BMJ Open is committed to open peer review. As part of this commitment we make the peer ... · For...

BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email

[email protected]

on October 28, 2020 by guest. P

rotected by copyright.http://bm

jopen.bmj.com

/B

MJ O

pen: first published as 10.1136/bmjopen-2018-026686 on 30 S

eptember 2019. D

ownloaded from

http://bmjopen.bmj.com/

[email protected]


For peer review only

Benefits and harms of lower blood pressure treatment targets – systematic review and meta-analysis of

randomized placebo-controlled trials

Journal: BMJ Open

Manuscript ID bmjopen-2018-026686

Article Type: Research

Date Submitted by the Author: 17-Sep-2018

Complete List of Authors: Brunström, Mattias ; Department of Public Health and Clinical Medicine, Medicine, Umeå University, Carlberg, Bo; Umeå University,, Department of Public Health and Clinical Medicine

Keywords: Hypertension < CARDIOLOGY, Adverse events < THERAPEUTICS, INTERNAL MEDICINE

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open on O

ctober 28, 2020 by guest. Protected by copyright.

http://bmjopen.bm

j.com/

BM

J Open: first published as 10.1136/bm

jopen-2018-026686 on 30 Septem

ber 2019. Dow

nloaded from



1

Benefits and harms of lower blood pressure treatment targets –

systematic review and meta-analysis of randomized placebo-

controlled trials

Postdoc researcher, Mattias Brunström MD, PhD

Associate Professor, Bo Carlberg MD, PhD

Dept. Public Health and Clinical Medicine, Umeå University

Corresponding author:

Dr Mattias Brunström

[email protected]

+46733693182


SE-901 87 Umeå

Sweden

3 539 words

2 figures

2 tables

Key words: Hypertension; Antihypertensive agent; Systolic blood pressure; Systematic

Review; Meta-analysis

Page 1 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



2

Abstract

Objectives

To assess the effect of antihypertensive treatment in the 130-140 mm Hg systolic blood

pressure range.

Design

Systematic review and meta-analysis.

Information sources

PubMed, CDSR and DARE were searched for systematic reviews, which were manually

browsed for clinical trials. PubMed and CENTRAL were searched for trials directly.

Eligibility criteria

Randomized double-blind trials with ≥ 1000 patient-years of follow-up, comparing any

antihypertensive agent against placebo..

Data extraction and risk of bias

Two reviewers extracted study-level data, and assessed risk of bias using Cochrane

Collaborations risk of bias assessment tool, independently.

Main outcomes and measures

Primary outcomes were all-cause mortality, major cardiovascular events and

discontinuation due to adverse events. Secondary outcomes were cardiovascular

mortality, myocardial infarction, stroke, heart failure, hypotension-related adverse

events and renal impairment.

Page 2 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



3

Results

Eighteen trials, including 92 567 participants (34 % women, mean age 63 years),

fulfilled the inclusion criteria. Primary preventive antihypertensive treatment was

associated with a neutral effect on all-cause mortality (relative risk 1.00, 95 %

confidence interval 0.95 to 1.06) and major cardiovascular events (1.01, 0.96 to 1.05),

but an increased risk of discontinuation due to adverse events (1.23, 1.03 to 1.47). None

of the secondary efficacy outcomes were significantly reduced, but the risk of

hypotension-related adverse events increased with treatment (1.71, 1.32 to 2.22). In

coronary artery disease secondary prevention, antihypertensive treatment was

associated with reduced risk of all-cause mortality (0.91, 0.83 to 0.99) and major

cardiovascular events (0.85, 0.77 to 0.94), but doubled the risk of adverse events leading

to discontinuation (2.05, 1.62 to 2.61).

Conclusion

Primary preventive blood pressure lowering in the 130 to 140 mm Hg systolic blood

pressure range adds no cardiovascular benefit, but increases the risk of adverse events.

In secondary prevention benefits should be weighed against harms.

Registration

Registered in PROSPERO, registration number CRD42018088642.

Page 3 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



4

Article Summary

Strengths and limitations of this study

- Meta-analysis restricted to randomized double-blind placebo-controlled trials,

thereby minimizing the risk of performance bias

- Adverse events included as co-primary outcome, putting emphasis on both

benefits and harms

- Separate analyses for primary and secondary preventive trials, reducing the risk

of confounding from coronary artery disease and increasing the usefulness of the

results in different clinical contexts

- Main limitation is the use of study-level data, with the potential for ecological

bias.

Page 4 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



5

Introduction

For decades, hypertension has been defined as a blood pressure (BP) ≥ 140/90 mm Hg.1

The definition has been uniform across the world, and for most patients the

recommended treatment goal has been < 140/90 mm Hg.2-4 In 2017, the American

Collage of Cardiology (ACC) and the American Heart Association (AHA) updated the U.S.

guidelines, changing the definition of hypertension to ≥ 130/80 mm Hg.5 For secondary

preventive patients, and for primary preventive patients with a 10-year cardiovascular

risk ≥ 10 per cent, the treatment goal is now < 130/80 mm Hg. Recently, the European

Society of Hypertension (ESH) and the European Society of Cardiology (ESC) followed,

retaining the old definition of hypertension, but lowering the treatment goal to 120-

130/70-80 mm Hg for most patients 6

The revision of both sets of guidelines were heavily influenced by the Systolic Blood

Pressure Intervention Trial (SPRINT).7 SPRINT randomized > 9 000 high-risk patients

(without previous stroke or diabetes) to a systolic blood pressure (SBP) target < 120

mm Hg compared to < 140 mm Hg, and was stopped preterm due to lower risk of death

and cardiovascular disease in the intensive treatment group.7 In addition to SPRINT, the

ACC/AHA performed a systematic review and meta-analysis including only non-blinded

randomized trials comparing different treatment goals.8

Blinding of participants and study personnel is desirable to minimize the risk of

performance bias.9 In non-blinded studies, such as SPRINT and those included in the

ACC/AHA systematic review, participants may be handled differently depending on

treatment group, thereby cofounding the assessment of the intervention. Meta-

epidemiological studies have found that trials with unclear or incomplete blinding

Page 5 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



6

produce more favourable results compared to trials that are double-blind.10

Additionally, in the clinic, we know the patients’ blood pressure, but not what blood

pressure he or she will have after adding an additional drug. Placebo-controlled trials

mimic the clinical situation where the question is – should we add another drug or not?

This systematic review and meta-analysis aims to evaluate the benefits and harms

associated with antihypertensive treatment in randomized double-blind placebo-

controlled trials with mean SBP 130-140 mm Hg at randomization. Such an approach

eliminates the risk of performance bias, yet produces treatment effect estimates

reasonably specific for the SBP interval for which the new recommendations differ from

previous ones.

Methods

We performed a systematic review and meta-analysis guided by the recommendations

from the Cochrane Collaboration.9 A protocol was registered a priori in the International

Prospective Register of Systematic Reviews (PROSPERO) with registration number

CRD42018088642. Reporting follows the Preferred Reporting for Systematic Reviews

and Meta-Analyses (PRISMA) guidelines.11

Studies were eligible if they were randomized double-blind placebo-controlled trials

with ≥ 1000 patient-years of follow-up; assessing the effect of any antihypertensive

agent against placebo, with mean baseline SBP ≥ 130 mm Hg and < 140 mm Hg. Target-

driven trials were excluded due to reasons described above, and trials comparing

different antihypertensive agents against each other were excluded because they risk

Page 6 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



7

assessing blood pressure-independent effects of agents. 9,10 We also excluded trials in

patients with acute myocardial infarction or heart failure/left ventricular dysfunction

because several antihypertensive agents are thought to have blood pressure

independent effects on clinical outcomes in these settings.12,13

We used one of our recent, more comprehensive systematic reviews for study

selection.14 Search strategies for the previous review are presented in the online

supplement (eMethods). In addition, we searched PubMed and Cochrane Central

Register of Controlled Trials (CENTRAL) from the date of the previous search until

February 2018, using search terms ("blood pressure lowering" OR "blood-pressure

lowering" OR "blood pressure-lowering" OR antihypertensive) AND (mortality OR

myocardial OR stroke). Titles were screened by M.B. and apparently irrelevant

publications were removed. Two authors judged abstracts separately, after which final

decision on eligibility was reached through discussion (eFigure 1).

Data were extracted from the included studies into specially designed Excel sheets by

two authors separately. When extracted data differed between authors, we revisited

original publications. Descriptive data were collected on study level, whereas blood

pressure data and outcome data were collected for each treatment group individually.

All trials were judged for risk of bias by two authors separately, using Cochrane

Collaboration´s Risk of Bias assessment tool.15 The risk of bias tool covers six specific

domains related to randomization, allocation concealment, blinding of participants and

personnel, blinding of outcome assessors, attrition and outcome reporting. Also, we

assessed sponsor involvement, protocol changes and premature study discontinuation

as other potential sources of bias. Trials judged to be at high risk of selection bias,

Page 7 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



8

performance bias, detection bias or attrition bias (first five domains), were excluded

from all analyses (eTable 1). Risk of bias for selective reporting should be considered

interpreting the overall analyses for each outcome rather than individual trials, because

it is the lack of data rather than biased data that may produce biased overall results.

Primary outcomes were all-cause mortality, MACE (defined as cardiovascular death,

myocardial infarction and stroke if not specified otherwise), and discontinuation due to

adverse events (AEs). Secondary outcomes were cardiovascular mortality, myocardial

infarction, stroke, heart failure, hypotension-related AEs, and discontinuation due to

renal impairment/acute kidney injury.

Results were analyzed according to the intention-to-treat principle, in the sense that

participants were analyzed in their assigned treatment group. When study participants

were lost to follow-up, relative risks (RR) were calculated using complete cases in the

denominator, according to the recommendations from the Cochrane Collaboration.9 In

two sets of sensitivity analyses, we calculated RRs using the observed number of events

in the numerator and the total number of randomized participants in the denominator

(assuming that all participants lost to follow-up were event free), and the observed

number of events plus number of participants lost to follow-up in the numerator and the

total number of randomized participants in the denominator (assuming that all

participants lost to follow-up had experienced an event). RRs were not standardized for

BP differences in trials, because such standardization is associated with increased

heterogeneity, unbalanced study weights, and biased overall results.16

Page 8 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



9

Relative risks from individual trials were pooled using DerSimonian-Laird random-

effects meta-analyses. We separated primary preventive studies from studies in people

with established coronary artery disease (CAD), because these represent clinically

different populations, and because we have previously observed potentially different

treatment effects in these groups.14 Trials with mixed populations were classified as

CAD trials if ≥ 50 % of participants had previous CAD. Treatment effect interaction

between primary preventive studies and CAD studies was assessed using random-

effects metaregression. Pre-specified sensitivity analyses, excluding trials in people with

diabetes, trials of dual renin-angiotensin-aldosterone system (RAAS) inhibition, trials

not reaching < 130 mm Hg in the intervention group, trials of previously

treated/hypertensive patients, and trials of treatment naïve patients, were performed to

test the impact of different patient/trial characteristics on overall results for primary

outcomes. We explored potential effect modification by diabetes and absolute

cardiovascular risk as continuous explanatory variables using random-effects

metaregression. Lastly, we performed ad-hoc subgroup analyses, stratifying primary

preventive trials by 10-year MACE event-rate above versus below 10 %, to approximate

the cut-off used in the 2017 ACC/AHA guidelines.5

Between-study heterogeneity in meta-analyses was assessed calculating I-squared,

which represents the percentage of variance between studies that cannot be explained

by chance alone. When statistical heterogeneity was present we sought for

corresponding clinical heterogeneity. If statistically deviating studies differed with

respect to clinical characteristics, they were excluded in sensitivity analyses. Small-

study effects were assessed through funnel plots for all primary and secondary

Page 9 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



10

outcomes, using Harbord´s test for asymmetry.17 All analyses were performed using

STATA v12.

Patient involvement

No patients were involved in setting the research question or the outcome measures,

nor were they involved in developing plans for design or implementation of the study.

No patients were asked to advice on interpretation or writing up of results. Since we

used only aggregated data from previous trials, we are unable to disseminate the results

of the research to study participants directly.

