ACE-inhibitors versus angiotensin receptor blockers for prevention of events in cardiovascular patients without heart failure — A network meta-analysis

    ACE-inhibitors versus angiotensin receptor blockers for prevention of events in cardiovascular patients without heart failure — A network meta-analysis Fabrizio Ricci, Augusto Di Castelnuovo, Gianluigi Savarese, Pasquale Perrone Filardi, Raffaele De Caterina PII: DOI: Reference:

S0167-5273(16)30831-2 doi: 10.1016/j.ijcard.2016.04.132 IJCA 22501

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

22 December 2015 28 March 2016 16 April 2016

Please cite this article as: Ricci Fabrizio, Di Castelnuovo Augusto, Savarese Gianluigi, Filardi Pasquale Perrone, De Caterina Raffaele, ACE-inhibitors versus angiotensin receptor blockers for prevention of events in cardiovascular patients without heart failure — A network meta-analysis, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.04.132

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ACCEPTED MANUSCRIPT Ricci F. et al., IJC-D-15-06350 R1, page 1

ACE-Inhibitors versus Angiotensin Receptor Blockers for Prevention of Events in Cardiovascular Patients without Heart Failure – a Network Meta-Analysis

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Short title: ACE-I versus ARBs in Patients without HF

Fabrizio Ricci, MD1, Augusto Di Castelnuovo, PhD2, Gianluigi Savarese, MD3, Pasquale Perrone Filardi, MD, PhD3, and Raffaele De Caterina, MD, PhD1

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From the 1University Cardiology Division, G. d’Annunzio University, Chieti; 2Department of Epidemiology and Prevention, IRCCS-Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS),

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and 3Cardiology Division, Federico II University, Naples, all in Italy

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Word count: 5057

Prof. Raffaele De Caterina

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Correspondence:

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Institute of Cardiology, G. d’Annunzio University – Chieti-Pescara C/o Ospedale SS. Annunziata

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Via dei Vestini 31

66100 Chieti, Italy Tel: 0871-41512

Fax: 0871-402817

ACCEPTED MANUSCRIPT Ricci F. et al., IJC-D-15-06350 R1, page 2

ABSTRACT

Background: Angiotensin receptor blockers (ARBs) are a valuable option to reduce cardiovascular

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(CV) mortality and morbidity in cardiac patients in whom ACE-inhibitors (ACE-Is) cannot be used. However, clinical outcome data from direct comparisons between ACE-Is and ARBs are scarce,

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and some data have recently suggested superiority of ACE-Is over ARBs.

Methods: We performed a Bayesian network-meta-analysis, with data from both direct and indirect comparisons, from 27 randomized controlled trials (RCT), including a total population of 125,330 patients, to assess the effects of ACE-Is and ARBs on the composite endpoint of CV death,

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myocardial infarction (MI) and stroke, and on all-cause death, new-onset heart failure (HF) and new-onset diabetes mellitus (DM) in high CV risk patients without HF.

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Results: Using placebo as a common comparator, we found no significant differences between ACE-Is and ARBs in preventing the composite endpoint of CV death, MI and stroke (RR: 0.92; 95% CI 0.78-1.08). When components of the composite outcome were analysed separately, ACEi

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and ARBs were associated with a similar risk of CV death (RR: 0.92; 95% CI 0.73-1.10), MI (RR: 0.91; 95% CI 0.78-1.07) and stroke (RR: 0.97; 95% CI 0.79-1.19), as well as a similar incident risk

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of all-cause death (RR: 0.94; 95% CI 0.85-1.05), new-onset HF (RR: 0.92; 95% CI 0.77-1.15) and new-onset DM (RR: 99; 95% CI 0.81-1.21).

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Conclusions: With the limitations of indirect comparisons, we found that in patients at high CV risk without HF, ARBs were similar to ACE-Is in preventing the composite endpoint of CV death,

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MI and stroke. Compared with ARBs, we found no evidence of statistical superiority for ACE-Is, as a class, in preventing incident risk of all-cause death, CV death, MI, stroke, new-onset DM and new-onset HF.

