardial infarction

(P U 0.86), cardiovascular mortality (P U 0.14) and total

mortality (P U 0.12).

Conclusion This overview suggests that angiotensin II

receptor blockers are as effective as angiotensin-converting

enzyme inhibitors on the risk of myocardial infarction,

cardiovascular mortality and total mortality. Angiotensin II

receptor blockers may be slightly more protective than

angiotensin-converting enzyme inhibitors on the risk of

stroke. J Hypertens 26:1282–1289 Q 2008 Wolters Kluwer

Health | Lippincott Williams & Wilkins.

Journal of Hypertension 2008, 26:1282–1289

Keywords: hypertension, meta-analysis, mortality, myocardial infarction,prevention, prognosis, stroke, therapy

Abbreviations: ACEIs, Angiotensin converting enzyme inhibitors; ARBs,Angiotensin receptor blockers; AT1, Angiotensyn type I; AT2, Angiotensintype II; BP, Blood Pressure; CHF, Congestive heart failure; CI, Confidenceinterval; MI, Myocardial infarction; RCTs, Randomised clinical trials

aDepartment of Internal Medicine, University of Perugia, bDepartment ofCardiology, Hospital ‘Santa Maria della Misericordia’, Perugia and cDepartment ofMedicine, University of Milano-Bicocca, Milan, Italy

Correspondence to Paolo Verdecchia, MD, FACC, FAHA, Clinical Research Unit‘Preventive Cardiology’, Department of Cardiology, Hospital ‘Santa Maria dellaMisericordia’, 06156 Perugia, ItalyE-mail: [email protected]

Received 16 April 2008 Revised 28 April 2008Accepted 30 April 2008

IntroductionAngiotensin-converting enzyme inhibitors (ACEIs) and

angiotensin II receptor blockers (ARBs) are widely used

in patients with hypertension, heart failure and diabetes

as well as in a wide spectrum of other clinical conditions

sharing an increased cardiovascular risk [1]. Individual

trials and meta-analyses showed that both ACEIs and

ARBs are effective in reducing the risk of total cardio-

vascular events and specific events [2,3] such as stroke,

myocardial infarction (MI) and heart failure. Further-

more, two systematic overviews [4,5] suggested that part

of the protective effects of ACEIs on coronary artery

disease may be independent of the degree of blood

pressure (BP) reduction, which appeared to explain,

however, the greater proportion of the benefit exerted

by these drugs.

Randomized comparative trials between ACEIs and ARBs

have been relatively rare and largely limited to specific

clinical conditions such as heart failure and a post-MI state

accompanied by left ventricular dysfunction [6–10]. This

has hindered information on a clinically important issue

because ACEIs and ARBs act on the renin–angiotensin

system at different levels, and experimental data suggest

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Comparison between ACEIs and angiotensin receptor blockers Reboldi et al. 1283

that such a difference might translate into a different

clinical outcome. For example, the increased levels of

bradykinin associated with the administration of ACEIs

but not, at least to a significant degree, with that of ARBs

might exert specific cardioprotective effects [11]. Further-

more, overstimulation of type 2 (AT2) receptors by the

increased levels of angiotensin II associated with long-

term selective blockade of type 1 (AT1) receptors might

trigger apoptosis, inhibit angiogenesis and reduce the

synthesis of fibrotic tissue [12–14]; these effects could

potentially lead to a depressed growth of collateral vessels

in the setting of ischemia as well as to a reduced collagen

content, a thinner cap and a greater vulnerability of ather-

omas to rupture [15]. Finally, unopposed overstimulation

of AT2 receptors could have protective cerebrovascular

effects by increasing recruitment of collateral vessels and

enhancing resistance of neurons to anoxia [16,17]. Indeed,

that differences in clinical outcome between ACEIs and

ARBs may exist is in line with the results of some clinical

trials in which ACEIs or ARBs were compared with other

antihypertensive treatments. One, on the basis of an

examination of selected trials, the hypothesis has been

advanced that ARBs reduce the risk of MI to a lesser

degree than that of obtained with other antihypertensive

drugs [18]. Two, some trials [19,20] have shown ARBs to

exert a greater protective effect against stroke than beta-

blockers and calcium antagonists for a similar reduction in

BP. The data provided by trials, and their systematic

overviews, are not entirely consistent, however [21–26].

