Assessing the risk of angiotensin receptor blockers on major cardiovascular events: a systematic review and meta-analysis of randomized controlled trials.

Background Angiotensin receptor blockers (ARBs) are commonly used as a treatment for many cardiovascular diseases, but their safety has been called into question. The VALUE trial found an increased risk of myocardial infarction in participants receiving ARBs compared to other antihypertensive. The aim of the meta-analysis was to synthetize the available evidence of randomised controlled trials (RCTs) and elucidate if ARBs increase the risk of cardiovascular events. Methods A comprehensive search was conducted to identify RCTs that assessed the safety of ARBs. Titles and abstracts of all papers were independently screened by two authors. Data extraction and quality assessment were also performed independently. The relative risk (RR) of all-cause mortality, myocardial infarction, and stroke were pooled using the IVhet model. Multiple sensitivity analyses were conducted to assess the effect of ARBs by restricting the analysis to different participants’ characteristics. Results Forty-five RCTs comprising of 170,794 participants were included in the analysis. The pooled estimates revealed that ARBs do not increase the risk of all-cause mortality (RR 1.00; 95%CI 0.97–1.04), myocardial infarction (RR 1.01; 95%CI 0.96–1.06), and stroke (RR 0.92; 95%CI 0.83–1.01). The sensitivity analysis did not yield a particular group of patients at increased risk of cardiovascular events with ARBs. Risk of all-cause mortality and stroke decreased with ARB when the proportion of smokers in a population was < 25% (RR 0.91; 95%CI 0.84–0.98) and in females (RR 0.76; 95%CI 0.68–0.84), respectively. Conclusions ARBs do not increase the risk of major cardiovascular events and are safe for use in patients.


Background
Cardiovascular diseases (CVDs) remain one of the most prevalent non-communicable diseases and impose a great burden on the healthcare systems. Globally, an estimated 16.7 million deaths in the year 2010 were attributed to CVD with projections showing a staggering 23.3 million deaths by 2030 [1]. Hypertension is the leading risk factor for CVD and it is associated with 57 million disability adjusted life years (DALYs) worldwide [2].
It is well known that the risk of major cardiovascular events can be reduced by a wide spectrum of antihypertensive drugs including angiotensin receptor blockers (ARBs) [3]. This type of drug works by inhibiting the angiotensin II receptors, thus causing systemic vasodilatation, thereby aiding in the reduction of blood pressure [4]. ARBs are one of the most common drugs used for controlling blood pressure, treating heart failure, and preventing kidney failure in people with diabetes or hypertension [5]. However, the safety of ARBs in comparison to other anti-hypertensive medications has been called into question.
The VALUE trial found that ARBs (valsartan) increased the risk of myocardial infarction (fatal and nonfatal) by 19% compared with calcium channel blockers (amlodipine) [6]. This observation led many researchers to examine cautiously the evidence surrounding ARBs and myocardial infarction. For example, the point estimate of the CHARM-alternative trial suggests a 36% increase in myocardial infarction with candesartan (versus placebo) regardless of the reduction in blood pressure [7]. On the other hand, the TRANSCEND trial found an 8% decrease in risk of cardiovascular admissions for those on telmisartan compared to placebo [8].
Angiotensin-converting-enzyme (ACE) inhibitors are known to have a cardioprotective effect and the safety profile of ACE inhibitors have been shown not to differ from ARBs [9]. Hence it was unclear the mechanism that could explain an increase in risk of myocardial infarction with ARBs. Due to the wide use of ARBs for many CVDs and the contradictory results, we decided to conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) to elucidate the cardiovascular safety profile of ARBs.

Methods
Findings of this systematic review and meta-analysis are presented according to PRISMA reporting guidelines [10].

Search strategy and selection criteria
A systematic search was conducted in PubMed in September 2018. The following search terms were included: randomized controlled trial, angiotensin receptor antagonist, cardiovascular disease, and mortality. The full search strategy is shown in the supplementary material (S1). To achieve a comprehensive evaluation of the published evidence, the systematic search was supplemented with a similarity search (i.e. the first 20 related citations of each included paper) as well as hand search of the reference lists of relevant studies. Titles and abstracts were uploaded on Rayyan (http://rayyan.qcri.org/) [11] for the screening process. Two authors (YW and RB) independently screened all the records by title and abstract. Disagreements were resolved through author consensus and involvement of a third author (LFK).       The inclusion of studies was restricted to human studies; RCTs comparing ARBs versus a control (either a placebo or another antihypertensive medication); followup of at least 12 months; and reported all-cause mortality, myocardial infarction, and stroke as outcomes. Recurrent myocardial infarction and stroke were also considered if the study only included patients that have had recently experienced myocardial infarction or stroke. Observational studies, studies where ARBs were not the first line of treatment, and conference abstracts were excluded.

Data extraction and quality assessment
The number of participants and the number events (i.e. all-cause mortality, myocardial infarction, and stroke) in each intervention group (ARBs [active] and non-ARBs [control]) were extracted. In addition, study characteristics (e.g. study sites and follow-up period) and participants' characteristics (e.g. mean age, proportion of males, mean BMI) were extracted. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials [12] was used to assess the risk of bias of the included studies.

