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. 2020 Apr 21;20:188. doi: 10.1186/s12872-020-01466-5

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

Yara Wanas 1,#, Rim Bashir 1,#, Nazmul Islam 2,✉, Luis Furuya-Kanamori 1,3
PMCID: PMC7175553  PMID: 32316917

Abstract

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.

Keywords: Cardiovascular events, Angiotensin receptor blockers, Meta-analysis, Risk

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 non-fatal) 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); follow-up 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 I2 index was used to assess heterogeneity among studies, an I2 > 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).

Result

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. The 44 publications reported data from 45 RCTs and 170,794 participants (85,544 participants in the ARB group and 85,250 participants in the placebo/control group) (Fig. 1). The publication by Chaturvedi et al. [15] reported findings from two RCTs, the DIRECT-Prevent 1 and DIRECT-Protect 1 studies.

Fig. 1.

Fig. 1

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PRISMA flow diagram of study selection

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/cm2). 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.

Table 1.

Characteristics of the RCTs included in the meta-analysis

Trial name, year publication Population Setting Intervention Control Follow up (in months) Male (%) Mean / median age (years) Mean BMI (kg/m2) Mean cholesterol (mg/dL) Mean LDL (mg/dL) Mean HDL (mg/dL) Mean triglyceride (mg/dL) Non-smoker (%) Hypertension (%) Heart failure (%) Diabetes mellitus (%) Ischaemic / coronary artery disease (%) Chronic kidney disease (%)
4C (2016) [16] Patients with IHD after coronary stent implantation 39 centres in Japan Candesartan Standard care without ARB 36 73 69 24 NR 111 49 140 83 73 8 35 100 NR
ACTIVE I (2011) [17] Patients with atrial fibrillation 600 centres worldwide Irbesartan Placebo 54 61 70 29 NR NR NR NR 50 88 32 20 NR NR
CARP (2011) [18] Patients that received a coronary stent 5 centres in Hiroshima, Japan Valsartan Non-ARB therapy 48 79 65 24 NR NR NR NR 50 75 NR 43 100 30
CASE-J (2008) [19] Patients with high-risk hypertension 527 physicians from Japan Candesartan Amlodipine 41 55 64 25 NR NR NR NR 79 100 0 43 43 24
CHARM-Added (2003) [20] Patients with CHF and LVEF< 40 618 centres in 26 countries Candesartan Placebo 41 79 64 28 NR NR NR NR 83 48 100 30 68 NR
CHARM-Alternative (2003) [7] Patients with symptomatic CHF and LVEF< 40% 618 centres in 26 countries Candesartan Placebo 34 68 67 28 NR NR NR NR 86 50 100 27 62 NR
CHARM-Preserved (2003) [21] Patients with HF and LVEF> 40 618 centres in 26 countries Candesartan Placebo 37 60 67 29 NR NR NR NR 87 64 100 28 56 NR
Cice et al. (2010) [22] Patients with CHF and in haemodialysis 30 clinics in Italy Telmisartan Placebo 36 90 63 NR NR NR NR NR 61 NR 100 29 57 100
DETAIL (2004) [23] Patients with diabetes mellitus and nephropathy 39 centres in northern Europe Telmisartan Enalapril 60 73 61 31 223 137 48 207 37 100 0 100 NR 100
DIRECT-Prevent 1 (2008) [15] Patients with type 1 diabetes a no retinopathy 309 centres worldwide Candesartan Placebo 56 56 30 24 184 NR 66 NR 74 NR NR 100 NR 0
DIRECT-Protect 1 (2008) [15] Patients with type 1 diabetes and retinopathy 309 centres worldwide Candesartan Placebo 56 57 32 25 186 NR 66 NR 74 NR NR 100 NR 0
DIRECT-Protect 2 (2008) [24] Patients with type 2 diabetes and retinopathy 309 centres worldwide Candesartan Placebo 56 50 57 29 205 NR NR NR 73 62 NR 100 5 0
E-COST (2005) [25] Patients with hypertension Centres in Saitama, Japan Candesartan Non-ARB therapy 37 48 NR NR NR NR NR NR NR 100 0 0 0 NR
E-COST-R (2005) [26] Patients with hypertension and mild renal impairment Centres in Saitama, Japan Candesartan Non-ARB therapy 37 59 67 NR 181 NR NR NR NR 100 0 0 6 100
ELITE (1997) [27] Patients with CHF and LVEF< 40% 125 centres in the USA, Europe, and South America Losartan Captopril 13 67 74 NR NR NR NR NR 88 57 100 25 50 7
ELITE II (2000) [28] Patients with CHF and LVEF< 40% 289 centres in 46 countries Losartan Captopril 23 69 71 NR NR NR NR NR NR 49 100 24 79 NR
GISSI-AF (2009) [29] Patients with history of atrial fibrillation 100 centres in Italy Valsartan Placebo 12 62 68 28 NR NR NR NR 81 85 8 15 12 3
HIJ-CREATE (2009) [30] Patients with coronary artery disease and hypertension 14 centres in Japan Candesartan Non-ARB therapy 50 80 66 25 193 NR 45 128 64 100 21 38 100 NR
HOPE-3 (2016) [31] Patients with intermediate cardiovascular risk 228 centres in 21 countries Candesartan + hydrochlorothiazide Placebo 67 54 66 27 201 128 45 128 72 38 0 5.8 0 0
