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Erschienen in: BMC Cardiovascular Disorders 1/2020

Open Access 01.12.2020 | Research article

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

verfasst von: Yara Wanas, Rim Bashir, Nazmul Islam, Luis Furuya-Kanamori

Erschienen in: BMC Cardiovascular Disorders | Ausgabe 1/2020

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.
Hinweise
Yara Wanas and Rim Bashir joint first authors

Supplementary information

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s12872-020-01466-5.

Publisher’s Note

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

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.
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
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).
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
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

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s12872-020-01466-5.

Acknowledgments

The publication of this article was funded by the Qatar National Library.
Not applicable, this is a systematic review and meta-analysis of published papers.
Not applicable.

Competing interests

The authors declare that they have no competing interests.
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Metadaten
Titel
Assessing the risk of angiotensin receptor blockers on major cardiovascular events: a systematic review and meta-analysis of randomized controlled trials
verfasst von
Yara Wanas
Rim Bashir
Nazmul Islam
Luis Furuya-Kanamori
Publikationsdatum
01.12.2020
Verlag
BioMed Central
Erschienen in
BMC Cardiovascular Disorders / Ausgabe 1/2020
Elektronische ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-020-01466-5

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