Results

Eighteen trials18-35, including 92 567 participants (34 % women; mean age 63 years),

fulfilled the inclusion criteria (table 1). During an average of 4.5 years under

randomized double-blind treatment, 2 042 participants were lost to follow-up (2.2 %),

resulting in 90 525 complete cases and 407 000 patient-years of follow-up. Twelve

trials19-22,25-27,30-33,35, including 54 020 participants, were classified as primary

preventive. Mean baseline SBP in these trials was 138 mm Hg, and mean SBP difference

between treatment groups during follow-up was 3.4 mm Hg. Six trials18,23,24,28,29,34,

including 38 547 participants, were classified as CAD trials; mean baseline SBP was 137

mm Hg, with 4.2 mm Hg SBP difference during follow-up.

In primary prevention (figure 1), treatment was not associated with any effect on all-

cause mortality (relative risk 1.00, 95 % confidence interval 0.95 to 1.06) or MACE

(1.01, 0.96 to 1.05), but an increased risk of AEs leading to discontinuation (1.23, 1.03 to

Page 10 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



11

1.47). In CAD trials (figure 2), treatment reduced the risk of all-cause mortality by 9 %

(0.91, 0.83 to 0.99), and the risk of MACE by 15 % (0.85, 0.77 to 0.94), but doubled the

risk of AEs leading to discontinuation (2.05, 1.62 to 2.61). Heterogeneity was low in

mortality and MACE analyses for primary prevention, moderate to high in CAD trials,

and very high for AEs in both cohorts. The difference between primary preventive trials

and CAD trials was significant for MACE (p=0.019) and borderline for all-cause mortality

and AEs (p=0.051 respectively 0.070).

None of the secondary efficacy outcomes were affected by primary preventive treatment

(table 2; online supplement eFigure 2-7). Hypotension-related AEs increased by 71 %

(1.71, 1.32 to 2.22) whereas discontinuation due to renal impairment showed a non-

significant tendency towards harm (1.20, 0.93 to 1.55). Of note, heterogeneity was high

in the renal impairment analysis, mostly due to one study in patients with type 1-

diabetes and macroalbuminuria.26 When this study was removed in a sensitivity

analysis, heterogeneity decreased and the observed risk increase became nominally

significant (1.30, 1.06 to 1.58).

In CAD trials (table 2; online supplement eFigure 2-7), treatment reduced the risk of

myocardial infarction (0.83, 0.72 to 0.97), stroke (0.79, 0.66 to 0.94), heart failure (0.76,

0.67 to 0.86), and cardiovascular death (0.86, 0.74 to 1.00, p=0.047). Differences

between primary prevention and CAD trials were significant or borderline significant for

all efficacy outcomes except stroke (eFigure 2-7). The relative risk of adverse events was

similar as in primary preventive studies, although estimates were less precise and

reporting was poor (only one trial reported renal impairment).

Page 11 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



12

Sensitivity analyses, testing the impact of different trial characteristics, shifted effect

estimates slightly (eFigure 8-12), but not enough to affect the interpretation of our main

findings. Metaregression analyses, exploring potential effect modification by observed

cardiovascular risk and diabetes mellitus were non-significant. Of note, the absolute 10-

years risk of MACE was well above the 10% threshold for recommending treatment in

the ACC/AHA guidelines, with an average risk across studies of 26 % (eTable 2);

subgroup analyses of primary preventive trials stratified by 10-year cardiovascular

event-rate found no interaction between risk of MACE and treatment effect (eFigure 13).

Risk of bias was generally judged as low for individual trials (eTable 3 & eResults). We

required studies to be described as randomized double-blind placebo-controlled trials

to be eligible. Loss to follow-up was limited, and sensitivity analyses imputing all

participants lost to follow-up as either having an event or being event-free did not alter

effect estimates (eFigure 14-15). Three trials were judged to be at high risk of bias for

individual domains.20,24,26 We performed sensitivity analyses, testing the impact of these

trials on our primary outcomes (eFigure 16). This had marginal effects on relative risks

and confidence intervals, but no effect on nominal significance for any analysis.

Funnel plots showed no signs of asymmetry (eFigure 17-25), with the possible

exception of hypotension-related adverse events (p=0.06). When we explored this

further, we found that treatment effect correlated with number of events but not study

size (eTable 4). The frequency of hypotension-related AEs varied by a factor of 50

between trials, presumably representing different thresholds for reporting. Thus, the

observed association between number of adverse events and the relative risk of adverse

Page 12 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



13

events might represent a stronger association between treatment and severe events

compared to less severe events.

Discussion

This systematic review and meta-analysis evaluates if antihypertensive treatment in the

130-140 mm Hg SBP interval is supported by findings from randomized double-blind

placebo-controlled trials. This does not seem to be the case in primary prevention, with

no treatment effect on all-cause mortality or MACE, but an increased risk of AEs leading

to discontinuation. In people with previous CAD, treatment might be beneficial, although

these findings should be interpreted more cautiously due to statistical heterogeneity

and wider confidence intervals. Overall, the results presented here question the recent

shift in SBP treatment goals from 140 mm Hg to 130 mm Hg for the majority of patients,

seen on both sides of the Atlantic.5,6

This paper has several important limitations that need to be addressed. Firstly, we only

had access to aggregated data, making analyses susceptible to ecological bias. Studies

were included based on average SBP levels, meaning that individual participants with an

SBP > 140 mm Hg or < 130 mm Hg were included in the analyses because the average

SBP in their trials were within the accepted range. Similarly, individual participants with

an SBP within our accepted range were missed because they were included in trials with

an average SBP outside our accepted range. Notably, this problem is not unique to this

review, but applies to most meta-analyses in the field, including those comparing

different blood pressure targets cited by guidelines. 8,36,37 Overcoming this would

require individual-patient data, unfortunately not available to date. Secondly, the

Page 13 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



14

aggregated nature of our data also affects categorization of trials as primary or

secondary preventive. In trials categorized as primary preventive, 17 % of participants

had CAD, whereas in secondary preventive trials the corresponding number was 95 %.

This represents reasonable separation between groups, although this aspect could also

be explored further in individual-patient data meta-analyses. Thirdly, SBP was only

moderately reduced in the trials included in our analyses; less so compared to previous

meta-analyses including target-driven trials. Although a less pronounced effect on

clinical outcomes would be expected, the observed SBP difference of 3.4 mm Hg during >

200 000 person-years of follow-up should have resulted in at least a tendency towards

primary preventive benefit if such were present. Instead confidence intervals were fairly

narrow around the null effect.

The arguments for lowering SBP treatment goals differ slightly between the ACC/AHA

guidelines compared to the ESH/ESC guidelines.5,6 Common to both sets of guidelines is

that they put emphasis on the results of systematic reviews and meta-analysis. Whereas

the ACC/AHA performed their own systematic review of trials comparing different

targets,8 the ESH/ESC refers mainly to two previously published papers combining

results from target-trials and placebo-controlled trials.36,37

The main strength of this review, compared to the systematic reviews underlying the

ACC/AHA and the ESH/ESC guidelines, is that it is limited to randomized double-blind

placebo-controlled trials, protecting it against performance bias. Although the

magnitude of this potential problem is unknown, target-driven trials may be susceptible

to performance bias due to their non-blinded nature.9 Possible indicators of such bias

might be 20-30 % more unscheduled visits in the intensive treatment group, and a large

Page 14 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



15

non-cardiovascular component of the all-cause mortality reduction, seen in SPRINT.7

Meta-analyses restricted to target-trials, such as the one by the ACC/AHA8, may be

especially susceptible to these kinds of biases, whereas the risk is probably lower in

meta-analyses combing target-trials and placebo-controlled trials, such as those

underlying the ESH/ESC recommendations.36,37 Notwithstanding, the different findings

in our analysis compared to the ACC/AHA analysis should raise the question if

performance bias does play a role in target-trials of antihypertensive treatment,

exaggerating treatment effect estimates.

Another important difference between this analysis and the ones underlying the

ACC/AHA and ESH/ESC guidelines is that we analyze primary preventive studies and

secondary preventive studies separately. This is important because the evidence for BP

lowering in the 130-140 mm Hg interval comes to a large extent from trials in people

with established coronary artery disease (CAD). Before primary and secondary

preventive trials are combined one has to ask if it is reasonable to extrapolate findings

from CAD patients to healthy individuals. To answer this, it is important to consider

possible mechanistic differences in these populations. In primary prevention,

development of atherosclerosis is a sine qua non for succeeding cardiovascular events,

and hence the effect of BP lowering treatment on the early stages of atherosclerosis

becomes most important. In people with established CAD, on the other hand, angina and

heart failure symptoms are closely related to myocardial oxygen balance, depending to a

large extent on cardiac afterload which is proportional to systolic blood pressure.38 Also,

systolic blood pressure has been associated with changes in atheroma size, indicating

that higher blood pressure may increase the risk of plaque rupture.39 Therefore, it is not

beyond reasonable doubt that BP lowering might work through different mechanisms

Page 15 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



16

depending on CAD status; in this situation, lumping trials with and without CAD patients

should be avoided. The analyses presented here provide statistical support to the

pathophysiologically based decision to separate patient categories. Indeed, it shows that

the observed benefit in previous analyses depends on inclusion of secondary preventive

studies.

Lastly, the systematic reviews referred to as supportive of lower treatment targets in the

ESH/ESC guidelines used meta-analyses standardized to systolic BP reductions of 10

mm Hg.36,37 This might seem reasonable at first, but affects the results in ways that

might not be clear to most readers.16 Firstly, standardization amplifies treatment effects

by about 50 %, because SBP reduction in the included trials was on average 6-8 mm Hg

whereas results are standardized to 10 mm Hg. Secondly, standardization assumes that

there is a linear association between blood pressure reduction and cardiovascular

outcomes, which may not be the case in this blood pressure interval and may also be

different for different outcomes. If indeed the association between BP reduction and

cardiovascular event reduction were linear, one would expect decreased heterogeneity

with standardization. Our previous results indicate that standardization increases

heterogeneity and makes analyses highly sensitive to choice of statistical methods.16

This is probably due to amplification of differences not related to BP lowering,

paradoxically making standardized results less blood pressure-dependent. Thirdly,

standardization of standard errors, which was applied in one of the referred meta-

analyses, disrupts the association between number of events within trials and weight

given to trials in meta-analyses.16,36 For example, the European Working Party on High

Blood Pressure in the Elderly (EWPHE) trial, were given 7.3 % weight the all-cause

Page 16 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



17

mortality analysis, despite contributing with less than 0.3 % of participants.36 Simply

put, standardization makes results less representative of the underlying data.

Although arguments can be made for including target-trials, lumping different

populations and using standardization, all these approaches build on assumptions that

the current analysis does not. If treatment benefit hinges on these assumptions, results

are simply not robust enough to change guidelines for hundreds of millions of people

worldwide. Meta-analyses using non-standardized methods have consistently found that

the effects of antihypertensive treatment are attenuated at lower BP levels.14,40-42 In a

recent paper, we found 22 % reduced risk of MACE if baseline SBP was > 160 mm Hg, 12

% reduced risk in the 140-159 mm Hg SBP range, whereas in trials with baseline SBP

below 140 mm Hg treatment effect was neutral for all efficacy outcomes. These results

are well in line with the third Heart Outcomes Prevention Evaluation (HOPE-3) study,

where 12 705 participants with average baseline BP 138/82 mm Hg were randomized

to candesartan/hydrochlorothiazide combination therapy or matching placebo.25 In fact,

HOPE-3 is the only mega-trial aiming to assess the effect of antihypertensive treatment

against double-blind placebo in mostly treatment naïve normotensive primary

preventive patients. Neither the primary combined endpoints nor individual

cardiovascular outcomes were reduced by treatment. However, there was a significant

interaction between baseline SBP and treatment effect on MACE, with treatment benefit

in the highest SBP tertile but a tendency towards harm in the lowest SBP tertile.

Treatment decisions should always be based on consideration of both benefit and harm.