Statistical analysis
The outcomes of interest were the relative risks (RRs) of all-cause mortality, myocardial infarction, and stroke with ARBs compared to the control group. The inverse variance heterogeneity (IVhet) model was used to pool the effect size [13]. The I 2 index was used to assess heterogeneity among studies, an I 2 > 50% was considered significant heterogeneity.
Sensitivity analyses were conducted to identify potential scenarios where ARBs increase the risk of all-cause mortality, myocardial infarction, and stroke. The following analyses restricting the meta-analysis to: control group (active medication, only ACE inhibitors, or placebo); follow-up period (≤40 weeks or > 40 weeks); proportion of males (≤50% or > 50%); age (≤65 years or > 65 years); BMI (normal range or overweight/obese); elevated total cholesterol (≥200 mg/dL); elevated LDL (≥120 mg/dL); decreased HDL (< 50 mg/dL); elevated triglyceride (≥150 mg/dL); proportion of smokers (< 25% or ≥ 25%); only patients with hypertension; only patients with or without chronic heart failure; only patients with or without diabetes mellitus; only patients with ischemic/coronary artery disease; and only patients with chronic kidney disease.
Publication bias was assessed through visual inspection of funnel and Doi plots and statistically through the Egger's regression p-value and the LFK index [14]. All the analyses were conducted in Stata MP 14 (StataCorp, College Station, TX, USA).

Study selection and study characteristics
One thousand seven hundred and eighty-six unique records were identified through the search strategy and the similarity search. Four hundred and seventy-four records remained after the title and abstract screening and 44 publications remained after the full-text screening.   (Fig. 1). The publication by Chaturvedi et al. [15] reported findings from two RCTs, the DIRECT-Prevent 1 and DIRECT-Protect 1 studies. Twenty four RCTs compared ARBs versus placebo, while 21 RCTs against an active medication. The majority of RCTs (n = 39) included a larger proportion of males (ranging from 54 to 90%). Only two RCTs, DIRECT-Prevent 1 and DIRECT-Protect 1 enrolled participants with a median age < 50 years. Among the studies that reported the median BMI, only 22% had participants with a normal BMI (< 25 kg/cm 2 ). Fourteen, nine, and eight RCTs included only patients with hypertension, chronic heart failure, and diabetes mellitus, respectively ( Table 1). All-cause mortality, myocardial infarction, and stroke were assessed in 39, 37, and 36 RCTs.
The Doi plots revealed minor asymmetry for all-cause mortality (LFK index = − 1.24) and myocardial infarction (LFK index = − 1.33) for RCTs reporting favourable results for ARBs. No asymmetry was observed for stroke (supplementary material S3).

Discussion
Findings from previous RCTs were controversial, the VALUE [6] and the CHARM-alternative [7] trials found increase in myocardial infarction with ARBs compared to amlodipine and placebo, respectively. While other large RCTs such as the LIFE [38] and the RENAAL [46] trials found a decrease in all-cause of death and myocardial infarction with ARBs. In 2011, Bangalore et al. [57] conducted a meta-analysis on ARBs and the risk of myocardial infarction and found that ARBs do not increase the risk of cardiovascular events. Since then, multiple RCTs have been published; in our meta-analysis we pooled the most updated evidence (45 RCTs comprising of 170,794 participants -8 RCTs and 23,000 more participants that Bangalore et al.) and corroborated that ARBs are safe medications as they do not increase the risk of all-cause mortality, myocardial infarction, or stroke. It is worth pointing out that our meta-analysis (in line with previous studies [57,58]) also found that ARBs do not reduce the risk of all-cause mortality and myocardial infarction when compared to placebo.
In addition, the safety profile of ARBs was examined in multiple scenarios by restricting the analysis to different study and participants characteristics (i.e. sensitivity analyses). In none of the cases, ARBs were found to increase the risk of all-cause mortality, myocardial infarction, and stroke. ARBs reduce the risk of all-cause mortality by 9% in populations with low prevalence of smokers and exerts a cerebrovascular protective effect in female patients and patients with abnormal total cholesterol or HDL.
Findings from our study are reassuring for patients and clinicians as ARBs are widely used to treat conditions such as hypertension, chronic kidney disease/kidney failure (especially in patients with diabetes mellitus), and heart failure. However, the findings need to be understood in light of some of the limitations. Only RCTs were included, but the possibility of confounding not accounted during the analysis of the RCTs cannot be completely ruled out. There was heterogeneity in the RCTs protocols (e.g. inclusion criteria, different ARBs, different doses, follow-up) that needs to be accounted in future research synthesis studies through individual patients meta-analysis.

Conclusion
In conclusion, our meta-analysis provides reassuring evidence for patients and clinicians that ARBs are safe drugs, and do not increase the risk of death, myocardial infarction, and stroke.
Additional file 1: S1. Search strategy S2. Risk of bias of the included studies S3. Doi (top) and funnel (bottom) plots for the studies assessing a) all-cause mortality, b) myocardial infarction, and c) stroke S4.