IDNT (2003) [32] Patients with diabetes mellitus and nephropathy Centres in the North America, Europe, Latin America, South East Asia, and Oceania Irbesartan Amlodipine or placeboa 31 64 59 31 NR NR NR NR NR 100 0 100 28 100
I-PRESERVE (2008) [33] Patients with CHF and LVEF > 45% Centres in 25 countries Irbesartan Placebo 50 40 72 30 NR NR NR NR NR 89 100 28 0 0
IRMA-2 (2001) [34] Patients with hypertension, diabetes mellitus, and micro-albuminuria 96 centres worldwide Irbesartanb Placebo 24 69 58 30 224 140 44 180 81 100 NR 100 6 0
J-RHYTHM II (2011) [35] Patients with hypertension and atrial fibrillation 48 centres in Japan Candesartan Amlodipine 12 69 66 NR NR NR NR NR NR 100 3 9 1 NR
Kondo et al. (2003) [36] Patients with history of coronary intervention Ogaki Municipal Hospital in Japan Standard care + Candesartan Standard care without candesartan 24 76 65 24 187 114 49 126 76 44 2 25 100 NR
KYOTO HEART (2009) [37] Patients with uncontrolled hypertension 31 centres from Kyoto, Japan Valsartan Non-ARB therapy 39 57 66 39 NR 122 55 149 78 100 7 27 23 NR
LIFE (2002) [38] Patients with hypertension and left ventricular hypertrophy 830 centres from the USA, the UK, and Scandinavia Losartan Atenolol 58 46 67 28 232 NR 58 NR 84 100 0 13 16 NR
MOSES (2005) [39] High-risk hypertensive patients Centres in Germany and Austria Eprosartan Nitredipine 45 54 68 28 NR NR NR NR NR 100 26 37 26 5.4
NAVIGATOR (2010) [40] Patients with impaired glucose tolerance 806 centres in 40 countries Valsartan Placebo 60 49 64 31 210 127 50 151 89 78 NR 49 12 11
OCTOPUS (2013) [41] Patients with hypertension and in haemodialysis 66 dialysis centres in Okinawa, Japan Olmesartan Non-ARB therapy 60 62 60 24 155 NR NR 155 65 100 NR 32 7 100
ONTARGET (2008) [42] Patients with coronary, peripheral, cerebrovascular disease or diabetes with end-organ damage 733 centres in 40 countries Telmisartan Ramipril or ramipril + telmisartanc 56 77 66 28 190 112 50 151 36 69 0 37 75 NR
OPTIMAAL (2002) [43] Patients with acute myocardial infarction and heart failure 329 centres in 7 European countries Losartan Captopril 35 69 67 27 212 130 45 168 NR 36 6 17 100 NR
ORIENT (2011) [44] Patients with diabetes mellitus with proteinuria Centres in Japan and Hong Kong Olmesartan Placebo 38 69 59 25 208 NR NR NR 75 100 4 100 5 100
PRoFESS (2008) [45] Patients with a recent ischaemic stroke 695 centres in 35 countries Telmisartan Placebo 30 64 66 27 NR NR NR NR 43 74 3 28 NR NR
RENAAL (2001) [46] Patients with diabetes and nephropathy 250 centres in 28 countries Losartan Placebo 41 63 60 30 228 142 45 219 82 93 0 100 11 100
ROAD (2007) [47] Patients with proteinuria and chronic renal insufficiency Nanfang Hospital Renal Division in China Losartan Benazepril 44 63 50 23 97 NR NR 177 NR 63 0 0 0 100
SCAST (2011) [48] Patients with acute stroke 146 centres in Europe Candesartan Placebo 6 58 71 NR NR NR NR NR NR 70 NR 16 NR NR
SCOPE (2003) [49] Patients with mild to moderate elevated blood pressure 527 centres in Europe Candesartan Placebo 45 36 76 27 239 NR NR NR 91 52 NR 12 4 NR
SUPPORT (2015) [50] Patients with hypertension and CHF 17 centres in Tohoku, Japan Olmesartan Non-ARB therapy 53 75 66 25 NR 108 NR NR NR 100 100 50 47 0
Suzuki et al. (2008) [51] Patients with kidney failure treated with haemodialysis 5 dialysis centres in Saitama, Japan Losartan, candesartan, or valsartan Non-ARB therapy 36 59 60 21 157 NR NR NR 78 93 16 52 2 100
Takahashi et al. (2006) [52] Patients with kidney failure treated with haemodialysis Enshu General Hospital in Japan Candesartan Nothing 19 58 61 20 NR NR NR NR NR 81 0 33 0 100
TRANSCEND (2008) [53] Patients with coronary, peripheral, cerebrovascular disease or diabetes with end-organ damage, and intolerant to ACE inhibitors 630 centres in 40 countries Telmisartan Placebo 56 57 67 28 197 117 49 158 47 76 0 36 74 NR
T-VENTURE (2009) [54] Patients with acute myocardial infarction 4 centres in Japan Valsartan ACE inhibitor therapy 6 83 63 NR NR NR NR NR 40 57 0 34 100 NR
Val-HeFT (2001) [55] Patients with heart failure 302 centres in 16 countries Valsartan Placebo 23 80 63 NR NR NR NR NR NR NR 100 25 57 NR
VALIANT (2003) [56] Patients with recent myocardial infarction and LVEF < 35% 931 centres in 24 countries Valsartan Captoprild 25 78 65 27 NR NR NR NR NR 56 15 23 100 NR
VALUE (2004) [6] Patients with hypertension and high risk of cardiac event Centres in 31 countries Valsartan Amlodipine 50 58 67 29 NR NR NR NR NR 93 6 NR 45 NR
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ACE Angiotensin-converting enzyme, ARB Angiotensin II receptor blockers, CHF Congestive heart failure, IHD Ischaemic heart disease, LVEF Left-ventricular ejection fraction, NR Not reported