In situations where interventions are unlikely to be harmful, one may consider

treatment despite weak or conflicting evidence. Unfortunately, randomized clinical

Page 17 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



18

trials, and systematic reviews of such trials, show incriminating signs of harm for

antihypertensive treatment at BP levels now recommended in guidelines. In people with

diabetes mellitus, we have previously shown that BP-lowering treatment at SBP levels <

140 mm Hg is associated with 15 % increased risk of cardiovascular death.40 Further

down the ladder of seriousness and irreversibility comes an increased risk of chronic

kidney disease,43 acute kidney injury,44 as well as hypotension-related adverse events

and adverse events leading to treatment discontinuation presented here.

In summary, randomized double-blind placebo-controlled trials do not support primary

preventive BP-lowering in the 130-140 mm Hg SBP range. Such treatment does not

affect all-cause mortality or incident cardiovascular disease, but increases the risk of

adverse events. In people with previous CAD, treatment may reduce the risk of all-cause

mortality and MACE, at the cost of more pronounced risk increase for adverse events. In

CAD patients, therefore, benefits should be balanced against potential harms for

individual patients.

Page 18 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



19

Acknowledgements

Ethical approval: No ethical approval was obtained for this study since it only used

aggregated data from previously published studies.

Author Contributions: Both authors contributed equally to the planning, conduct and

reporting of the work described in this article. MB takes responsibility for the overall

content as guarantors, and attests that both authors meet authorship criteria and that no

others meeting the criteria have been omitted.

Conflict of Interest Disclosures: All authors have completed the ICMJE uniform

disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any

organisation for the submitted work; no financial relationships with any organisations

that might have an interest in the submitted work in the previous three years; no other

relationships or activities that could appear to have influenced the submitted work.

Funding/Support: This study was supported by the Avtal om Läkarutbildning och

medicinsk Forskning (ALF) agreement (for medical education and research) from

Västerbotten County Council; and by the Heart Foundation of Northern Sweden.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of

the study; collection, management, analysis, and interpretation of the data; preparation,

review, or approval of the manuscript; and decision to submit the manuscript for

publication.

Page 19 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



20

Transparency statement: The guarantor affirms that the manuscript is an honest,

accurate, and transparent account of the study being reported; that no important

aspects of the study have been omitted; and that any discrepancies from the study as

originally planned (and, if relevant, registered) have been explained.

Data sharing: This study analyzed previously published data that are available to

readers through the cited references. All data used for outcome analyses are presented

in the article or its online supplement.

Licence for publication: The corresponding author has the right to grant on behalf of

all authors, and does grant on behalf of all authors, a worldwide licence to the Publishers

and its licensees in perpetuity, in all forms, formats and media (whether known now or

created in the future), to i) publish, reproduce, distribute, display and store the

Contribution, ii) translate the Contribution into other languages, create adaptations,

reprints, include within collections and create summaries, extracts and/or, abstracts of

the Contribution, iii) create any other derivative work(s) based on the Contribution, iv)

to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links

from the Contribution to third party material where-ever it may be located; and, vi)

licence any third party to do any or all of the above.

Page 20 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



21

References

1. Pfeffer MA, McMurray JJ. Lessons in Uncertainty and Humility - Clinical

Trials Involving Hypertension. N Engl J Med 2016; 375(18): 1756-66.

2. Weber MA, Schiffrin EL, White WB, et al. Clinical Practice Guidelines for the

Management of Hypertension in the Community A Statement by the American Society of

Hypertension and the International Society of Hypertension. J Hypertens 2014; 32(1): 3-

15.

3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for

themanagement of arterial hypertension The Task Force for the management ofarterial

hypertension of the European Society ofHypertension (ESH) and of the European

Society of Cardiology (ESC). J Hypertens 2013; 31(7): 1281-357.

4. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the

Management of High Blood Pressure in Adults Report From the Panel Members

Appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5): 507-20.

5. Whelton PK, Carey RM, Aronow WS, et al. 2017

ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the

Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A

Report of the American College of Cardiology/American Heart Association Task Force on

Clinical Practice Guidelines. Hypertension 2017.

6. Williams B, Mancia G, et al. 2018 ESC/ESH Hypertension Guidelines. J

Hypertens; 2018 (in press).

7. Wright JT, Williamson JD, Whelton PK, et al. A Randomized Trial of

Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015; 373(22): 2103-

16.

8. Reboussin DM, Allen NB, Griswold ME, et al. Systematic Review for the

2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for

the Prevention, Detection, Evaluation, and Management of High Blood Pressure in

Adults: A Report of the American College of Cardiology/American Heart Association

Task Force on Clinical Practice Guidelines. Hypertension 2017.

9. Higgins JPT, Green S, Cochrane Collaboration. Cochrane handbook for

systematic reviews of interventions. Chichester, West Sussex ; Hoboken NJ: Wiley-

Blackwell; 2008.

10. Savović J, Jones HE, Altman DG, et al. Influence of reported study design

characteristics on intervention effect estimates from randomized, controlled trials. Ann

Intern Med 2012; 157(6): 429-38.

11. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting

systematic reviews and meta-analyses of studies that evaluate healthcare interventions:

explanation and elaboration. BMJ 2009; 339: 37.

12. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the

diagnosis and treatment of acute and chronic heart failure 2012 The Task Force for the

Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European

Society of Cardiology. Developed in collaboration with the Heart Failure Association

(HFA) of the ESC. Eur Heart J 2012; 33(14): 1787-847.

13. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute

myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J

2012; 33(20): 2569-619.

Page 21 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



22

14. Brunström M, Carlberg B. Association of Blood Pressure Lowering With

Mortality and Cardiovascular Disease Across Blood Pressure Levels: A Systematic

Review and Meta-analysis. JAMA Intern Med 2018; 178(1): 28-36.

15. Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's

tool for assessing risk of bias in randomised trials. BMJ 2011; 343.

16. Brunström M, Carlberg B. Standardization according to blood pressure

lowering in meta-analyses of antihypertensive trials: comparison of three

methodological approaches. J Hypertens 2018; 36(1): 4-15.

17. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in

meta-analyses of controlled trials with binary endpoints. Stat Med 2006; 25(20): 3443-

57.

18. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine

on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364(9437): 849-57.

19. Yusuf S, Healey JS, Pogue J, et al. Irbesartan in Patients with Atrial

Fibrillation. N Engl J Med 2011; 364(10): 928-38.

20. Parving HH, Brenner BM, McMurray JJV, et al. Cardiorenal End Points in a

Trial of Aliskiren for Type 2 Diabetes. N Engl J Med 2012; 367(23): 2204-13.

21. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose

metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness:

Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study

(BCAPS). Circulation 2001; 103(13): 1721-6.

22. Bosch J, Yusuf S, Gerstein HC, et al. Effect of ramipril on the incidence of

diabetes. N Engl J Med 2006; 355(15): 1551-62.

23. Fox KM, Investigators EtOrocewPiscAd. Efficacy of perindopril in reduction

of cardiovascular events among patients with stable coronary artery disease:

randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).

Lancet 2003; 362(9386): 782-8.

24. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-

enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med

2000; 342(3): 145-53.

25. Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-Pressure Lowering in

Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med 2016.

26. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The Effect Of Angiotensin-

Converting Enzyme-Inhibition On Diabetic Nephropathy. N Engl J Med 1993; 329(20):

1456-62.

27. McMurray JJ, Holman RR, Haffner SM, et al. Effect of valsartan on the

incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362(16): 1477-90.

28. MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebo-controlled

trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary

or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of

Atherosclerosis with Ramipril. J Am Coll Cardiol 2000; 36(2): 438-43. 29. Braunwald E, Pfeffer MA, Domanski M, et al. Angiotensin-converting-

enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351(20): 2058-

68.

30. Luders S, Schrader J, Berger J, et al. The PHARAO study: prevention of

hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients

with high-normal blood pressure - a prospective, randomized, controlled prevention

trial of the German Hypertension League. J Hypertens 2008; 26(7): 1487-96.

Page 22 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



23

31. Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and

pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation

2004; 110(18): 2809-16.

32. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of

enalapril to attenuate decline in renal function in normotensive, normoalbuminuric

patients with type 2 diabetes mellitus - A randomized, controlled trial. Ann Intern Med

1998; 128(12): 982-+.

33. Haller H, Ito S, Izzo JL, et al. Olmesartan for the Delay or Prevention of

Microalbuminuria in Type 2 Diabetes. N Engl J Med 2011; 364(10): 907-17.

34. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering

and angiotensin-converting enzyme inhibition on coronary atherosclerosis - The

Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000;

102(15): 1748-54. 35. Fried LF, Emanuele N, Zhang JH, et al. Combined Angiotensin Inhibition for

the Treatment of Diabetic Nephropathy. N Engl J Med 2013; 369(20): 1892-903.

36. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention

of cardiovascular disease and death: a systematic review and meta-analysis. Lancet

2016; 387(10022): 957-67.

37. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on

outcome incidence in hypertension: 7. Effects of more vs. less intensive blood pressure

lowering and different achieved blood pressure levels - updated overview and meta-

analyses of randomized trials. J Hypertens 2016; 34(4): 613-22.

38. Rosendorff C, Lackland DT, Allison M, et al. Treatment of Hypertension in

Patients With Coronary Artery Disease. J Am Coll Cardiol 2015; 65(18): 1998-2038.

39. Sipahi I, Tuzcu EM, Schoenhagen P, et al. Effects of normal, pre-

hypertensive, and hypertensive blood pressure levels on progression of coronary

atherosclerosis. J Am Coll Cardiol 2006; 48(4): 833-8.

40. Brunström M, Carlberg B. Effect of antihypertensive treatment at different

blood pressure levels in patients with diabetes mellitus: systematic review and meta-

analyses. BMJ 2016; 352: i717.

41. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood Pressure Targets in

Subjects With Type 2 Diabetes Mellitus/Impaired Fasting Glucose Observations From

Traditional and Bayesian Random-Effects Meta-Analyses of Randomized Trials.

Circulation 2011; 123(24): 2799-+.

42. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood

Pressure Lowering in Type 2 Diabetes A Systematic Review and Meta-analysis. JAMA

2015; 313(6): 603-15.

43. Beddhu S, Greene T, Boucher R, et al. Intensive systolic blood pressure

control and incident chronic kidney disease in people with and without diabetes

mellitus: secondary analyses of two randomised controlled trials. Lancet Diabetes

Endocrinol 2018; 6(7): 555-63.

44. Rocco MV, Sink KM, Lovato LC, et al. Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention

Trial (SPRINT). Am J Kidney Dis 2018; 71(3): 352-61.

Page 23 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



24

Table 1. Study characteristics

Acronym

(year)

Participants

(n, age, sex)

Co-

morbidity

Intervention/

Control

Baseline

SBP/DBP

(mm Hg)

SBP/DBP

difference

(mm Hg)

ACTION

(2004)

7665

63 years

21 % female

100 % CAD

14 % DM

Nifedipine

60 mg

vs. placebo

137.5/

79.8

5.7/ 3.0

ACTIVE I

(2011)

9016

70 years

29 % female

36 % CAD

20 % DM

100 % AF

Irbesartan

300 mg

vs. placebo

138.3/

82.4

2.9/ 1.9

ALTITUDE

(2012)

8561

64 years

32 % female

26 % CAD

100 % DM

98 % CKD

Aliskiren

300 mg

vs. placebo

137.3/

74.2

1.3/ 0.6

BCAPS

(2001)

793

62 years

55 % female

4 % CAD

3 % DM

All had

carotid

plaques

Metoprolol

CR/XL 25 mg

vs. placebo

138.9/

84.7

1.3/ -

DREAM

(2006)

5269

55 years

59 % female

0 % CAD

0 % DM

All had

IGT/IFG

Ramipril

15 mg

vs. placebo

136/

83.4

4.3/ 2.7

EUROPA

(2003)

12 218

60 years

15 % female

100 % CAD

12 % DM

Perindopril

8 mg

vs. placebo

137/ 82 5/ 2

HOPE

(2000)

9297

66 years

27 % female

81 % CAD

38 % DM

Ramipril

10 mg

vs. placebo

139/ 79 3/ 2*

HOPE-3

(2016)

12 705

66 years

46 % female

0 % CAD

6 % DM

Candesartan/

HCTZ

16/12.5 mg

vs. placebo

138.1/

81.9

6/ 3

Lewis (1993)

409 35 years

47 % female

100 % DM (type 1)