The recent publication [26] of the results of a large trial

on patients at high cardiovascular risk with or without

hypertension who were randomized to an ARB or an

ACEI has substantially increased the availability of data

comparing these two treatments, and expanded it beyond

specific conditions such as heart failure and MI with left

ventricular dysfunction. We have included this trial in a

meta-analysis of randomized clinical trials comparing

ACEIs and ARBs for their ability to affect the incidence

of total and specific cardiovascular events, and this study

reports the results.

MethodsWe searched for randomized controlled outcome trials

which met all of the following prespecified criteria;

comparison between ARBs and ACEIs regardless of

the background therapy in either group, publication in

peer-reviewed journals indexed in Medline, MI, stroke,

cardiovascular mortality and total mortality as prespeci-

fied events, although not necessarily a primary endpoint,

follow-up of at least 1 year, total sample size of 200

patients or more. Some of the trials did not report

completely the total number of patients who developed

cardiovascular or coronary events, as well as the number

of those with congestive heart failure (CHF). Further-

more, CHF was absent at entry in some trials [10,26],

but not in others [6–9]. Therefore, these important

opyright © Lippincott Williams & Wilkins. Unauth

clinical outcomes were not included in our overview

(see Discussion).

We searched for eligible studies through Medline, using

research Methodology Filters [27].

The search identified six trials [6–11], which fulfilled all

inclusion criteria. Data were extracted on the basis of an

intention-to-treat approach. Discrepancies were resolved

in conference.

We accepted the definition of MI, stroke, cardiovascular

mortality and total mortality as reported in the eligible

trials. The number of patients with MI and stroke (fatal

and nonfatal events) in the valsartan-treated patients

recruited for acute myocardial infarction (VALIANT)

trial was not reported in the original article [9], but

published later [28].

We calculated odds ratios (ORs) and 95% confidence

intervals (CIs) for stroke, MI, cardiovascular mortality

and total mortality for each trial according to fixed and

random-effect models, and we undertook a series of

‘head-to-head’ meta-analyses [29]. For multiarm trials,

we analyzed only preplanned comparisons defined in the

original study design [29]. Thus, each meta-analysis

included two subgroups formed by the comparison of

ARBs vs. ACEIs [6–10,26] or ARBsþACEIs vs. ACEIs

[9,26]. The statistical significance of subgroup inter-

actions and heterogeneity between groups was assessed

[29]. Comparisons not included in the original study

protocol were not performed. We tested the null hypo-

thesis of homogeneity by the chi-squared test. Pooled

estimates were assessed for heterogeneity by computing

the I2 statistic. Typically, values above 50% are deemed

to suggest large between-study heterogeneity, values of

25–50% are deemed to show modest heterogeneity, and

values below 25% denote low heterogeneity [30].

We assessed the influence of individual studies on pooled

estimates by excluding one study at the time according to

Tobias’ method [31]. If the point estimate of the pooled

effect with one study omitted lies outside the CI of the

overall estimate with all available trials contributing, then

the study in question has an excessive influence.

The Jadad’s score was used to assess the methodological

quality of the randomized controlled trials included in our

systematic review [32]. This validated score lies in the

range of 0–5. Studies are scored according to the presence

of three key methodological features of randomization,

blinding and accountability of all patients, including

withdrawals [32].

Analyses were done using Stata, version 10 (StataCorp

LP, College Station, Texas, USA) and R version 2.6.2

(R Foundation for Statistical Computing, Vienna, Austria).

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1284 Journal of Hypertension 2008, Vol 26 No 7

Table 1 Randomized comparative trials between ARBs and ACEIs

Study ARB ACEIPublication

yearFollow-up

yearsPatients in the

ARB armPatients in the

ACEI armJadad’sScore

ELITE [6] Losartan Captopril 1997 1 352 370 4ELITE-II [7] Losartan Captopril 2000 1.5 1578 1574 5OPTIMAAL [8] Losartan Captopril 2002 2.7 2744 2733 5VALIANT/Val [9,28] Valsartan Captopril 2003, 2006 2.1 4909 4909 5VALIANT/ValþCap [9,28] Valsartan Captopril 2003, 2006 2.1 4885 4909DETAIL [10] Telmisartan Enalapril 2004 5 120 130 4ONTARGET/Tel [26] Telmisartan Ramipril 2008 4.7 8542 8576 5ONTARGET/Tel + Ram [26] Telmisartan Ramipril 2008 4.7 8502 8576