Key words: ACE-inhibitors; angiotensin receptor blockers; sartans; cardiovascular risk; network meta-analysis.

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INTRODUCTION The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the development of hypertension and in the pathogenesis and progression of atherosclerosis, leading to cardiovascular

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disease. During the past decade, the benefits of and clinical indications to RAAS inhibitors— especially angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers

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(ARBs)—have been clearly defined in several cardiovascular conditions, consistent with their potential usefulness in patients with chronic heart failure (HF), asymptomatic left ventricular dysfunction, acute myocardial infarction (MI), hypertension, as well as in all patients at high

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cardiovascular (CV) risk without HF [1, 2]. Importantly, controlled clinical trials have demonstrated that these drugs can reduce cardiovascular morbidity and mortality [3]. ACE-Is and ARBs, however, differ in their mechanisms of action, and the similarity of their effectiveness in reducing

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clinical, particularly cardiovascular outcomes, cannot be given for granted [4]. Since the goal of cardiovascular prevention must be the reduction of cardiovascular morbidity and total mortality and not only of surrogates outcome measures, such as blood pressure and proteinuria, particular

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attention should be paid to the choice of optimal agent in high-risk hypertensive patients [4]. Results of recent clinical trials and meta-analyses have indeed suggested that ACE-Is, but not

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ARBs, reduce both cardiovascular morbidity and all-cause mortality, and that therefore ACE-Is should be considered the drugs of first choice, with ARBs restricted to patients intolerant of ACE

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inhibitors [5]. The effects on major clinical events of RAAS inhibitors in high-risk patients without HF have been evaluated in several trials reporting conflicting results. A recent meta-analysis of 26

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randomized controlled trials (RCT) comparing ACE-Is or ARBs versus placebo in a population of patients at high cardiovascular risk (n=108,212 patients), has concluded on the absence of significant differences between the two classes of drugs, but also on the absence of a mortality reduction with ARBs [6]. Nonetheless, the only large-scale RCT comparing telmisartan versus ramipril in patients with high CV risk without HF showed no difference between these two drug classes [7]. In the absence of multiple “head-to-head” direct comparisons in large prospective RCTs, an alternative method to assess the relative effect of different interventions is to perform indirect comparisons on the basis of published trials using a common comparator [8]. We therefore sought to perform an indirect comparison analysis of ACE-Is and ARBs for their relative efficacy against each other on the composite endpoint of all-cause death, CV death, MI, stroke, and new-onset HF and new-onset diabetes mellitus (DM) in high CV risk patients without HF, using a method— network meta-analysis—well accepted, in the absence of head-to-head trials, to provide valuable statistical inference [9].

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METHODS

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Primary hypothesis

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We hypothesized a superiority of ACE-Is vs ARBs in reducing the composite of CV death, MI, and stroke, on the basis of a trend shown in a previous similar meta-analysis conducted with traditional techniques [6], under the assumption that a network meta-analysis may be more powerful to reveal differences. Secondary hypotheses were the existence of significant differences on individual

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components of the composite endpoint, as well as on total mortality, new-onset HF and new-onset

Data sources and literature search

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DM.

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We searched PubMed, the Cochrane Data-base, ISI Web of Sciences, and SCOPUS for articles with no language restrictions from January 1966 through December 2015. Studies were identified by the

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following headings: angiotensin receptor blocker, antagonist of angiotensin II receptor 1, ARB, angiotensin-converting enzyme, ACE, randomly, random, randomized controlled trial, and clinical

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trial. We also searched reference lists of all identified articles for additional relevant studies, including hand-searching reviews and previous meta-analyses.

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Study selection

We designed this study according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [10]. Only randomized, double-blind, clinical trials comparing either an ARB or an ACE-I with placebo, or directly comparing an ARB with an ACE-I and reporting clinical events (including all-cause and CV death, MI, stroke, new-onset HF, and newonset DM) recorded during a minimum 1-year follow-up period, with the deliberate exclusion of patients with systolic or diastolic HF, were considered for the analysis [6].