All with

nephropathy

Captopril 75 mg

vs. placebo

138.5/ 85.5

1.5/ 2.5

NAVIGATOR

(2010)

9306

64 years

51 % female

24 % CAD

0 % DM

100 % IGT

Valsartan

160 mg

vs. placebo

139.7/

82.6

2.8/ 1.4

PART-2

(2000)

617

61 years

18 % female

68 % CAD

(100 % CVD)

9 % DM

Ramipril

5-10 mg

vs. placebo

133/ 79 5.5/ 4

PEACE

(2004)

8290

64 years

18 % female

100 % CAD

17 % DM

Trandolapril

4 mg

vs. placebo

133/ 78 3.0/ 1.2

PHARAO

(2008)

1008

62 years

52 % female

6 % CAD

13 % DM

Ramipril

5 mg

vs. placebo

134.4/

83.6

2.8/ 0.9

Page 24 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



25

PREVEND-IT

(2004)

864

51 years

35 % female

3 % CAD

3 % DM

Fosinopril

20 mg

vs. placebo

130/ 76 3/ 3

Ravid

(1998)

194

55 years

51 % female

0 % CAD

100 % DM

Enalapril

10 mg

vs. placebo

MAP 97 -/ -

ROADMAP

(2011)

4447

58 years

54 % female

25 % CAD

100 % DM

Olmesartan

40 mg

vs. placebo

136.5/

80.5

3.1/ 1.9

SCAT

(2000)

460

61 years

11 % female

100 % CAD

11 % DM

Enalapril

10 mg

vs. placebo

130/ 77.5 5.2/ 3.3

VA-NEPHRON

(2013)

1448

65 years

0.3 % female

23 % CAD

100 % DM

with nephro-

pathy

Losartan/

lisinopril

100/10-40 mg

vs. losartan

100 mg

137.0/

72.7

1.5/ 1.0

* A sub-study assessing ABPM found larger BP differences between groups during

follow-up, indicating potentially underestimated BP differences in the main publication.

SBP = systolic blood pressure. DBP = diastolic blood pressure. CAD = coronary artery

disease. DM = diabetes mellitus. AF = atrial fibrillation. CKD = chronic kidney disease.

IGT = impaired glucose tolerance. IFG = impaired fasting glucose. HCTZ =

hydrochlorothiazide. MAP = mean arterial pressure.

Page 25 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



26

Table 2. Secondary outcomes

RR = relative risk. CI = confidence interval. AEs = adverse events

Primary prevention trials Coronary artery disease trials

Trials/

participants/

events (n)

RR (95 % CI) I2 (%)

Trials/

participants/

events (n)

RR (95 % CI) I2 (%)

Efficacy

outcomes

Cardiovascular

mortality 8 / 49 685 / 2390 1.07 (0.95-1.21) 27.3 5 / 37 589 / 1802 0.86 (0.74-1.00) 55.7

Myocardial

infarction 8 / 46 682 / 1092 1.03 (0.91-1.15) 0.0 5 / 29 893 / 2367 0.83 (0.72-0.97) 60.0

Stroke 9 / 47 546 / 1536 0.89 (0.73-1.09) 52.9 6 / 38 049 / 943 0.79 (0.66-0.94) 36.6

Heart failure 6 / 44 881 / 1903 0.90 (0.81-1.00) 17.7 5 / 37 589 / 957 0.76 (0.67-0.86) 0.0

Safety

outcomes Hypotension-

related AEs 6 / 44 058 / 5141 1.71 (1.32-2.22) 90.3 3 / 28 817 / 793 1.63 (1.01-2.63) 85.9

Renal

impairment 8 / 49 627 / 992 1.20 (0.93-1.55) 71.6 1 / 12 215 / 36 1.25 (0.65-2.41) -

Page 26 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

on October 28, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-026686 on 30 September 2019. Downloaded from



27

Figure legends

Figure 1 – Treatment effect on primary outcomes in primary prevention. CI =

confidence interval.

Figure 2 – Treatment effect on primary outcomes in coronary artery disease trials.

CI = confidence interval.

Page 27 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



Figure 1 – Treatment effect on primary outcomes in primary prevention. CI = confidence interval.

1057x793mm (72 x 72 DPI)

Page 28 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



Figure 2 – Treatment effect on primary outcomes in coronary artery disease trials. CI = confidence interval.

1057x793mm (72 x 72 DPI)

Page 29 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



ONLINESUPPLEMENT

Benefitsandharmsoflowerbloodpressuretreatmenttargets–systematicreviewandmeta-analysisofrandomizedplacebo-

controlledtrials

PostdocresearcherMattiasBrunströmMD,PhDAssociateProfessorBoCarlbergMD,PhD

DepartmentofPublicHealthandClinicalMedicine

UmeåUniversityUmeå,Sweden

EMETHODS-SEARCHSTRATEGYFORPREVIOUSSYSTEMATICREVIEW....................................................................2EFIGURE1-PRISMAFLOWCHART................................................................................................................................3EFIGURE2–FORESTPLOTFORCARDIOVASCULARMORTALITY................................................................................4EFIGURE3–FORESTPLOTFORMYOCARDIALINFARCTION........................................................................................5EFIGURE4–FORESTPLOTFORSTROKE.........................................................................................................................6EFIGURE5–FORESTPLOTFORHEARTFAILURE...........................................................................................................7EFIGURE6–FORESTPLOTFORHYPOTENSION-RELATEDAES..................................................................................8EFIGURE7–FORESTPLOTFORRENALIMPAIRMENT...................................................................................................9EFIGURE8–SENSITIVITYANALYSISEXCLUDINGTRIALSNOTREACHING<130MMHG...................................10EFIGURE9–SENSITIVITYANALYSISEXCLUDINGTRIALSINPEOPLEWITHDIABETES........................................11EFIGURE10–SENSITIVITYANALYSISEXCLUDINGTRIALSOFDUALRAAS-INHIBITION....................................12EFIGURE11–SENSITIVITYANALYSISEXCLUDINGTRIALSINPEOPLEWITHHYPERTENSION............................13EFIGURE12–SENSITIVITYANALYSISRESTRICTEDTOTRIALSINPEOPLEWITHHYPERTENSION....................14EFIGURE13–PRIMARYPREVENTIVETRIALSSTRATIFIEDBY10-YEARCARDIOVASCULARRISK....................15EFIGURE14-LOSTTOFOLLOW-UPIMPUTEDASEVENT-FREE...............................................................................17EFIGURE15-LOSTTOFOLLOW-UPIMPUTEDASHAVINGANEVENT.....................................................................18EFIGURE16-ADHOCSENSITIVITYANALYSESBASEDONRISKOFBIASASSESSMENT........................................19EFIGURE17–FUNNELPLOTFORALL-CAUSEMORTALITY......................................................................................20EFIGURE18–FUNNELPLOTFORMAJORCARDIOVASCULAREVENTS....................................................................20EFIGURE19–FUNNELPLOTFORADVERSEEVENTSLEADINGTODISCONTINUATION.......................................21EFIGURE20–FUNNELPLOTFORCARDIOVASCULARMORTALITY..........................................................................21EFIGURE21–FUNNELPLOTFORMYOCARDIALINFARCTION.................................................................................22EFIGURE22–FUNNELPLOTFORSTROKE..................................................................................................................22EFIGURE23–FUNNELPLOTFORHEARTFAILURE....................................................................................................23EFIGURE24–FUNNELPLOTFORHYPOTENSION-RELATEDADVERSEEVENTS....................................................23EFIGURE25–FUNNELPLOTFORRENALIMPAIRMENT............................................................................................24ETABLE1–STUDIESEXCLUDEDDUETOHIGHRISKOFBIAS...................................................................................25ETABLE2-ABSOLUTERISKOFMACEINPRIMARYPREVENTIVETRIALS............................................................26ETABLE3-RISKOFBIASTABLE...................................................................................................................................27ETABLE4-HYPOTENSION-RELATEDADVERSEEVENTS..........................................................................................28ERESULTS-RISKOFBIASASSESSMENTANDDESCRIPTION......................................................................................29EREFERENCES...................................................................................................................................................................30

Page 30 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



2

eMethods - Search strategy for previous systematic review

Theprevioussystematicreviewusedatwo-stageapproach.First,wesearchedforsystematicreviewsofrandomizedcontrolledtrialsassessingantihypertensivetreatment.Alltrialsincludedinanyprevioussystematicreviewwerejudgedinfulltextagainstoureligibilitycriteria.Wethenperformedanadditionalsearchforrandomizedcontrolledtrialspublishedafterthelatestprevioussearch(withafewmonthsoverlaptoaccountfortimelaginindexing).SearchstrategysystematicreviewsWeusedthephrase("bloodpressurelowering"OR"blood-pressurelowering"OR"bloodpressure-lowering"ORantihypertensive)AND(mortalityORmyocardialORstroke)inalldatabases,addingthefilterformeta-analysesinPubMed.ThetitlesoftheretrievedarticleswerebrowsedtoidentifyreviewsconcerningtheeffectofBPloweringondeath,cardiovasculareventsandrenaldisease.Reviewsconcerningtreatmentofotherconditions,effectsofspecificagents,ortheeffectofBPloweringonotheroutcomes,werediscarded.Allrandomizedcontrolledtrialsincludedinanyofthereviewsdeemedrelevantwereretrievedinfulltextandjudgedaccordingtotheaboveeligibilitycriteria.SearchstrategyforrandomizedcontrolledtrialsWeusedthephrase("bloodpressurelowering"OR"blood-pressurelowering"OR"bloodpressure-lowering"ORantihypertensive)AND(mortalityORmyocardialORstroke),adding("2015/11/01"[Date–Publication]:"3000"[Date–Publication])tothePubMedsearchandlimitingtheCENTRALsearchto2015-2017.WealsoperformedanalternativePubMedsearch,usingthephrase(("bloodpressurelowering"OR"blood-pressurelowering"OR"bloodpressure-lowering"ORantihypertensive)AND("2015/11/01"[Date-Publication]:"3000"[Date-Publication]))withRCTfilter.

Page 31 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



3

eFigure 1 - PRISMA flow chart

CENTRAL=CochraneCentralRegisterforControlledTrials.MI=myocardialinfarction.CHF=congestiveheartfailure.LVD=leftventriculardysfunction.BP=bloodpressure.

Primaryrecordsscreenedby/tles:1024

-PubMed:841-CENTRAL:183

Numberoftrialsincludedinourfinal

analyses:18

Trialsiden/fiedthroughprevioussystema/c

review:220

Trialsassessedbyabtratcs:21

Trialsincludedfromprimarysearchfor

trials:0

Trialsexcluded:201-  46trialscomparingagents-  60MI/CHF/LVDtrials-  31trialsofinsufficientsize-  9trialswithhighriskofbias-  4trialswithoutBPor

outcomedata-  53trialsoutsideBPlimits-  2trialswithopen-label

targetsTrialsincludedfrompreviousreview:18

Page 32 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



4

eFigure 2 – Forest plot for cardiovascular mortality

CV=cardiovascular.Random-effectsmetaregressionforinteraction(p=0.047)

NOTE: Weights are from random effects analysis

.

.