aIDNT (2003): Two control groups, placebo group was excluded

bIRMA-2 (2001): Two intervention groups, irbesartan 150 mg daily and irbesartan 300 mg daily were combined

cONTARGET (2008): Three intervention groups, ramipril + telmisartan group was excluded

dVALIANT (2003) Three intervention groups, valsartan + captopril group was excluded

Quantitative synthesis

After pooling all the available evidence, it was found 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), or stroke (RR 0.92; 95%CI 0.83–1.01) (Fig. 2). Sensitivity analyses based on different study and participants characteristics showed no increase in risk of any of the three outcomes of interest. However, it was also noticed that ARBs did not reduce the risk of all-cause mortality (RR 0.99; 95%CI 0.95–1.04) or myocardial infarction (RR 0.96; 95%CI 0.88–1.05) when compared to placebo, ARBs only decreased the risk of stroke (RR 0.91; 95%CI 0.85–0.98) (Table 2). Sensitivity analyses also revealed a decreased in all-cause mortality risk with ARBs when the proportion of smokers is small (< 25%) (RR 0.91; 95%CI 0.84–0.98); and stroke in females (RR 0.76; 95%CI 0.68–0.84), patients with elevated total cholesterol (RR 0.82; 95%CI 0.82–0.91) and lower levels of HDL (RR 0.90; 95%CI 0.80–0.98) (Table 2).