Data extraction and quality assessment

Two reviewers (F.R. and G.S.) independently selected potentially eligible trials. Discrepancies were resolved by discussion and consensus. Two reviewers independently read the full text of retained

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studies, which were checked to avoid inclusion of data published in duplicate. Data on baseline characteristics, presence of DM, hypertension, coronary artery disease, concomitant medications and pre-specified outcomes, including all-cause and CV death, MI, stroke, new-onset HF, and new-

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onset DM, were abstracted. Out of 25,661 citations identified and retrieved by the initial research, 45 potentially relevant

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articles were reviewed for more detailed evaluation. Nineteen articles did not fit our inclusion criteria and were therefore discarded, i.e., clinical events not reported, studies including patients with HF, follow-up duration <1 year (Fig. 1). We finally included 26 articles in our quantitative analysis, corresponding to 27 RCT. Thirteen trials compared ARBs with placebo [11-22], 13 trials

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compared ACE-Is with placebo [19, 23-35] and 1 RCT compared directly an ACE-I to an ARB [7].

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Statistical methods

We combined direct and indirect evidence from all available studies by using a network meta-

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analysis. Network meta-analysis is a mathematical way of estimating the comparative effectiveness of interventions that are not directly compared in actual studies, but that can be indirectly compared

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by use of modelling [36]. Using a full Bayesian evidence network, all indirect comparisons are taken into account to arrive at a single, integrated, estimate of the effect of all included treatments

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based on all included studies. The network meta-analysis was conducted by using the GeMTC package in R [37]. The GeMTC package synthesizes evidence on the relative effects of multiple treatments by fitting generalized linear model under a Bayesian framework. We performed

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Bayesian analyses by using a Markov chain Monte Carlo simulation to calculate the hazard ratios and 95% confidence intervals. The statistical analysis is based on Poisson likelihoods with a log link function. Flat prior distributions were assumed for all outcomes. Prior distributions of the relative treatment effects were normal, with zero mean and variance of 10, while a uniform distribution with range zero to five was used as the prior of the between-study standard deviation. To allow for heterogeneity between studies, random effects models were evaluated. All results were based on 50,000 iterations on four chains, with 20,000 tuning iterations and thinning interval equal 10 and a variance scaling factor equal to 2.5. Convergence was assessed using the Brooks-GelmanRubin method [38]. This method compares within-chain and between-chain variance to calculate the potential scale reduction factor (PSRF). A PSRF close to one indicates approximate convergence has been reached. To check the robustness of our results, we carried out several posthoc sensitivity analyses including a restriction to RCTs with an all-cause death rate above 1% per patient-year.

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RESULTS

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Characteristics of trials included in this analysis

Baseline characteristics of the 27 RCT being compared in this analysis are summarized in Table 1.

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Duration of follow-up ranged from 2.0 to 6.5 years (3.7±1.1 years). The overall mean age of subjects was 58 ± 11 years, and 33,9% 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

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compared with 44% in ARB trials (p < 0.05). The length of follow-up was not different between ACE-I (3.7±0.9 years) and ARB (3.7±1.3 years) (p=NS) trials. The baseline risk of the population in the trials was quite variable (Table 1), but only one trial [39] investigated a population with a

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baseline risk >10 major cardiovascular events/100 patients-year. Mean differences between reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) for ACE-I compared with ARB trials were minor, and namely 1.25 mmHg (p=NS) and 0.5 mmHg (p=NS), respectively

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(OS Table 1). Placebo patients enrolled in ACE-I trials compared with placebo patients enrolled in ARB trials showed non-significant differences in the incident rate of the composite outcome (27 vs

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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-

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onset DM (15 vs 24 events per 1,000 patient-years; p=0.176). Table 2 shows the results of the both standard and network meta-analyses with placebo as the standard of comparison. All the

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simulations rapidly converged (PSRF close to one).