Primary prevention

ACTIVE I

ALTITUDE

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT

ROADMAP

Subtotal (I-squared = 27.3%, p = 0.211)

Coronary artery disease

ACTION

EUROPA

HOPE

PART-2

PEACE


acronym

Study

666

246

12

155

128

0

5

15

178

215

282

8

146

treated

deaths

CV

4498

4151

2571

6291

4194

505

431

2182

3644

6107

4645

308

4092

treated (n)

Participants

646

215

10

170

116

0

3

3

177

249

377

18

152

control

deaths

CV

4478

4188

2593

6301

4207

503

433

2159

3661

6108

4652

308

4064

control (n)

Participants

1.03 (0.93, 1.13)

1.15 (0.97, 1.38)

1.21 (0.52, 2.80)

0.91 (0.74, 1.13)

1.11 (0.86, 1.42)

1.00 (0.02, 50.10)

1.67 (0.40, 6.96)

4.95 (1.43, 17.06)

1.07 (0.95, 1.20)

1.01 (0.82, 1.24)

0.86 (0.72, 1.03)

0.75 (0.65, 0.87)

0.44 (0.20, 1.01)

0.95 (0.76, 1.19)

0.86 (0.74, 1.00)

Risk (95% CI)

Relative

38.29

23.73

1.86

18.91

15.60

0.09

0.66

0.87

100.00

22.73

25.08

28.25

3.05

20.90

100.00

Weight

%

1.03 (0.93, 1.13)

1.15 (0.97, 1.38)

1.21 (0.52, 2.80)

0.91 (0.74, 1.13)

1.11 (0.86, 1.42)

1.00 (0.02, 50.10)

1.67 (0.40, 6.96)

4.95 (1.43, 17.06)

1.07 (0.95, 1.20)

1.01 (0.82, 1.24)

0.86 (0.72, 1.03)

0.75 (0.65, 0.87)

0.44 (0.20, 1.01)

0.95 (0.76, 1.19)

0.86 (0.74, 1.00)

Risk (95% CI)

Relative

38.29

23.73

1.86

18.91

15.60

0.09

0.66

0.87

100.00

22.73

25.08

28.25

3.05

20.90

100.00

Weight

%

Favours treatment Favours no treatment 1.5 2

Cardiovascular mortality

Page 33 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



5

eFigure 3 – forest plot for myocardial infarction

MI=myocardialinfarction.Random-effectsmetaregressionforinteraction(p=0.061)


.

.

Primary prevention

ACTIVE I

ALTITUDE

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

VA NEPHRON



ACTION

EUROPA

HOPE

PART-2

SCAT


acronym

Study

143

147

3

13

52

138

4

52

267

320

459

22

8

treated

MI

4498

4151

396

2571

6291

4194

505

704

3644

6107

4645

308

229

treated (n)

Participants

135

142

5

11

62

140

5

40

257

418

570

33

13

control

MI

4478

4188

397

2593

6301

4207

503

705

3661

6108

4652

308

231

control (n)

Participants

1.05 (0.84, 1.33)

1.04 (0.83, 1.31)

0.60 (0.14, 2.50)

1.19 (0.53, 2.66)

0.84 (0.58, 1.21)

0.99 (0.78, 1.25)

0.80 (0.22, 2.95)

1.30 (0.87, 1.94)

1.03 (0.91, 1.15)

1.04 (0.88, 1.23)

0.77 (0.66, 0.88)

0.81 (0.72, 0.91)

0.67 (0.40, 1.12)

0.62 (0.26, 1.47)

0.83 (0.72, 0.97)

Risk (95% CI)

Relative

25.49

26.61

0.67

2.13

10.15

25.56

0.80

8.59

100.00

27.34

30.01

32.86

6.98

2.81

100.00

Weight

%

1.05 (0.84, 1.33)

1.04 (0.83, 1.31)

0.60 (0.14, 2.50)

1.19 (0.53, 2.66)

0.84 (0.58, 1.21)

0.99 (0.78, 1.25)

0.80 (0.22, 2.95)

1.30 (0.87, 1.94)

1.03 (0.91, 1.15)

1.04 (0.88, 1.23)

0.77 (0.66, 0.88)

0.81 (0.72, 0.91)

0.67 (0.40, 1.12)

0.62 (0.26, 1.47)

0.83 (0.72, 0.97)

Risk (95% CI)

Relative

25.49

26.61

0.67

2.13

10.15

25.56

0.80

8.59

100.00

27.34

30.01

32.86

6.98

2.81

100.00

Weight

%


Myocardial infarction

Page 34 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



6

eFigure 4 – forest plot for stroke

Random-effectsmetaregressionforinteraction(p=0.329)


.

.

Primary prevention

ACTIVE I

ALTITUDE

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT

VA NEPHRON



ACTION

EUROPA

HOPE

PART-2

PEACE

SCAT


acronym

Study

379

147

1

4

75

105

3

1

18

77

98

156

7

71

2

treated

Stroke

4498

4151

396

2571

6291

4194

505

431

704

3644

6107

4645

308

4092

229

treated (n)

Participants

411

122

7

8

94

132

1

10

18

99

102

226

4

92

9

control

Stroke

4478

4188

397

2593

6301

4207

503

433

705

3661

6108

4652

308

4064

231

control (n)

Participants

0.92 (0.80, 1.05)

1.22 (0.96, 1.54)

0.14 (0.02, 1.16)

0.50 (0.15, 1.67)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

2.99 (0.31, 28.63)

0.10 (0.01, 0.78)

1.00 (0.53, 1.91)

0.89 (0.73, 1.09)

0.78 (0.58, 1.05)

0.96 (0.73, 1.27)

0.69 (0.57, 0.84)

1.75 (0.52, 5.92)

0.77 (0.56, 1.04)

0.22 (0.05, 1.03)

0.79 (0.66, 0.94)

Risk (95% CI)

Relative

26.99

21.55

0.90

2.59

18.17

20.67

0.78

0.94

7.41

100.00

21.56

23.25

31.15

2.11

20.56

1.37

100.00

Weight

%

0.92 (0.80, 1.05)

1.22 (0.96, 1.54)

0.14 (0.02, 1.16)

0.50 (0.15, 1.67)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

2.99 (0.31, 28.63)

0.10 (0.01, 0.78)

1.00 (0.53, 1.91)

0.89 (0.73, 1.09)

0.78 (0.58, 1.05)

0.96 (0.73, 1.27)

0.69 (0.57, 0.84)

1.75 (0.52, 5.92)

0.77 (0.56, 1.04)

0.22 (0.05, 1.03)

0.79 (0.66, 0.94)

Risk (95% CI)

Relative

26.99

21.55

0.90

2.59

18.17

20.67

0.78

0.94

7.41

100.00

21.56

23.25

31.15

2.11

20.56

1.37

100.00

Weight

%


Stroke

Page 35 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



7

eFigure 5 – forest plot for heart failure



.

.

Primary prevention

ACTIVE I

ALTITUDE

DREAM

HOPE-3

NAVIGATOR

VA NEPHRON



ACTION

EUROPA

HOPE

PART-2

PEACE


acronym

Study

482

205

12

21

91

89

86

63

141

7

115

treated

failure

Heart

4498

4151

2571

6291

4194

704

3644

6107

4645

308

4092

treated (n)

Participants

551

219

4

29

94

106

121

103

160

9

152

control

failure

Heart

4478

4188

2593

6301

4207

705

3661

6108

4652

308

4064

control (n)

Participants

0.87 (0.78, 0.98)

0.94 (0.78, 1.14)

3.03 (0.98, 9.37)

0.73 (0.41, 1.27)

0.97 (0.73, 1.29)

0.84 (0.65, 1.09)

0.90 (0.81, 1.00)

0.71 (0.54, 0.94)

0.61 (0.45, 0.84)

0.88 (0.71, 1.10)

0.78 (0.29, 2.06)

0.75 (0.59, 0.95)

0.76 (0.67, 0.86)

Risk (95% CI)

Relative

44.53

24.51

0.90

3.54

12.30

14.23

100.00

21.50

16.47

32.21

1.68

28.13

100.00

Weight

%

0.87 (0.78, 0.98)

0.94 (0.78, 1.14)

3.03 (0.98, 9.37)

0.73 (0.41, 1.27)

0.97 (0.73, 1.29)

0.84 (0.65, 1.09)

0.90 (0.81, 1.00)

0.71 (0.54, 0.94)

0.61 (0.45, 0.84)

0.88 (0.71, 1.10)

0.78 (0.29, 2.06)

0.75 (0.59, 0.95)

0.76 (0.67, 0.86)

Risk (95% CI)

Relative

44.53

24.51

0.90

3.54

12.30

14.23

100.00

21.50

16.47

32.21

1.68

28.13

100.00

Weight

%


Heart failure

Page 36 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



8

eFigure 6 – forest plot for hypotension-related AEs

AEs=adverseeventsRandom-effectsmetaregressionforinteraction(p=0.798)


.

.

Primary prevention

ACTIVE I

ALTITUDE

HOPE-3

NAVIGATOR

ROADMAP

VA NEPHRON



ACTION

EUROPA

HOPE


acronym

Study

127

519

217

1964

58

11

304

60

88

treated

Hypotension

4498

4151

6291

4194

2182

704

3644

6107

4645

treated (n)

Participants

64

357

130

1680

6

8

254

17

70

control

Hypotension

4478

4188

6301

4207

2159

705

3661

6108

4652

control (n)

Participants

1.98 (1.47, 2.66)

1.47 (1.29, 1.67)

1.67 (1.35, 2.07)

1.17 (1.12, 1.23)

9.56 (4.14, 22.12)

1.38 (0.56, 3.40)

1.71 (1.32, 2.22)

1.20 (1.02, 1.41)

3.53 (2.06, 6.04)

1.26 (0.92, 1.72)

1.63 (1.01, 2.63)

Risk (95% CI)

Relative

18.54

23.11

20.98

24.26

6.92

6.19

100.00

38.71

26.75

34.53

100.00

Weight

%

1.98 (1.47, 2.66)

1.47 (1.29, 1.67)

1.67 (1.35, 2.07)

1.17 (1.12, 1.23)

9.56 (4.14, 22.12)

1.38 (0.56, 3.40)

1.71 (1.32, 2.22)

1.20 (1.02, 1.41)

3.53 (2.06, 6.04)

1.26 (0.92, 1.72)

1.63 (1.01, 2.63)

Risk (95% CI)

Relative

18.54

23.11

20.98

24.26

6.92

6.19

100.00

38.71

26.75

34.53

100.00

Weight

%


Hypotension-related AE

Page 37 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



9

eFigure 7 – forest plot for renal impairment



.

.

Primary prevention

ACTIVE I

ALTITUDE

DREAM

HOPE-3

Lewis -93

NAVIGATOR

ROADMAP

VA NEPHRON



EUROPA

Subtotal (I-squared = .%, p = .)

acronym

Study

43

65

99

32

25

136

5

130

20

treated

impairment

Renal

4498

4151

2571

6291

205

4194

2182

704

6107

treated (n)

Participants

24

54

88

20

43

146

2

80

16

control

impairment

Renal

4478

4188

2593

6301

200

4207

2159

705

6108

control (n)

Participants

1.78 (1.08, 2.93)

1.21 (0.85, 1.74)

1.13 (0.86, 1.50)

1.60 (0.92, 2.80)

0.57 (0.36, 0.89)

0.93 (0.74, 1.18)

2.47 (0.48, 12.74)

1.63 (1.26, 2.11)

1.20 (0.93, 1.55)

1.25 (0.65, 2.41)

1.25 (0.65, 2.41)

Risk (95% CI)

Relative

11.33

14.31

16.03

10.21

12.24

17.16

2.16

16.55

100.00

100.00

100.00

Weight

%

1.78 (1.08, 2.93)

1.21 (0.85, 1.74)

1.13 (0.86, 1.50)

1.60 (0.92, 2.80)

0.57 (0.36, 0.89)

0.93 (0.74, 1.18)

2.47 (0.48, 12.74)

1.63 (1.26, 2.11)

1.20 (0.93, 1.55)

1.25 (0.65, 2.41)

1.25 (0.65, 2.41)

Risk (95% CI)

Relative

11.33

14.31

16.03

10.21

12.24

17.16

2.16

16.55

100.00

100.00

100.00

Weight

%


Discontinuation due to renal impairment

Page 38 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



10

eFigure 8 – Sensitivity analysis excluding trials not reaching < 130 mm Hg


.

.

.