Fig. 2.

Fig. 2

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Forest plot depicting the relative risk of ARBs on a) all-cause mortality, b) myocardial infarction, and c) stroke

Table 2.

Sensitivity analyses

All-cause mortality Myocardial infarction Stroke
RR (95%CI) I2 N RR (95%CI) I2 N RR (95%CI) I2 N
Type of control
 Placebo 0.99 (0.95–1.04) 13 18 0.96 (0.88–1.05) 0 14 0.91 (0.85–0.98) 7 14
 Active 1.01 (0.95–1.08) 28 21 1.03 (0.96–1.11) 7 23 0.93 (0.79–1.08) 54 22
 Active only ACE inhibitors 1.04 (0.95–1.13) 46 8 1.01 (0.93–1.09) 0 9 0.98 (0.88–1.10) 0 8
Follow-up period
 ≤ 40 weeks 1.01 (0.91–1.14) 51 19 0.98 (0.88–1.10) 12 18 0.94 (0.74–1.20) 40 18
 > 40 weeks 1.00 (0.96–1.03) 0 20 1.03 (0.96–1.10) 0 19 0.90 (0.82–1.00) 45 18
Proportion of males
 ≤ 50% 0.93 (0.86–1.00) 0 6 1.02 (0.85–1.22) 37 5 0.76 (0.68–0.84) 0 5
 > 50% 1.02 (0.97–1.06) 23 33 1.01 (0.95–1.07) 0 32 0.96 (0.87–1.05) 28 31
Age
 ≤ 65 years 0.98 (0.88–1.09) 32 18 0.95 (0.85–1.06) 0 15 1.03 (0.80–1.34) 22 12
 > 65 years 1.01 (0.98–1.05) 10 20 1.04 (0.98–1.10) 0 21 0.92 (0.84–1.00) 41 23
BMI
 Normal range 0.84 (0.60–1.19) 31 7 0.81 (0.41–1.57) 0 6 1.21 (0.77–1.90) 0 5
 Overweight and obese 1.01 (0.98–1.04) 0 24 1.01 (0.96–1.07) 5 24 0.92 (0.83–1.01) 49 23
Elevated total cholesterol
 ≥ 200 mg/dL 0.98 (0.91–1.05) 15 10 0.99 (0.91–1.08) 0 8 0.82 (0.74–0.91) 6 7
Elevated LDL
 ≥ 120 mg/dL 1.01 (0.90–1.14) 36 7 0.97 (0.87–1.07) 0 6 0.86 (0.70–1.07) 45 5
Decreased HDL
 < 50 mg/dL 1.01 (0.95–1.08) 15 11 0.99 (0.89–1.09) 20 10 0.90 (0.82–0.98) 0 8
Elevated triglyceride
 ≥ 150 mg/dL 1.01 (0.94–1.08) 13 8 0.99 (0.90–1.09) 16 8 0.92 (0.83–1.01) 0 7
Proportion of smokers
 < 25% 0.91 (0.84–0.98) 2 12 0.99 (0.88–1.11) 0 13 0.81 (0.67–0.99) 41 12
 ≥ 25% 0.99 (0.95–1.05) 7 15 0.99 (0.91–1.01) 0 12 0.92 (0.87–0.98) 0 12
Hypertension
 Only patients with hypertension 0.98 (0.89–1.07) 0 12 1.02 (0.80–1.29) 27 12 0.82 (0.66–1.03) 57 13
Chronic heart failure (CHF)
 Only patients without CHF 0.97 (0.92–1.03) 0 11 0.99 (0.83–1.18) 43 12 0.85 (0.73–1.00) 47 11
 Only patients with CHF 1.00 (0.85–1.19) 75 6 1.06 (0.86–1.32) 0 8 1.04 (0.81–1.32) 14 8
Diabetes mellitus (DM)
 Only patients without DM 0.99 (0.38–2.61) 0 2 0.65 (0.26–1.59) 48 3 0.72 (0.50–1.04) 37 3
 Only patients with DM 1.04 (0.88–1.23) 0 7 0.99 (0.53–1.80) 67 4 1.31 (0.73–2.35) 30 3
Ischemic/coronary artery disease
 Only patients with ischemic/coronary artery disease 1.06 (0.91–1.22) 25 7 0.97 (0.88–1.07) 0 7 1.02 (0.84–1.24) 0 5
Chronic kidney disease
 Only patients with chronic kidney disease 0.86 (0.66–1.12) 50 8 0.99 (0.71–1.41) 20 9 1.08 (0.83–1.39) 0 8
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CI confidence interval; N number of studies; RR relative risk; ACE angiotensin-converting-enzyme