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; DETAIL, diabetics exposed to telmisartan and enalapril; ELITE, evaluation of losartan inthe elderly study; ELITE-II, losartan heart failure survival study; ONTARGET, the ongoing telmisartan alone and in combination with ramipril global endpoint trial; OPTIMAAL,optimal trial in myocardial infarction with the angiotensin II antagonist losartan; Tel, telmisartan vs. ramipril; Tel+Ram, telmisartanþ ramipril vs. ramipril; Val, valsartan vs.caproptil; ValþCap, valsartanþ captopril vs. captopril; VALIANT, valsartan in acute myocardial infarction study.

ResultsTable 1 shows the list of trials, which satisfied the

predefined inclusion criteria. The six eligible trials

included 31 632 patients randomized to ARBs and

18 292 patients randomized to ACEIs. In the ARB group,

the number of events was 2857 for MI, 1273 for stroke,

3534 for cardiovascular death and 4776 for all-cause

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Fig. 1

Comparisons between angiotensin receptor blockers (ARBs) and ACE inhconverting enzyme; CI, confidence interval; DETAIL, diabetics exposed to teELITE-II, losartan heart failure survival study; ONTARGET, the ongoing telmOPTIMAAL, optimal trial in myocardial infarction with the angiotensin II antainfarction study.

death. The corresponding figures for the ACEI group

were 1628, 768, 2622 and 2707.

The overall estimate for the risk of MI between ARBs

and ACEIs was not dissimilar from unity (Fig. 1), the OR

being 1.01 with 95% CI 0.95–1.07 with both the fixed-

effect and random-effect model (P¼ 0.747). The results

rized reproduction of this article is prohibited.

ibitors (ACEIs) on the risk of myocardial infarction. ACE, angiotensin-lmisartan and enalapril; ELITE, evaluation of losartan in the elderly study;isartan alone and in combination with ramipril global endpoint trial;

gonist losartan; OR, odds ratio; VALIANT, valsartan in acute myocardial

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Comparison between ACEIs and angiotensin receptor blockers Reboldi et al. 1285

Fig. 2

Comparisons between angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs) on the risk of cardiovascular mortality. ACE, angiotensin-converting enzyme; CI, confidence interval; DETAIL, diabetics exposed to telmisartan and enalapril; ELITE, evaluation of losartan in the elderly study;ELITE-II, losartan heart failure survival study; ONTARGET, the ongoing telmisartan alone and in combination with ramipril global endpoint trial;OPTIMAAL, optimal trial in myocardial infarction with the angiotensin II antagonist losartan; OR, odds ratio; VALIANT, valsartan in acute myocardialinfarction study.

were similar also for the separate subgroup analyses of

ARBs vs. ACEIs and ARBsþACEIs vs. ACEIs, with a

low to null heterogeneity across the trials (P¼ 0.769,

I2¼ 0%) and no evidence of heterogeneity or interaction

between subgroups.

Cardiovascular mortality (Fig. 2) and all-cause mortality

(Fig. 3) were also not dissimilar between ARBs and

ACEIs. The overall estimate for cardiovascular mortality

was 1.03 with 95% CI 0.98–1.08 (P¼ 0.227) without

significant heterogeneity (P¼ 0.198, I2¼ 29%). The

OR for all-cause mortality was 1.03 with 95% CI 0.98–

1.08, with a modest though nonsignificant heterogeneity

P¼ 0.178, I2¼ 31%).

The overall estimate for the risk of stroke (Fig. 4) was 8%

lower with ARBs than with ACEIs (OR 0.92, 95% CI

0.85–0.99 with both the fixed-effect and the random-

effect model; P¼ 0.036). In the separate subgroup

analyses of ARBs vs. ACEIs and ARBsþACEIs vs.

ACEIs, the lesser stroke risk with ARBs did not achieve

statistical significance, although the subgroup estimates

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were consistent and without significant between group

heterogeneity (P¼ 0.714).