All-cause mortality

DREAM

HOPE-3

PREVEND IT

ROADMAP


Major cardiovascular events

DREAM

HOPE-3

PREVEND IT


AEs leading to discontinuation

HOPE-3

PREVEND IT

ROADMAP


acronym

Study

2571

6291

431

2182

2571

6291

431

6291

431

2182

treated

Participants (n)

2593

6301

433

2159

2593

6301

433

6301

433

2159

control

Participants (n)

31

342

5

26

27

260

18

448

58

85

treated

Events (n)

32

349

4

15

29

279

24

346

18

89

control

Events (n)

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

1.26 (0.34, 4.64)

1.72 (0.91, 3.23)

1.01 (0.88, 1.16)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

0.75 (0.42, 1.37)

0.92 (0.79, 1.07)

1.30 (1.13, 1.49)

3.24 (1.94, 5.40)

0.94 (0.71, 1.26)

1.49 (0.92, 2.41)

Risk (95% CI)

Relative

7.57

86.80

1.07

4.56

100.00

8.54

84.94

6.52

100.00

38.30

27.23

34.48

100.00

Weight

%

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

1.26 (0.34, 4.64)

1.72 (0.91, 3.23)

1.01 (0.88, 1.16)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

0.75 (0.42, 1.37)

0.92 (0.79, 1.07)

1.30 (1.13, 1.49)

3.24 (1.94, 5.40)

0.94 (0.71, 1.26)

1.49 (0.92, 2.41)

Risk (95% CI)

Relative

7.57

86.80

1.07

4.56

100.00

8.54

84.94

6.52

100.00

38.30

27.23

34.48

100.00

Weight

%

Favours treatment Favours control

1.5 2

Primary prevention - restricted to trials reaching < 130 mm Hg


.

.

.

All-cause mortality

EUROPA

PART-2

PEACE

SCAT



EUROPA

PART-2

PEACE

SCAT



EUROPA

PART-2

PEACE


acronym

Study

6107

308

4092

229

6107

308

4092

229

6107

308

4092

treated

Participants (n)

6108

308

4064

231

6108

308

4064

231

6108

308

4064

control

Participants (n)

375

16

299

8

488

29

396

16

224

31

589

treated

Events (n)

420

25

334

11

603

37

420

30

113

3

264

control

Events (n)

0.89 (0.78, 1.02)

0.64 (0.35, 1.17)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.88 (0.80, 0.97)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.84 (0.73, 0.96)

1.98 (1.59, 2.48)

10.33 (3.19, 33.44)

2.22 (1.93, 2.55)

2.33 (1.70, 3.20)

Risk (95% CI)

Relative

53.22

2.62

42.95

1.21

100.00

45.20

8.07

41.38

5.34

100.00

43.46

6.46

50.08

100.00

Weight

%

0.89 (0.78, 1.02)

0.64 (0.35, 1.17)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.88 (0.80, 0.97)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.84 (0.73, 0.96)

1.98 (1.59, 2.48)

10.33 (3.19, 33.44)

2.22 (1.93, 2.55)

2.33 (1.70, 3.20)

Risk (95% CI)

Relative

53.22

2.62

42.95

1.21

100.00

45.20

8.07

41.38

5.34

100.00

43.46

6.46

50.08

100.00

Weight

%


1.5 2

Coronary artery disease - restricted to trials reaching < 130 mm hg

Page 39 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



11

eFigure 9 – sensitivity analysis excluding trials in people with diabetes

Note:NoneofCADtrialswereprimarilyinpeoplewithdiabetes.Hence,nosensitivityanalysiswasperformed.


.

.

.

All-cause mortality

ACTIVE I

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT



ACTIVE I

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT



HOPE-3

NAVIGATOR

PREVEND IT


acronym

Study

4498

396

2571

6291

4194

505

431

4498

396

2571

6291

4194

505

431

6291

4194

431

treated

Participants (n)

4478

397

2593

6301

4207

503

433

4478

397

2593

6301

4207

503

433

6301

4207

433

control

Participants (n)

949

4

31

342

295

5

5

963

5

27

260

375

7

18

448

556

58

treated

Events (n)

929

7

32

349

327

2

4

963

13

29

279

377

6

24

346

531

18

control

Events (n)

1.02 (0.94, 1.10)

0.57 (0.17, 1.94)

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

0.90 (0.78, 1.05)

2.49 (0.49, 12.78)

1.26 (0.34, 4.64)

0.99 (0.93, 1.05)

1.00 (0.92, 1.08)

0.39 (0.14, 1.07)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

0.98 (0.92, 1.04)

1.30 (1.13, 1.49)

1.05 (0.94, 1.17)

3.24 (1.94, 5.40)

1.45 (1.03, 2.02)

Risk (95% CI)

Relative

61.45

0.27

1.65

18.92

17.33

0.15

0.23

100.00

61.80

0.37

1.42

14.17

20.81

0.33

1.09

100.00

39.01

39.86

21.13

100.00

Weight

%

1.02 (0.94, 1.10)

0.57 (0.17, 1.94)

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

0.90 (0.78, 1.05)

2.49 (0.49, 12.78)

1.26 (0.34, 4.64)

0.99 (0.93, 1.05)

1.00 (0.92, 1.08)

0.39 (0.14, 1.07)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

0.98 (0.92, 1.04)

1.30 (1.13, 1.49)

1.05 (0.94, 1.17)

3.24 (1.94, 5.40)

1.45 (1.03, 2.02)

Risk (95% CI)

Relative

61.45

0.27

1.65

18.92

17.33

0.15

0.23

100.00

61.80

0.37

1.42

14.17

20.81

0.33

1.09

100.00

39.01

39.86

21.13

100.00

Weight

%


1.5 2

Primary prevention - excluding diabetes trials

Page 40 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



12

eFigure 10 – sensitivity analysis excluding trials of dual RAAS-inhibition

Note:NoneofCADtrialsweretestingdualRAASinhibition.Hence,nosensitivityanalysiswasperformed.


.

.

.

All-cause mortalityBCAPSDREAMHOPE-3Lewis -93NAVIGATORPHARAOPREVEND ITROADMAPRavid -98Subtotal (I-squared = 0.0%, p = 0.442)

Major cardiovascular eventsBCAPSDREAMHOPE-3NAVIGATORPHARAOPREVEND ITSubtotal (I-squared = 0.0%, p = 0.517)

AEs leading to discontinuationHOPE-3Lewis -93NAVIGATORPREVEND ITROADMAPRavid -98Subtotal (I-squared = 83.3%, p = 0.000)

acronymStudy

396257162912054194505431218291

396257162914194505431

62912054194431218291

treatedParticipants (n)

397259363012004207503433215993

397259363014207503433

63012004207433215993

controlParticipants (n)

431342829555263

527260375718

4483155658853

treatedEvents (n)

7323491432724152

1329279377624

3464653118893

controlEvents (n)

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.90 (0.78, 1.05)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)0.96 (0.87, 1.06)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.87, 1.14)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.96 (0.86, 1.06)

1.30 (1.13, 1.49)0.66 (0.44, 0.99)1.05 (0.94, 1.17)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.16 (0.90, 1.51)

Risk (95% CI)Relative

0.664.1047.031.3843.090.370.582.470.32100.00

0.973.7337.1054.490.862.85100.00

24.2915.7824.8312.9919.632.48100.00

Weight%

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.90 (0.78, 1.05)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)0.96 (0.87, 1.06)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.87, 1.14)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.96 (0.86, 1.06)

1.30 (1.13, 1.49)0.66 (0.44, 0.99)1.05 (0.94, 1.17)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.16 (0.90, 1.51)


0.664.1047.031.3843.090.370.582.470.32100.00

0.973.7337.1054.490.862.85100.00

24.2915.7824.8312.9919.632.48100.00

Weight%


1.5 2

Primary prevention - excluding trials of dual RAAS inhibition

Page 41 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



13

eFigure 11 – sensitivity analysis excluding trials in people with hypertension


.

.

.

All-cause mortalityBCAPSDREAMHOPE-3PHARAOPREVEND ITROADMAPRavid -98Subtotal (I-squared = 0.0%, p = 0.521)

Major cardiovascular eventsBCAPSDREAMHOPE-3PHARAOPREVEND ITSubtotal (I-squared = 0.0%, p = 0.494)

AEs leading to discontinuationHOPE-3PREVEND ITROADMAPRavid -98Subtotal (I-squared = 82.2%, p = 0.001)

acronymStudy

39625716291505431218291

39625716291505431

6291431218291


39725936301503433215993

39725936301503433

6301433215993


43134255263

527260718

44858853

treatedEvents (n)

73234924152

1329279624

34618893

controlEvents (n)

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)1.01 (0.88, 1.16)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.91 (0.78, 1.05)

1.30 (1.13, 1.49)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.45 (0.93, 2.26)


1.197.3984.690.671.044.450.57100.00

2.138.2081.511.906.26100.00

36.1325.0432.246.60100.00

Weight%

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)1.01 (0.88, 1.16)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.91 (0.78, 1.05)

1.30 (1.13, 1.49)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.45 (0.93, 2.26)


1.197.3984.690.671.044.450.57100.00

2.138.2081.511.906.26100.00

36.1325.0432.246.60100.00

Weight%


1.5 2

Primary prevention - excluding previous hypertension


.

.

.

All-cause mortality

EUROPA

HOPE

PEACE

SCAT



EUROPA

HOPE

PEACE

SCAT



EUROPA

HOPE

PEACE


acronym

Study

6107

4645

4092

229

6107

4645

4092

229

6107

4645

4092

treated

Participants (n)

6108

4652

4064

231

6108

4652

4064

231

6108

4652

4064

control

Participants (n)

375

482

299

8

488

651

396

16

224

88

589

treated

Events (n)

420

569

334

11

603

826

420

30

113

70

264

control

Events (n)

0.89 (0.78, 1.02)

0.85 (0.76, 0.95)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.87 (0.81, 0.94)

0.81 (0.72, 0.91)

0.79 (0.72, 0.87)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.83 (0.74, 0.92)

1.98 (1.59, 2.48)

1.26 (0.92, 1.72)

2.22 (1.93, 2.55)

1.82 (1.36, 2.43)

Risk (95% CI)

Relative

31.08

43.12

25.09

0.71

100.00

31.96

36.12

28.74

3.17

100.00

33.53

28.19

38.27

100.00

Weight

%

0.89 (0.78, 1.02)

0.85 (0.76, 0.95)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.87 (0.81, 0.94)

0.81 (0.72, 0.91)

0.79 (0.72, 0.87)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.83 (0.74, 0.92)

1.98 (1.59, 2.48)

1.26 (0.92, 1.72)

2.22 (1.93, 2.55)

1.82 (1.36, 2.43)

Risk (95% CI)

Relative

31.08

43.12

25.09

0.71

100.00

31.96

36.12

28.74

3.17

100.00

33.53

28.19

38.27

100.00

Weight

%


1.5 2

Coronary artery disease - excluding previous hypertension

Page 42 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



14

eFigure 12 – sensitivity analysis restricted to trials in people with hypertension


.

.

.

All-cause mortality

ACTIVE I

ALTITUDE

Lewis -93

NAVIGATOR

VA NEPHRON



ACTIVE I

ALTITUDE

NAVIGATOR

VA NEPHRON



ALTITUDE

Lewis -93

NAVIGATOR

VA NEPHRON


acronym

Study

4498

4151

205

4194

704

4498

4151

4194

704

4151

205

4194

704

treated

Participants (n)

4478

4188

200

4207

705

4478

4188

4207

705

4188

200

4207

705

control

Participants (n)

949

376

8

295

63

963

590

375

134

563

31

556

173

treated

Events (n)

929

358

14

327

60

963

539

377

136

437

46

531

115

control

Events (n)

1.02 (0.94, 1.10)

1.06 (0.92, 1.22)

0.56 (0.24, 1.30)

0.90 (0.78, 1.05)

1.05 (0.75, 1.47)

1.00 (0.93, 1.07)

1.00 (0.92, 1.08)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

0.99 (0.80, 1.22)

1.02 (0.97, 1.08)

1.30 (1.16, 1.46)

0.66 (0.44, 0.99)

1.05 (0.94, 1.17)

1.51 (1.22, 1.86)

1.14 (0.92, 1.42)

Risk (95% CI)

Relative

53.38

22.54

0.69

19.18

4.22

100.00

49.89

26.51

16.80

6.80

100.00

29.81

15.12

30.08

24.99

100.00

Weight

%

1.02 (0.94, 1.10)

1.06 (0.92, 1.22)

0.56 (0.24, 1.30)

0.90 (0.78, 1.05)

1.05 (0.75, 1.47)

1.00 (0.93, 1.07)

1.00 (0.92, 1.08)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

0.99 (0.80, 1.22)

1.02 (0.97, 1.08)

1.30 (1.16, 1.46)

0.66 (0.44, 0.99)

1.05 (0.94, 1.17)

1.51 (1.22, 1.86)

1.14 (0.92, 1.42)

Risk (95% CI)

Relative

53.38

22.54

0.69

19.18

4.22

100.00

49.89

26.51

16.80

6.80

100.00

29.81

15.12

30.08

24.99

100.00

Weight

%


1.5 2

Primary prevention - restricted to previous hypertension


.