Statistically significant results are emboldened

The most common deficiencies were no blinding of participants and personnel (n = 14; 31%), followed by no blinding of the outcome assessor (n = 10; 22%) and incomplete outcome data (n = 10; 22%). Overall, the RCTs showed low risk of bias except for E-COST [25], E-COST-R [26], and Kondo et al. [36] (S2).

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.

Supplementary information

12872_2020_1466_MOESM1_ESM.docx (54.7KB, docx)

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.

Acknowledgments

The publication of this article was funded by the Qatar National Library.

Abbreviations

ARB

Angiotensin receptor blocker

ACE

Angiotensin-converting-enzyme

CVD

Cardiovascular disease

DALYs

Disability adjusted life years

IVhet

Inverse variance heterogeneity

RCT

Randomised controlled trial

RR

Relative risk

Authors’ contribution

Conception and design of the study: LFK. Collection and assembly of the dataset: YW, RB, LFK. Analysis of the dataset and interpretation of results: YW, RB, NI, LFK. Manuscript writing: YW, RB, NI, LFK. Final approval of manuscript: YW, RB, NI, LFK

Availability of data and materials

he data used in the study was extracted from published studies.

Ethics approval and consent to participate

Not applicable, this is a systematic review and meta-analysis of published papers.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yara Wanas and Rim Bashir joint first authors

Supplementary information

Supplementary information accompanies this paper at 10.1186/s12872-020-01466-5.