In sensitivity analyses, none of the trials had a significant

influential effect on the overall estimates (Fig. 5) for both

stroke and MI. The methodological quality of the studies

was excellent for most of the included studies (mean

Jadad’s score 4.7) and did not affect the overall estimates.

DiscussionOur meta-analysis shows that the risk of MI, cardiovas-

cular mortality and total mortality did not differ in

patients treated with ARBs as compared with patients

treated with ACEIs. It further shows that when all

available data were considered, administration of ARBs

was associated with a small but statistically significant

reduction in the risk of stroke compared with adminis-

tration of ACEIs, a trend in a similar direction being

observed also when the subgroup analysis limited the

comparison with only ACEI-treated vs. only ARB-treated

patients. This allows to conclude that ARB and ACEI-

based treatments provide a similar protective effect on

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1286 Journal of Hypertension 2008, Vol 26 No 7

Fig. 3

Comparisons between angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs) on the risk of all-cause mortality. ACE, angiotensinconverting enzyme; CI, confidence interval; DETAIL, diabetics exposed to telmisartan and enalapril; ELITE, evaluation of losartan in the elderly study;ELITE-II, losartan heart failure survival study; ONTARGET, the ongoing telmisartan alone and in combination with ramipril global endpoint trial;OPTIMAAL, optimal trial in myocardial infarction with the angiotensin II antagonist losartan; OR, odds ratio; VALIANT, valsartan in acute myocardialinfarction study.

overall risk of fatal cardiovascular events and all-cause

mortality, but that blockade of the renin–angiotensin

system by antagonizing AT1 receptor stimulation by

angiotensin II may be associated with a slightly superior

cerebrovascular protective effect than blockade of ACE.

This may apply not only to patients with heart failure or a

MI that impairs cardiac function, but also to patients with

a broad range of conditions characterized by a high

cardiovascular risk, including a history of cardiac disease,

a history of cerebrovascular disease or diabetes.

The slightly greater protective effect of ARB vs. ACEI

treatment on stroke deserves a comment. First, although

never statistically significant a trend in favor of a lower

incidence of stroke was seen in trials using different

ARBs which suggests that the somewhat greater cerebro-

vascular protective effect possibly associated with ARB

treatment is class-related rather than drug-related.

Second, meta-analyses of trial data cannot provide a

mechanistic explanation of the effects that are seen.

There is some experimental evidence that ARBs might

have a specific cerebrovascular protective effect. For

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example, the neurological outcome following induction

of cerebral ischemia in the rat was improved by intracer-

ebral administration of low doses of the ARB irbesartan,

and such effect was prevented by the coadministration of

an AT2 receptor blocker [16,33]. In rats injured by

cerebral artery occlusion and pretreated with candesartan

or ramipril at subhypotensive doses, the infarct size was

reduced by the ARB, not by the ACEI [34]. Also, the

neurological damage induced by cerebral ischemia as

well as the reduction in blood flow around the necrotic

area were found to be more severe in AT2 receptor

deleted mice than in control mice [35]. However, the

small difference in stroke incidence emerged in our

meta-analysis could also be due, in principle, to a lesser

protective effect of ACEIs, perhaps via a reduced AT2

receptor stimulation. Furthermore, it cannot be excluded

that use of ARBs was associated with a slightly greater BP

reduction than use of ACEIs, an explanation that is in line

with a profound effect on stroke of even small BP changes

and that may account for the greater protective effect on

stroke reported for calcium antagonists vs. other drugs

[2,3,36]. In the present study, the effect of ARBs and

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Comparison between ACEIs and angiotensin receptor blockers Reboldi et al. 1287

Fig. 4

Comparisons between angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs) on the risk of stroke. ACE, angiotensin converting enzyme;CI, confidence interval; DETAIL, diabetics exposed to telmisartan and enalapril; ELITE, evaluation of losartan in the elderly study; ELITE-II, losartanheart failure survival study; ONTARGET, the ongoing telmisartan alone and in combination with ramipril global endpoint trial; OPTIMAAL, optimal trialin myocardial infarction with the angiotensin II antagonist losartan; OR, odds ratio; VALIANT, valsartan in acute myocardial infarction study.

ACEIs on BP could not be included because they were

not available in a number of eligible studies.