.

.

All-cause mortality

ACTION



ACTION



ACTION


acronym

Study

3644

3644

3644

treated

Participants (n)

3661

3661

3661

control

Participants (n)

310

444

389

treated

Events (n)

291

458

172

control

Events (n)

1.07 (0.92, 1.25)

1.07 (0.92, 1.25)

0.97 (0.86, 1.10)

0.97 (0.86, 1.10)

2.27 (1.91, 2.70)

2.27 (1.91, 2.70)

Risk (95% CI)

Relative

100.00

100.00

100.00

100.00

100.00

100.00

Weight

%

1.07 (0.92, 1.25)

1.07 (0.92, 1.25)

0.97 (0.86, 1.10)

0.97 (0.86, 1.10)

2.27 (1.91, 2.70)

2.27 (1.91, 2.70)

Risk (95% CI)

Relative

100.00

100.00

100.00

100.00

100.00

100.00

Weight

%

Favours treatment Favours control 1.5 2

Coronary artery disease - restricted to previous hypertension

Page 43 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



15

eFigure 13 – Primary preventive trials stratified by 10-year cardiovascular risk


.

.

Overall (I-squared = 0.0%, p = 0.566)

PHARAO

Lewis -93


ROADMAP

PREVEND IT

acronym


VA NEPHRON

ACTIVE I

NAVIGATOR

10-year risk < 10 %

Ravid -98

DREAM

BCAPS

HOPE-3

ALTITUDE

Study

10-year risk ≥ 10 %

5

8

26

5

treated

63

949

295

3

31

4

342

376

Deaths

505

205

2182

431

treated (n)

704

4498

4194

91

2571

396

6291

4151

Participants

2

14

15

4

control

60

929

327

2

32

7

349

358

Deaths

503

200

2159

433

control (n)

705

4478

4207

93

2593

397

6301

4188

Participants

1.00 (0.95, 1.06)

2.49 (0.49, 12.78)

0.56 (0.24, 1.30)

0.98 (0.85, 1.13)

1.72 (0.91, 3.23)

1.26 (0.34, 4.64)

Risk (95% CI)

1.01 (0.94, 1.08)

1.05 (0.75, 1.47)

1.02 (0.94, 1.10)

0.90 (0.78, 1.05)

1.53 (0.26, 8.96)

0.98 (0.60, 1.60)

0.57 (0.17, 1.94)

0.98 (0.85, 1.13)

1.06 (0.92, 1.22)

Relative

100.00

0.12

0.44

16.66

0.79

0.18

Weight

83.34

2.77

48.78

13.76

0.10

1.31

0.21

15.02

16.52

%

1.00 (0.95, 1.06)

2.49 (0.49, 12.78)

0.56 (0.24, 1.30)

0.98 (0.85, 1.13)

1.72 (0.91, 3.23)

1.26 (0.34, 4.64)

Risk (95% CI)

1.01 (0.94, 1.08)

1.05 (0.75, 1.47)

1.02 (0.94, 1.10)

0.90 (0.78, 1.05)

1.53 (0.26, 8.96)

0.98 (0.60, 1.60)

0.57 (0.17, 1.94)

0.98 (0.85, 1.13)

1.06 (0.92, 1.22)

Relative

100.00

0.12

0.44

16.66

0.79

0.18

Weight

83.34

2.77

48.78

13.76

0.10

1.31

0.21

15.02

16.52

%


All-cause mortality by 10-year risk


.

.



HOPE-3


Study

DREAM


ALTITUDE

NAVIGATOR

10-year risk < 10 %

PHARAO

PREVEND IT

ACTIVE I

VA NEPHRON

BCAPS

acronym

260

MACE

27

590

375

7

18

963

134

5

treated

6291

Participants

2571

4151

4194

505

431

4498

704

396

treated (n)

279

MACE

29

539

377

6

24

963

136

13

control

6301

Participants

2593

4188

4207

503

433

4478

705

397

control (n)

1.01 (0.96, 1.06)

0.93 (0.79, 1.10)

1.02 (0.97, 1.08)

Relative

0.94 (0.56, 1.58)

0.92 (0.79, 1.07)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

1.00 (0.92, 1.08)

0.99 (0.80, 1.22)

0.39 (0.14, 1.07)

Risk (95% CI)

100.00

10.39

88.02

%

1.06

11.98

23.45

15.12

0.25

0.81

42.41

6.23

0.28

Weight

1.01 (0.96, 1.06)

0.93 (0.79, 1.10)

1.02 (0.97, 1.08)

Relative

0.94 (0.56, 1.58)

0.92 (0.79, 1.07)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

1.00 (0.92, 1.08)

0.99 (0.80, 1.22)

0.39 (0.14, 1.07)

Risk (95% CI)

100.00

10.39

88.02

%

1.06

11.98

23.45

15.12

0.25

0.81

42.41

6.23

0.28

Weight


Major cardiovascular events by 10-year risk

Page 44 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



16


.

.


PREVEND IT



10-year risk < 10 %

HOPE-3


Lewis -93

ROADMAP

Ravid -98

ALTITUDE

VA NEPHRON

NAVIGATOR

acronym

Study

58

448

31

85

3

563

173

556

treated

AEs

431

6291

205

2182

91

4151

704

4194

treated (n)

Participants

18

346

46

89

3

437

115

531

control

AEs

433

6301

200

2159

93

4188

705

4207

control (n)

Participants

1.23 (1.03, 1.47)

3.24 (1.94, 5.40)

1.22 (0.97, 1.52)

1.30 (1.13, 1.49)

1.30 (1.13, 1.49)

0.66 (0.44, 0.99)

0.94 (0.71, 1.26)

1.02 (0.21, 4.93)

1.30 (1.16, 1.46)

1.51 (1.22, 1.86)

1.05 (0.94, 1.17)

Risk (95% CI)

Relative

100.00

7.49

82.49

17.51

17.51

9.57

12.83

1.21

17.97

15.30

18.12

Weight

%

1.23 (1.03, 1.47)

3.24 (1.94, 5.40)

1.22 (0.97, 1.52)

1.30 (1.13, 1.49)

1.30 (1.13, 1.49)

0.66 (0.44, 0.99)

0.94 (0.71, 1.26)

1.02 (0.21, 4.93)

1.30 (1.16, 1.46)

1.51 (1.22, 1.86)

1.05 (0.94, 1.17)

Risk (95% CI)

Relative

100.00

7.49

82.49

17.51

17.51

9.57

12.83

1.21

17.97

15.30

18.12

Weight

%


Adverse events by 10-year risk

Page 45 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



17

eFigure 14 - Lost to follow-up imputed as event-free


.

.

.

All-cause mortalityACTIVE IALTITUDEBCAPSDREAMHOPE-3Lewis -93NAVIGATORPHARAOPREVEND ITROADMAPRavid -98VA NEPHRONSubtotal (I-squared = 0.0%, p = 0.596)

Major cardiovascular eventsACTIVE IALTITUDEBCAPSDREAMHOPE-3NAVIGATORPHARAOPREVEND ITVA NEPHRONSubtotal (I-squared = 0.0%, p = 0.448)

AEs leading to discontinuationALTITUDEHOPE-3Lewis -93NAVIGATORPREVEND ITROADMAPRavid -98VA NEPHRONSubtotal (I-squared = 81.2%, p = 0.000)

acronymStudy

45184274396262363562074631505431223297724

45184274396262363564631505431724

427463562074631431223297724

treatmentrandomized toTotal (n)

44984287397264663492024675503433221597724

44984287397264663494675503433724

428763492024675433221597724

controlrandomized toTotal (n)

94937643134282955526363

963590527260375718134

5634483155658853173

treatedEvents (n)

929358732349143272415260

9635391329279377624136

4373464653118893115

controlEvents (n)

1.02 (0.94, 1.10)1.05 (0.92, 1.21)0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.91 (0.78, 1.06)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.24)1.50 (0.26, 8.78)1.05 (0.75, 1.47)1.00 (0.95, 1.06)

1.00 (0.92, 1.08)1.10 (0.98, 1.22)0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.88, 1.15)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.79, 1.22)1.01 (0.96, 1.06)

1.29 (1.15, 1.45)1.29 (1.13, 1.48)0.66 (0.44, 0.99)1.06 (0.95, 1.18)3.24 (1.94, 5.40)0.95 (0.71, 1.27)1.00 (0.21, 4.83)1.50 (1.22, 1.86)1.23 (1.03, 1.46)


48.8316.520.211.3115.040.4413.680.120.180.790.102.77100.00

43.8423.230.261.0110.0614.640.230.775.94100.00

18.0617.589.4918.207.4112.791.1815.30100.00

Weight%

1.02 (0.94, 1.10)1.05 (0.92, 1.21)0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.91 (0.78, 1.06)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.24)1.50 (0.26, 8.78)1.05 (0.75, 1.47)1.00 (0.95, 1.06)

1.00 (0.92, 1.08)1.10 (0.98, 1.22)0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.88, 1.15)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.79, 1.22)1.01 (0.96, 1.06)

1.29 (1.15, 1.45)1.29 (1.13, 1.48)0.66 (0.44, 0.99)1.06 (0.95, 1.18)3.24 (1.94, 5.40)0.95 (0.71, 1.27)1.00 (0.21, 4.83)1.50 (1.22, 1.86)1.23 (1.03, 1.46)


48.8316.520.211.3115.040.4413.680.120.180.790.102.77100.00

43.8423.230.261.0110.0614.640.230.775.94100.00

18.0617.589.4918.207.4112.791.1815.30100.00

Weight%


1.5 2

Primary prevention - all lost event-free


.

.

.

All-cause mortalityACTIONEUROPAHOPEPART-2PEACESCATSubtotal (I-squared = 31.4%, p = 0.200)

Major cardiovascular eventsACTIONEUROPAHOPEPART-2PEACESCATSubtotal (I-squared = 59.7%, p = 0.029)

AEs leading to discontinuationACTIONEUROPAHOPEPART-2PEACESubtotal (I-squared = 79.1%, p = 0.001)

acronymStudy

3825611046453084158229

3825611046453084158229

3825611046453084158


3840610846523094132231

3840610846523094132231

3840610846523094132


310375482162998

4444886512939616

3892248831589

treatedEvents (n)

2914205692533411

4586038263742030

172113703264

controlEvents (n)

1.07 (0.92, 1.25)0.89 (0.78, 1.02)0.85 (0.76, 0.95)0.64 (0.35, 1.18)0.89 (0.77, 1.03)0.73 (0.30, 1.79)0.90 (0.83, 0.99)

0.97 (0.86, 1.10)0.81 (0.72, 0.91)0.79 (0.72, 0.87)0.79 (0.50, 1.25)0.94 (0.82, 1.07)0.54 (0.30, 0.96)0.85 (0.77, 0.94)

2.27 (1.91, 2.70)1.98 (1.58, 2.48)1.26 (0.92, 1.72)10.37 (3.20, 33.55)2.22 (1.93, 2.55)2.05 (1.62, 2.61)


21.1224.7229.372.0721.750.98100.00

22.3523.3925.794.2321.432.81100.00

25.7823.6719.803.6327.12100.00

Weight%

1.07 (0.92, 1.25)0.89 (0.78, 1.02)0.85 (0.76, 0.95)0.64 (0.35, 1.18)0.89 (0.77, 1.03)0.73 (0.30, 1.79)0.90 (0.83, 0.99)

0.97 (0.86, 1.10)0.81 (0.72, 0.91)0.79 (0.72, 0.87)0.79 (0.50, 1.25)0.94 (0.82, 1.07)0.54 (0.30, 0.96)0.85 (0.77, 0.94)

2.27 (1.91, 2.70)1.98 (1.58, 2.48)1.26 (0.92, 1.72)10.37 (3.20, 33.55)2.22 (1.93, 2.55)2.05 (1.62, 2.61)


21.1224.7229.372.0721.750.98100.00

22.3523.3925.794.2321.432.81100.00

25.7823.6719.803.6327.12100.00

Weight%


1.5 2

Coronary artery disease - all lost event-free

Page 46 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



18

eFigure 15 - lost to follow-up imputed as having an event


.