References

  • 1.Bansilal S, Castellano JM, Fuster V. Global burden of CVD: focus on secondary prevention of cardiovascular disease. Int J Cardiol. 2015;201(Suppl 1):S1–S7. doi: 10.1016/S0167-5273(15)31026-3. [DOI] [PubMed] [Google Scholar]
  • 2.World Health Organization. Global Health Observatory Data - Raised blood pressure. http://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_text/en/ (Accessed Sep 2019).
  • 3.Suzanne Oparil RES. New approaches in the treatment of hypertension. Circ Res. 2015;116(6):1075. doi: 10.1161/CIRCRESAHA.116.303603. [DOI] [PubMed] [Google Scholar]
  • 4.Miklos Z, Molnar KK-Z, Evan H, Lott JLL, Malakauskas SM, Jennie Z, et al. J Am Coll Cardiol. 2013;63(7):650–658. doi: 10.1016/j.jacc.2013.10.050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Schmieder RE, Ruilope LM, Barnett AH. Renal protection with angiotensin receptor blockers: where do we stand. J Nephrol. 2011;24(5):569–580. doi: 10.5301/JN.2011.6445. [DOI] [PubMed] [Google Scholar]
  • 6.Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet (London, England) 2004;363(9426):2022–2031. doi: 10.1016/S0140-6736(04)16451-9. [DOI] [PubMed] [Google Scholar]
  • 7.Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-alternative trial. Lancet (London, England) 2003;362(9386):772–776. doi: 10.1016/S0140-6736(03)14284-5. [DOI] [PubMed] [Google Scholar]
  • 8.Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet (London, England) 2008;372(9644):1174–1183. doi: 10.1016/S0140-6736(08)61242-8. [DOI] [PubMed] [Google Scholar]
  • 9.Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? Insights from 254,301 patients from randomized trials. Mayo Clin Proc. 2016;91(1):51–60. doi: 10.1016/j.mayocp.2015.10.019. [DOI] [PubMed] [Google Scholar]
  • 10.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210. doi: 10.1186/s13643-016-0384-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed) 2011;343:d5928. doi: 10.1136/bmj.d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Doi SA, Barendregt JJ, Khan S, Thalib L, Williams GM. Advances in the meta-analysis of heterogeneous clinical trials I: the inverse variance heterogeneity model. Contemp Clin Trials. 2015;45(Pt A):130–138. doi: 10.1016/j.cct.2015.05.009. [DOI] [PubMed] [Google Scholar]
  • 14.Furuya-Kanamori L, Barendregt JJ, Doi SAR. A new improved graphical and quantitative method for detecting bias in meta-analysis. Intl J Evid-Based Healthc. 2018;16(4):195–203. doi: 10.1097/XEB.0000000000000141. [DOI] [PubMed] [Google Scholar]
  • 15.Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, et al. Effect of candesartan on prevention (DIRECT-prevent 1) and progression (DIRECT-protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet (London, England) 2008;372(9647):1394–1402. doi: 10.1016/S0140-6736(08)61412-9. [DOI] [PubMed] [Google Scholar]
  • 16.Sakamoto T, Ogawa H, Nakao K, Hokimoto S, Tsujita K, Koide S, et al. Impact of candesartan on cardiovascular events after drug-eluting stent implantation in patients with coronary artery disease: the 4C trial. J Cardiol. 2016;67(4):371–377. doi: 10.1016/j.jjcc.2015.06.009. [DOI] [PubMed] [Google Scholar]
  • 17.Yusuf S, Healey JS, Pogue J, Chrolavicius S, Flather M, Hart RG, et al. Irbesartan in patients with atrial fibrillation. N Engl J Med. 2011;364(10):928–938. doi: 10.1056/NEJMoa1008816. [DOI] [PubMed] [Google Scholar]
  • 18.Okada T, Yamamoto H, Okimoto T, Otsuka M, Ishibashi K, Dohi Y, et al. Beneficial effects of valsartan on target lesion revascularization after percutaneous coronary interventions with bare-metal stents. Circ J. 2011;75(7):1641–1648. doi: 10.1253/circj.CJ-10-1064. [DOI] [PubMed] [Google Scholar]
  • 19.Ogihara T, Nakao K, Fukui T, Fukiyama K, Ueshima K, Oba K, et al. Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension (Dallas, Tex : 1979) 2008;51(2):393–398. doi: 10.1161/HYPERTENSIONAHA.107.098475. [DOI] [PubMed] [Google Scholar]
  • 20.McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-added trial. Lancet (London, England) 2003;362(9386):767–771. doi: 10.1016/S0140-6736(03)14283-3. [DOI] [PubMed] [Google Scholar]
  • 21.Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet (London, England) 2003;362(9386):777–781. doi: 10.1016/S0140-6736(03)14285-7. [DOI] [PubMed] [Google Scholar]