Another important result of our meta-analysis regards the

risk of MI. Our results strongly argue against the hypoth-

esis that ARBs may increase the risk of MI [18] when

compared with ACEIs. In our study, the 95% CIs of the

pooled estimate broadly crossed the identity line (0.96–

1.07 both in a random-effect and fixed-effect model).

Interestingly, the nonsignificant 7% higher risk of MI

observed in the ARB group in the ongoing telmisartan

alone and in combination with ramipril global endpoint

trial (ONTARGET) [26] is counterbalanced by the 6%

lesser risk of MI in the combination group, as compared

with the ACEI group, in VALIANT [9]. Values of OR

nearly identical to unit were observed in the optimal trial

in myocardial infarction with the angiotensin II antagon-

ist losartan (OPTIMAAL) study [8] and in the ARBs vs.

ACEIs comparison in VALIANT [9]. Overall, these data

strongly suggest that ARBs are as effective as ACEIs in

reducing the risk of MI.

opyright © Lippincott Williams & Wilkins. Unauth

Further support to our findings also comes from two

recently published large observational studies [37,38].

The first was a population-based study designed to

compare the rates of hospital admission for acute coronary

syndromes (ACSs) between users of ARBs relative to the

use of ACEIs. The rate of hospitalizations for ACS was

lower [adjusted relative risk 0.89 (95% CI 0.76–1.04)] in

patients on ARBs (n¼ 16 456) relative to ACEIs users

(n¼ 49 037). The authors concluded that ARBs offered

�11% greater relative risk reduction relative to ACEIs

[37]. The second study retrospectively analyzed a total of

29 357 hypertensive patients who initiated therapy with

an ARB (valsartan, n¼ 6645) or an ACEI (lisinopril,

n¼ 17 320). Interestingly, patients receiving an ARB

had an 11% lower risk of a major cardiovascular or renal

event than those receiving an ACEI, although the differ-

ence did not reach statistical significance (hazard ratio,

0.89; 95% CI 0.74–1.07) [38].

Our meta-analysis has the usual limitations of this

approach, including the pooling of data obtained in

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1288 Journal of Hypertension 2008, Vol 26 No 7

Fig. 5

Results of sensitivity analysis for myocardial infarction and stroke. The diamond denotes the pooled estimate (all studies). The circles denote theestimate obtained after omitting the named study. The dashed line denotes the 95% confidence intervals of the pooled estimate. DETAIL, diabeticsexposed to telmisartan and enalapril; ELITE, evaluation of losartan in the elderly study; ELITE-2, losartan heart failure survival study; ONTARGET, theongoing telmisartan alone and in combination with ramipril global endpoint trial; OPTIMAAL, optimal trial in myocardial infarction with the angiotensinII antagonist losartan; VALIANT, valsartan in acute myocardial infarction study.

different populations at different levels of baseline

cardiovascular risk or the use of different drugs at differ-

ent doses within a given class. Three specific limitations

need to be mentioned, however. First, because CHF was

not reported in some trials while in the others it referred

to either the first episode or the aggravation and hospi-

talization of an already existing condition we did not

include this event in the calculation. Second, because of

the heterogeneity of the diagnostic criteria used in trials,

total cardiovascular morbidity and coronary heart disease

were also not included. Consequently, no information is

provided by our study on the impact of ACEIs vs. ARBs

on some important clinical outcomes, such as the protec-

tion against cardiac decompensation or coronary events

other than MI. Finally, our meta-analyses was based on

aggregate rather than on individual patient data, which

represents the standard to which all other systematic

reviews should be compared.

In conclusion, the overall evidence provided by random-

ized controlled trials supports the conclusion that ARBs

and ACEI are equally protective against the risk of

cardiovascular events and all-cause mortality in patients

belonging to a wide range of conditions characterized by a

high cardiovascular risk. They also support the hypo-

thesis, however, that ARBs have a specific, albeit small,

effect against stroke, which may enhance cerebrovascular

protection beyond the overwhelming one due to BP

reduction per se [2,3], which is emphasized as the major

protective factor by the recent Guidelines of the Euro-

pean Society of Hypertension and the European Society

of Cardiology [39]. This might favor ARB treatment

opyright © Lippincott Williams & Wilkins. Unautho

when the risk of stroke is predominant over that of other

cardiovascular events such as in Asian patients [40] or in

patients with a history of cerebrovascular events [41].

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