Effects of ACE-Is

According to the results of our standard meta-analysis, treatment with ACE-Is compared with placebo significantly reduced the incident risk of the combined endpoint of CV death, MI and stroke (RR: 0.81; 95% CI 0.72-0.91) and was associated with a 7% reduction in all-cause mortality (RR: 0.93; 95% CI 0.85-1.00). When components of the composite outcome were considered separately, the 9% reduction of CV death did not achieve statistical significance (RR: 0.91; 95% CI 0.80-0.108), whereas ACE-Is significantly reduced the incident risk of MI (RR: 0.80; 95% CI 0.720.90) and stroke (RR: 0.80; 95% CI 0.69-0.94). Furthermore, all-cause death, new-onset HF and new-onset DM were significantly lower with ACE-Is compared with placebo.

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Effect of ARBs

Compared with placebo, ARBs reduced the risk of the composite outcome by 12%, but this failed to

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reach statistical significance (RR: 0.88; 95% CI 0.77-1.01). Stroke (RR: 0.83; 95% CI 0.70-0.98) and new-onset DM (RR: 0.82; 95% CI 0.70-0.96) were significantly lower with ARBs as compared

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with placebo. No significant effect was found on the risk of all-cause death (RR: 0.98; 95% CI 0.90-1.07), CV death (RR: 0.99; 95% CI 0.86-1.23), MI (RR: 0.88; 95% CI 0.77-1.00) and newonset HF (RR: 0.87; 95% CI 0.73-1.00).

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ACEIs vs ARBs

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According to the results of our network meta-analysis, with placebo as the standard of comparison, we observed a non-statistically significantly different risk of the combined endpoint of CV death, MI and stroke (RR: 0.92; 95% CI 0.78-1.08) and of all-cause death (RR: 0.94; 95% CI 0.85-1.05)

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for ACE-Is versus ARBs. When components of the composite outcome were considered separately, there were no significant differences for ACE-Is versus ARBs in preventing CV death, MI and

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stroke. Finally, as far as new-onset HF and new-onset DM, our indirect comparison analysis did not find any significant differences between ACE-Is versus ARBs.

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main analyses.

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Details of the sensitivity analyses are presented in OS Table 2: results were all compatible with

DISCUSSION

To our knowledge, this is the first study attempting to (indirectly) compare ACEIs vs ARBs in patients at high CV risk without HF, obviating to the paucity of head-to-head comparative studies. In this indirect comparison analysis we found that, in patients at high CV risk without HF, there were no significant differences for ARBs versus ACE-Is in preventing all-cause death, CV death, major adverse cardiac and cerebrovascular events, new-onset DM and new-onset HF. This finding is in line with the results of a randomized comparative trial published on this subject, the ONTARGET study [7], claiming non-inferiority of ARBs versus ACE-Is in high-risk patients without HF [40]. Yet, the ONTARGET trial is currently the only randomized clinical study that head-to-head compared an ACEI vs an ARB in high-risk, not necessarily hypertensive patients without HF. Thus, we exploited the potential of network meta-analysis, that allows statistical

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inference from indirect comparisons, to re-evaluate this issue, with the hypothesis that the trend to greater efficacy of ACEIs compared to ARBs shown in previous studies [6] might be confirmed in an analysis purposely designed to compare these two classes of drugs.

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Whether clinically meaningful differences exist in the cardioprotective activity of ACEIs and ARBs has been long debated. In fact, although both classes of drugs act on the RAAS, and may appear

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similar at first glance in their effects [5, 41], differences in BP-dependent effects (e.g., the magnitude of BP decrease), BP-independent effects (e.g., the reduction of oxidative stress and endothelial dysfunction, improvement in glucose metabolism, and inhibition and stabilization of atherosclerotic plaque) [42], as well as other differential features of the two classes of compounds

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may exist. Thus, the possibility of the so called ARB-MI paradox related to the unexpected lack of efficacy or ARBs on MI [43] has been raised, claiming that this might account for differences seen

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in mortality and morbidity reduction between these two types of RAAS inhibitor [5, 44]. Results from a previous meta-analysis indicate that ACE-Is and ARBs have different effects on mortality reduction among hypertensive patients [45], or high-risk, mostly non hypertensive patients without

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HF [6].