  • 22.Cice G, Di Benedetto A, D'Isa S, D’Andrea A, Marcelli D, Gatti E, et al. Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure a double-blind, placebo-controlled trial. J Am Coll Cardiol. 2010;56(21):1701–1708. doi: 10.1016/j.jacc.2010.03.105. [DOI] [PubMed] [Google Scholar]
  • 23.Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004;351(19):1952–1961. doi: 10.1056/NEJMoa042274. [DOI] [PubMed] [Google Scholar]
  • 24.Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-protect 2): a randomised placebo-controlled trial. Lancet (London, England) 2008;372(9647):1385–1393. doi: 10.1016/S0140-6736(08)61411-7. [DOI] [PubMed] [Google Scholar]
  • 25.Suzuki H, Kanno Y. Effects of candesartan on cardiovascular outcomes in Japanese hypertensive patients. Hypertens Res. 2005;28(4):307–314. doi: 10.1291/hypres.28.307. [DOI] [PubMed] [Google Scholar]
  • 26.Nakamura T, Kanno Y, Takenaka T, Suzuki H. An angiotensin receptor blocker reduces the risk of congestive heart failure in elderly hypertensive patients with renal insufficiency. Hypertens Res. 2005;28(5):415–423. doi: 10.1291/hypres.28.415. [DOI] [PubMed] [Google Scholar]
  • 27.Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (evaluation of losartan in the elderly study, ELITE) Lancet (London, England) 1997;349(9054):747–752. doi: 10.1016/S0140-6736(97)01187-2. [DOI] [PubMed] [Google Scholar]
  • 28.Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the losartan heart failure survival study ELITE II. Lancet (London, England) 2000;355(9215):1582–1587. doi: 10.1016/S0140-6736(00)02213-3. [DOI] [PubMed] [Google Scholar]
  • 29.Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni AP, et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009;360(16):1606–1617. doi: 10.1056/NEJMoa0805710. [DOI] [PubMed] [Google Scholar]
  • 30.Kasanuki H, Hagiwara N, Hosoda S, Sumiyoshi T, Honda T, Haze K, et al. Angiotensin II receptor blocker-based vs. non-angiotensin II receptor blocker-based therapy in patients with angiographically documented coronary artery disease and hypertension: the heart Institute of Japan Candesartan Randomized Trial for evaluation in coronary artery disease (HIJ-CREATE) Eur Heart J. 2009;30(10):1203–1212. doi: 10.1093/eurheartj/ehp101. [DOI] [PubMed] [Google Scholar]
  • 31.Lonn EM, Bosch J, Lopez-Jaramillo P, Zhu J, Liu L, Pais P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374(21):2009–2020. doi: 10.1056/NEJMoa1600175. [DOI] [PubMed] [Google Scholar]
  • 32.Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, et al. Cardiovascular outcomes in the Irbesartan diabetic nephropathy trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med. 2003;138(7):542–549. doi: 10.7326/0003-4819-138-7-200304010-00010. [DOI] [PubMed] [Google Scholar]
  • 33.Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359(23):2456–2467. doi: 10.1056/NEJMoa0805450. [DOI] [PubMed] [Google Scholar]
  • 34.Parving H-H, Lehnert H, Bröchner-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(12):870–878. doi: 10.1056/NEJMoa011489. [DOI] [PubMed] [Google Scholar]
  • 35.Yamashita T, Inoue H, Okumura K, Kodama I, Aizawa Y, Atarashi H, et al. Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study) Europace. 2011;13(4):473–479. doi: 10.1093/europace/euq439. [DOI] [PubMed] [Google Scholar]
  • 36.Kondo J, Sone T, Tsuboi H, Mukawa H, Morishima I, Uesugi M, et al. Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease. Am Heart J. 2003;146(6):E20. doi: 10.1016/S0002-8703(03)00443-5. [DOI] [PubMed] [Google Scholar]
  • 37.Sawada T, Yamada H, Dahlof B, Matsubara H. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART study. Eur Heart J. 2009;30(20):2461–2469. doi: 10.1093/eurheartj/ehp363. [DOI] [PubMed] [Google Scholar]
  • 38.Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet (London, England) 2002;359(9311):995–1003. doi: 10.1016/S0140-6736(02)08089-3. [DOI] [PubMed] [Google Scholar]
  • 39.Schrader J, Luders S, Kulschewski A, Hammersen F, Plate K, Berger J, et al. Morbidity and mortality after stroke, Eprosartan compared with Nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES) Stroke. 2005;36(6):1218–1226. doi: 10.1161/01.STR.0000166048.35740.a9. [DOI] [PubMed] [Google Scholar]