Interestingly, in a recent meta-analysis of mortality reduction with RAAS inhibition in hypertensive

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patients, van Vark et al. demonstrated a statistically significant 10% reduction in all-cause mortality and a trend towards a 12% reduction in cardiovascular mortality with ACE-Is, while no significant

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mortality reduction was observed with ARBs [5, 45]. Nonetheless, as stated by the same authors, the test for heterogeneity in effects on cardiovascular mortality between ACE-Is and ARBs was statistically non-significant (P= 0.227) [45]. Consistent results were also reported by Savarese et al.

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[6] in a more recent meta-analysis showing a significant reduction of all-cause mortality, MI and new onset HF with ACEIs but not ARBs in high-risk patients without HF. In contrast, McAlister et al. [46] reported no significant differences between ACEIs and ARBs in CV mortality or morbidity reduction in high risk atherosclerotic patients but their analysis also included trials in patients with HF, in whom both classes of drugs have demonstrated favourable effects. Furthermore, although in the meta-analysis by Van Vark et al. [46] the mortality reduction observed in the overall group of RAAS inhibitors was mainly driven by the beneficial effect of the ACE-Is [45], the largest mortality reductions were observed in ASCOT-BPLA, ADVANCE, and HYVET, all of which studied the long-acting ACE-I perindopril [44, 47-49]. Most RAAS inhibitors have common molecular structures, and it is clear that both ACE-Is and ARBs have “class effects”. However, recent clinical studies have demonstrated that not all ARBs have the same effects, and some benefits conferred by ARBs may not fall into “class effects”, but rather be “molecular effects” [50]. Basic research clearly demonstrated some molecular effects of ACE-Is and ARBs, and more

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evidence is likely to emerge on the existence of differences among individual ACE-Is, ARBs and the newer class of direct renin inhibitors [5]. Future research should be oriented to determine

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whether these basic findings can influence the clinical outcome directly or indirectly [51].

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Study limitations

We acknowledge limitations in our analysis. First, although the indirect comparison using a common comparator may be considered the gold standard approach to perform indirect comparisons in the absence of head-to-head clinical trials between different classes of agents (such

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as ACE-Is and ARBs), inter-trial comparisons are always fraught with problems related to differences in study design and in trial populations. Results should therefore not be over-interpreted.

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Second, the current analysis assumes the existence of “class effects” among different ACE-Is and ARBs, although both classes include several agents with different pharmacokinetic and pharmacodynamics properties. Third, we used trial level data, rather than individual patient data,

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and information on background therapy and co-morbidities were not available in several trial reports. Finally, there was a great deal of variation between the studied populations: ACE-I trials

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were mostly conducted in patients with coronary or other vascular atherosclerotic disease, whilst ARB trials were mostly conducted in patients with DM or impaired glucose intolerance.

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Nevertheless, the level of risk in the placebo arms of the ACE-I and ARB trials was not

Conclusions

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significantly different for any outcome considered.

We found no significant differences between ACE-Is and ARBs in patients at high CV risk without HF in preventing the composite endpoint of CV death, MI and stroke. When indirectly compared with ARBs by using placebo as a common comparator, as well as in the single trial offering a direct comparison, we found no statistical support to the hypothesis of a superiority of ACE-Is, as a class, in preventing incident risk of all-cause death, CV death, MI, stroke, new-onset DM and new-onset HF, even exploiting the sensitive tool of a network meta-analysis.

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[41] Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials.

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[42] Blood Pressure Lowering Treatment Trialists C, Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-8.

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renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J. 2012;33:2088-97.

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[52] Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-8. [53] Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The Study on Cognition and

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[56] Imai E, Chan JC, Ito S, Yamasaki T, Kobayashi F, Haneda M, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia. 2011;54:2978-86. [57] The PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-

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lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.

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[58] Pitt B, O'Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease

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EUROPA study). Lancet. 2003;362:782-8. [60] Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551-62.

ACCEPTED MANUSCRIPT Ricci F. et al., IJC-D-15-06350 R1, page 15

LEGEND TO FIGURES

AC

CE

PT

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MA

NU

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Figure 1. Flowchart depicting the study selection process

ACCEPTED MANUSCRIPT Ricci F. et al., IJC-D-15-06350 R1, page 16 Table 1: Baseline characteristics of studies included.

Randomized Controlled Trial (Acronym or First Author et al.)

Reference

Year

Treatment Placebo (n) (n)

Treatment

Follow-up (yrs)

Age (yrs)

Women (%)

Hypertension (n)

DM (n)

CAD (%)

Betablockers (%)

Calcium Aspirin Statins Diuretics Channel (%) (%) (%) Blockers (%)

Baseline Risk* Study Population Specifics Death Rate (per 100 patients-year) Hypertensive patients with type 2 DM and microalbuminuria Patients with a history of stroke or transient ischemic attack

[52]

2001

Irbesartan

404

207

2.0

58

31

100

100

8

NA

NA

NA

NA

NA

0.3

RENAAL

[14]

2001

Losartan

751

762

3.4

60

37

94

100

21

NA

NA

9

NA

NA

6.6

IDNT

[39]

2003

Irbesartan

579

567

2.6

59

32

100

100

28

21

NA

47

21

24

12.4

Kondo et al.

[16]

2003 Candesartan

203

203

2.0

65

24

44

25

100

58

75

55

33

40

2.7

SCOPE

[53]

2003 Candesartan

2477

2460

3.7

76

65

53

12

5

NA

NA

NA

NA

NA

2.9

DIRECT-PREVENT-1

[54]

2008 Candesartan

711

710

4.7

30

44

0

100

0

5

15

14

NA

NA

0.3

Patients with normotensive, normoalbuminuric type 1 DM without retinopathy

DIRECT-PROTECT-1

[54]

2008 Candesartan

951

954

4.8

32

43

0

100

0

39

37

38

32

32

0.3

Patients with normotensive, normoalbuminuric type 1 DM with retinopathy

DIRECT-PROTECT-2

[55]

2008 Candesartan

951

954

4.7

57

50

62

100

0

17

20

53

37

68

1.6

Normoalbuminuric, normotensive, or treated hypertensive people with type 2 DM and retinopathy

PROFESS

[19]

2008

10146

10186

2.5

66

36

74

28

NA

18

NA

NA

58

71

2.6

Patients with a recent ischemic stroke High-risk patients intolerant to ACE-Is

2008

Telmisartan

2954

2972

4.7

67

43

NAVIGATOR

[21]

2010

Valsartan

4631

4675

6.5

64

51

ORIENT

[56]

2011

Olmesartan

282

284

3.2

59

69

ROADMAP

[22]

2011

Omesartan

2232

2215

3.2

58

54

Lewis et al.

[34]

1993

Captopril

207

202

3.0

AIPRI

[23]

1996

Benazepril

300

283

3.0

HOPE

[24]

2000

Ramipril

4645

4652

5.0

PART-2

[27]

2000

Ramipril

308

309

4.7

SCAT

[35]

2000

Enalapril

229

PROGRESS

[57]

2001

Perindopril

3051

QUIET

[58]

2001

Quinapril

878

EUROPA

[59]

2003

Perindopril

6110

PEACE

[29]

2004

Trandolapril

4158

CAMELOT

[30]

2004

Enalapril

673

DIABHYCAR

[31]

2004

Ramipril

2443

DREAM

[60]

2006

Ramipril

IMAGINE

[33]

2007

Quinapril

76

SC RI

[20]

Patients with type 2 DM nephropathy and hypertension, with very high baseline risk Patients with history of coronary intervention and no significant coronary stenosis on follow-up Elderly patients with hypertension and MMSE test score >24

36

75

NA

NA

NA

NA

NA

3.8

78

0

28

47

NA

NA

NA

8

1.2

94

100

8

15

18

18

23

NA

2

NA

100

31

NA

NA

NA

NA

NA

0.2

Patients with type 2 DM

MA

TRANSCEND

NU

Telmisartan

PT

IRMA-2

Patients with impaired glucose tolerance and established CV disease or CV risk factors Type 2 DM patients with overt nephropathy

47

76

100

NA

NA

NA

NA

NA

NA

6.9

Patients with diabetic nephropathy

51

28

82

NA

NA

62

92

59

9

31

0.1

Patients with renal insufficiency

66

27

47

39

80

38

NA

NA

23

48

2.9

High-risk patients with evidence of vascular disease or DM plus 1 other CV risk factor