  • 40.The NAVIGATOR Study Group Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1477–1490. doi: 10.1056/NEJMoa1001121. [DOI] [PubMed] [Google Scholar]
  • 41.Iseki K, Arima H, Kohagura K, Komiya I, Ueda S, Tokuyama K, et al. Effects of angiotensin receptor blockade (ARB) on mortality and cardiovascular outcomes in patients with long-term haemodialysis: a randomized controlled trial. Nephrol Dial Transplant. 2013;28(6):1579–1589. doi: 10.1093/ndt/gfs590. [DOI] [PubMed] [Google Scholar]
  • 42.Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–1559. doi: 10.1056/NEJMoa0801317. [DOI] [PubMed] [Google Scholar]
  • 43.Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal trial in myocardial infarction with angiotensin II antagonist losartan. Lancet (London, England) 2002;360(9335):752–760. doi: 10.1016/S0140-6736(02)09895-1. [DOI] [PubMed] [Google Scholar]
  • 44.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(12):2978–2986. doi: 10.1007/s00125-011-2325-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12):1225–1237. doi: 10.1056/NEJMoa0804593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–869. doi: 10.1056/NEJMoa011161. [DOI] [PubMed] [Google Scholar]
  • 47.Hou FF, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, et al. Renoprotection of optimal Antiproteinuric doses (ROAD) study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol. 2007;18(6):1889–1898. doi: 10.1681/ASN.2006121372. [DOI] [PubMed] [Google Scholar]
  • 48.Sandset EC, Bath PM, Boysen G, Jatuzis D, Korv J, Luders S, et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet (London, England) 2011;377(9767):741–750. doi: 10.1016/S0140-6736(11)60104-9. [DOI] [PubMed] [Google Scholar]
  • 49.Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21(5):875–886. doi: 10.1097/00004872-200305000-00011. [DOI] [PubMed] [Google Scholar]
  • 50.Sakata Y, Shiba N, Takahashi J, Miyata S, Nochioka K, Miura M, et al. Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial. Eur Heart J. 2015;36(15):915–923. doi: 10.1093/eurheartj/ehu504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Suzuki H, Kanno Y, Sugahara S, Ikeda N, Shoda J, Takenaka T, et al. Effect of angiotensin receptor blockers on cardiovascular events in patients undergoing hemodialysis: an open-label randomized controlled trial. Am J Kidney Dis. 2008;52(3):501–506. doi: 10.1053/j.ajkd.2008.04.031. [DOI] [PubMed] [Google Scholar]
  • 52.Takahashi A, Takase H, Toriyama T, Sugiura T, Kurita Y, Ueda R, et al. Candesartan, an angiotensin II type-1 receptor blocker, reduces cardiovascular events in patients on chronic haemodialysis--a randomized study. Nephrol Dial Transplant. 2006;21(9):2507–2512. doi: 10.1093/ndt/gfl293. [DOI] [PubMed] [Google Scholar]
  • 53.The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174–1183. doi: 10.1016/S0140-6736(08)61242-8. [DOI] [PubMed] [Google Scholar]
  • 54.Suzuki H, Geshi E, Nanjyo S, Nakano H, Yamazaki J, Sato N, et al. Inhibitory effect of valsartan against progression of left ventricular dysfunction after myocardial infarction: T-VENTURE study. Circ J. 2009;73(5):918–924. doi: 10.1253/circj.CJ-08-0959. [DOI] [PubMed] [Google Scholar]
  • 55.Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667–1675. doi: 10.1056/NEJMoa010713. [DOI] [PubMed] [Google Scholar]
  • 56.Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau J-L, Køber L, Maggioni AP, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893–1906. doi: 10.1056/NEJMoa032292. [DOI] [PubMed] [Google Scholar]
  • 57.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. BMJ (Clinical research ed) 2011;342:d2234. doi: 10.1136/bmj.d2234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Strauss MH, Hall AS. Angiotensin receptor blockers do not reduce risk of myocardial infarction, cardiovascular death, or Total mortality: further evidence for the ARB-MI paradox. Circulation. 2017;135(22):2088–2090. doi: 10.1161/CIRCULATIONAHA.117.026112. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

12872_2020_1466_MOESM1_ESM.docx (54.7KB, docx)

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.

Data Availability Statement

he data used in the study was extracted from published studies.

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