61

18

NA

9

100

NA

19

29

NA

NA

1.8

Patients with coronary or other occlusive arterial disease

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35

4.0

62

11

36

11

100

17

14

13

16

13

1.2

Patients with CAD

4.0

64

30

48

13

8

26

73

0

NA

0

2.6

Patients with previous stroke or transient ischemic attack

872

3.0

58

18

47

16

100

48

90

NA

NA

15

1.4

Patients with CAD

6108

4.2

60

15

27

12

100

63

95

83

NA

37

1.6

Patients with stable CAD

4132

4.8

64

18

46

17

100

43

81

29

NA

25

1.4

Patients with stable CAD

655

2.0

58

28

60

19

100

40

76

29

15

47

0.5

Patients with documented CAD

2469

4.0

65

30

56

100

6

60

91

70

13

36

3.6

Type 2 DM patients with persistent microalbuminuria or proteinuria

2623

2646

3.0

55

59

44

0

NA

NA

NA

NA

NA

NA

0.4

Patients without CV disease but with impaired fasting glucose levels or impaired glucose tolerance

1280

1273

3.0

61

13

47

9

100

77

95

83

30

9

0.7

Low-risk patients early after coronary artery bypass surgery

CE

PT

231

3054

Patients with vascular disease or DM with endorgan damage and without heart failure Abbreviations: 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 0 DIabetic REtinopathy Candesartan Trials; DM = diabetes mellitus; DREAM = Diabetes REduction Assessment with ramipril and 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; ONTARGET = The Ongoing Telmisartan Alone and in Combination with Ramipril Global End- point Trial; 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. *Study-level baseline risk on placebo: event rate for all-cause mortality expressed as number of events (deaths) per 100 patients-year. Telmisartan

[7]

8542

2008

AC

ONTARGET

Ramipril

8576

0

4.7

66.4

26.8

68.8

37.3

74.5

56.7

75.6

61.5

28.1

32.8

NA

ACCEPTED MANUSCRIPT Ricci F. et al., IJC-D-15-06350 R1, page 17

Table 2: Network meta-analysis outcomes as to the various outcomes analyzed

ARBs vs Placebo

10

ACE-Is vs ARBs

23

SC RI

12

Stroke

NU

ACE-Is vs Placebo

MI

MA

N*

CV death

PT

All-cause death RR RR RR RR RR N N N N (95%CI) (95%CI) (95%CI) (95%CI) (95%CI) 0.81 0.91 0.80 0.80 0.93 12 12 11 13 (0.72-0.91) (0.80-1.08) (0.72-0.90) (0.69-0.94) (0.85-1.00) 0.88 0.99 0.88 0.83 0.98 8 10 7 12 (0.77-1.01) (0.86-1.23) (0.77-1.00) (0.70-0.98) (0.90-1.07) 0.92 0.92 0.91 0.97 0.94 21 23 19 26 (0.78-1.08) (0.73-1.10) (0.78-1.07) (0.79-1.19) (0.85-1.05)

Composite

PT ED

OUTCOME

new HF

new DM

RR (95%CI) 0.80 9 (0.69-0.93) 0.87 7 (0.73-1.00) 0.92 17 (0.77-1.15)

RR (95%CI) 0.81 5 (0.69-0.94) 0.82 4 (0.70-0.96) 0.99 10 (0.81-1.21)

N

N

AC CE

Composite: CV death, MI, and stroke. Abbreviations: CV = cardiovascular; HF = heart failure; DM = diabetes mellitus; N = number of trials analyzed; RR = relative risk; CI = confidence intervals.* Number of studies. For the “ACE-Is vs Placebo” and “ARBs vs Placebo” comparisons it represents the number of studies for which a direct comparison between treatments is possible. For “ACE-Is vs ARBs” it represents the total number of studies used in the network-meta-analysis.

ACCEPTED MANUSCRIPT

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MA

NU

SC RI

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Ricci F. et al., IJC-D-15-06350 R1, page 18