.

.




acronymStudy

45184274396262363562074631505431223297724

45184274396262363564631505431724

427463562074631431223297724


44984287397264663492024675503433221597724

44984287397264663494675503433724

428763492024675433221597724


969499483407107325576983

983713579325812718154

68651333993581359193

treatedevents (n)Maximum

949457785397167952471679

9836381382327845624155

53639448999181457134

controlevents (n)Maximum

1.02 (0.94, 1.10)1.10 (0.97, 1.23)0.57 (0.17, 1.94)0.99 (0.73, 1.33)1.02 (0.90, 1.17)0.61 (0.28, 1.31)0.93 (0.85, 1.02)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.06 (0.77, 1.46)1.50 (0.56, 4.05)1.05 (0.79, 1.40)1.01 (0.96, 1.05)

1.00 (0.92, 1.08)1.12 (1.02, 1.24)0.39 (0.14, 1.07)0.97 (0.72, 1.32)0.99 (0.85, 1.15)0.97 (0.89, 1.06)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.82, 1.21)1.01 (0.95, 1.07)

1.28 (1.16, 1.43)1.30 (1.15, 1.48)0.67 (0.45, 1.00)1.00 (0.93, 1.08)3.24 (1.94, 5.40)0.92 (0.74, 1.16)1.29 (0.50, 3.31)1.44 (1.19, 1.75)1.20 (1.01, 1.43)


36.0115.870.152.5612.680.3926.950.080.132.240.232.69100.00

28.8721.950.313.2911.7325.410.270.897.28100.00

17.2416.769.3617.737.1014.012.8514.94100.00

Weight%

1.02 (0.94, 1.10)1.10 (0.97, 1.23)0.57 (0.17, 1.94)0.99 (0.73, 1.33)1.02 (0.90, 1.17)0.61 (0.28, 1.31)0.93 (0.85, 1.02)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.06 (0.77, 1.46)1.50 (0.56, 4.05)1.05 (0.79, 1.40)1.01 (0.96, 1.05)

1.00 (0.92, 1.08)1.12 (1.02, 1.24)0.39 (0.14, 1.07)0.97 (0.72, 1.32)0.99 (0.85, 1.15)0.97 (0.89, 1.06)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.82, 1.21)1.01 (0.95, 1.07)

1.28 (1.16, 1.43)1.30 (1.15, 1.48)0.67 (0.45, 1.00)1.00 (0.93, 1.08)3.24 (1.94, 5.40)0.92 (0.74, 1.16)1.29 (0.50, 3.31)1.44 (1.19, 1.75)1.20 (1.01, 1.43)


36.0115.870.152.5612.680.3926.950.080.132.240.232.69100.00

28.8721.950.313.2911.7325.410.270.897.28100.00

17.2416.769.3617.737.1014.012.8514.94100.00

Weight%


1.5 2

Primary prevention - all lost with event


.

.

.




acronymStudy

3825611046453084158229

3825611046453084158229

3825611046453084158


3840610846523094132231

3840610846523094132231

3840610846523094132


491378482163658

6254916512946216

5702278831655


4704205692640211

6376038263848830

351113704332


1.05 (0.93, 1.18)0.90 (0.79, 1.03)0.85 (0.76, 0.95)0.62 (0.34, 1.13)0.90 (0.79, 1.03)0.73 (0.30, 1.79)0.91 (0.83, 1.00)

0.99 (0.89, 1.09)0.81 (0.73, 0.91)0.79 (0.72, 0.87)0.77 (0.48, 1.21)0.94 (0.83, 1.06)0.54 (0.30, 0.96)0.86 (0.77, 0.96)

1.63 (1.44, 1.85)2.01 (1.61, 2.51)1.26 (0.92, 1.72)7.78 (2.78, 21.76)1.96 (1.73, 2.22)1.81 (1.48, 2.22)


25.4322.6526.162.2022.541.03100.00

23.6522.4024.284.7221.823.13100.00

27.8922.7018.043.4827.90100.00

Weight%

1.05 (0.93, 1.18)0.90 (0.79, 1.03)0.85 (0.76, 0.95)0.62 (0.34, 1.13)0.90 (0.79, 1.03)0.73 (0.30, 1.79)0.91 (0.83, 1.00)

0.99 (0.89, 1.09)0.81 (0.73, 0.91)0.79 (0.72, 0.87)0.77 (0.48, 1.21)0.94 (0.83, 1.06)0.54 (0.30, 0.96)0.86 (0.77, 0.96)

1.63 (1.44, 1.85)2.01 (1.61, 2.51)1.26 (0.92, 1.72)7.78 (2.78, 21.76)1.96 (1.73, 2.22)1.81 (1.48, 2.22)


25.4322.6526.162.2022.541.03100.00

23.6522.4024.284.7221.823.13100.00

27.8922.7018.043.4827.90100.00

Weight%


1.5 2

Coronary artery disease - all lost with event

Page 47 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



19

eFigure 16 - Ad hoc sensitivity analyses based on risk of bias assessment



ACTIVE I

acronym

HOPE-3

NAVIGATOR

PREVEND IT

DREAM

VA NEPHRON

Study

BCAPS

PHARAO

379

treated

75

105

1

4

18

Stroke

1

3

4498

treated (n)

6291

4194

431

2571

704

Participants

396

505

411

control

94

132

10

8

18

Stroke

7

1

4478

control (n)

6301

4207

433

2593

705

Participants

397

503

0.83 (0.68, 1.01)

0.92 (0.80, 1.05)

ES (95% CI)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

0.10 (0.01, 0.78)

0.50 (0.15, 1.67)

1.00 (0.53, 1.91)

0.14 (0.02, 1.16)

2.99 (0.31, 28.63)

100.00

38.94

Weight

22.17

26.36

0.88

2.48

7.60

%

0.85

0.73

0.83 (0.68, 1.01)

0.92 (0.80, 1.05)

ES (95% CI)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

0.10 (0.01, 0.78)

0.50 (0.15, 1.67)

1.00 (0.53, 1.91)

0.14 (0.02, 1.16)

2.99 (0.31, 28.63)

100.00

38.94

Weight

22.17

26.36

0.88

2.48

7.60

%

0.85

0.73


Stroke - primary prevention excl. ALTITUDE



ACTION

PEACE

SCAT

Study

EUROPA

PART-2

acronym

444

396

16

MACE

488

29

treated

3644

4092

229

Participants

6107

308

treated (n)

458

420

30

MACE

603

37

control

3661

4064

231

Participants

6108

308

control (n)

0.88 (0.78, 0.99)

0.97 (0.86, 1.10)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

ES (95% CI)

100.00

30.13

28.86

3.81

%

31.45

5.75

Weight

0.88 (0.78, 0.99)

0.97 (0.86, 1.10)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

ES (95% CI)

100.00

30.13

28.86

3.81

%

31.45

5.75

Weight


MACE - CAD trials excl. HOPE

Page 48 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



20

eFigure 17 – Funnel plot for all-cause mortality

RR=relativerisk.SE=standarderror.Harbord’stestforsmall-studyeffectsp=0.938

eFigure 18 – Funnel plot for major cardiovascular events

RR=relativerisk.SE=standarderror.MACE=majorcardiovascularevents.Harbord’stestforsmall-studyeffectsp=0.410

0.2

.4.6

.81

SE o

f log

RR

for m

orta

lity

-2 -1 0 1 2Log RR for mortality

Funnel plot with pseudo 95% confidence limits0

.2.4

.6SE

of L

og R

R fo

r MAC

E

-1 -.5 0 .5 1Log RR for MACE

Funnel plot with pseudo 95% confidence limits

Page 49 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



21

eFigure 19 – Funnel plot for adverse events leading to discontinuation

RR=relativerisk.SE=standarderror.AEs=adverseevents.Harbord’stestforsmall-studyeffectsp=0.712

eFigure 20 – Funnel plot for cardiovascular mortality

RR=relativerisk.SE=standarderror.CV=cardiovascular.Harbord’stestforsmall-studyeffectsp=0.507

0.2

.4.6

.8SE o

f log

RR

for A

Es le

adin

g to

dis

cont

inua

tion

-1 0 1 2 3Log RR for AEs leading to discontinuation


.51

1.5

2SE

of l

og R

R fo

r CV

mor

talit

y

-4 -2 0 2 4Log RR for CV mortality


Page 50 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



22

eFigure 21 – Funnel plot for myocardial infarction


eFigure 22 – Funnel plot for stroke


0.2

.4.6

.8SE

of l

og R

R fo

r myo

card

ial i

nfar

ctio

n

-2 -1 0 1 2Log RR for myocardial infarction


.51

1.5

SE o

f log

RR

for s

troke

-2 -1 0 1 2Log RR for stroke


Page 51 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



23

eFigure 23 – Funnel plot for heart failure


eFigure 24 – Funnel plot for hypotension-related adverse events


0.2

.4.6

SE o

f log

RR

for h

eart

failu

re

-1.5 -1 -.5 0 .5 1Log RR for heart failure


.1.2

.3.4

.5SE

of l

og R

R fo

r hyp

oten

sion

-1 0 1 2Log RR for hypotension


Page 52 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



24

eFigure 25 – Funnel plot for renal impairment


0.2

.4.6

.8SE

of l

og R

R fo

r ren

al im

pairm

ent

-2 -1 0 1 2Log RR for renal impairment


Page 53 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



25

eTable 1 – Studies excluded due to high risk of bias or missing data StudyID ReasonforexclusionDIRECTPrevent11DIRECTProtect11DIRECTProtect21,2

Cardiovasculareventswereevaluatedasadverseevents,andthereforenotblinded.Also,cardiovasculareventswerenotfollowed-upinpeoplewhodiscontinuedtreatment,meaningthat>700patientswerelosttofollow-upregardingtheseevents.Basedontheabove,wejudgetheDIRECTtrialstobeathighriskofbothdetectionbiasandattritionbias.

EUCLID3 NooutcomedataHDFP4 Patientsintheinterventiongroupandpatientsin

thecontrolgroupweretreatedatdifferentclinics.Wethereforejudgethistrialtobeathighriskofperformancebias.

Hunanstudy5 Originalpublicationcouldnotberetrieved.Datafrompreviousmeta-analyseswereofuncertainquality.ForexamplenumberofstrokesdifferedbytenfoldintheanalysesbyEttehadetal.andLawetal.Riskofbiasassessmentcouldnotbemade.

INTACT6 Nobloodpressuredifferencebetweengroups.MDRD7 Nooutcomedata.NICOLE8 Nobloodpressuredata.PATS9 30%ofpatientswerelosttofollow-up.Thiswas

aboutfivetimesthenumberofevents,whichmeansthistrialisathighriskofattritionbias.

STONE10 Randomisationlikelytohavefailedbasedonlargedifferenceinnumberofparticipantsineachtreatmentarm.Wejudgedthistrialtobeathighriskofselectionbias.

Suzuki-0811 Allpatientsreceivedhemodialysisandtherewasnodifferenceinbloodpressurebetweentreatmentgroups.Althoughhemodialysiswasnotapre-specifiedexclusioncriteria,italtersphysiology,affectingbloodpressureanddrugpharmacokineticsinsuchawaythattheresultsinthesepatientsarenotapplicabletothegeneralpopulation.

Syst-China12 Treatmentallocationwasnotrandom.Thereforethistrialisathighriskofselectionbiasanddoesnotfulfiltheinclusioncriteriaofthissystematicreview.

USPHS13 >30%ofpatientsdroppedout,notspecifiedhowmanywerelosttofollow-uprespectivelyfollowedforoutcomes.Vitalstatusnotknownfor26patients,comparedto6deaths.Thissuggestshighriskofattritionbias.Furthermore,treatmentgroupsdifferedby2mmHginsystolicbloodpressureatbaseline,and60%vs40%onpriorantihypertensivetherapy.

Note:Severalofthestudiespresentedabovewereoutsidetheeligiblebloodpressurerange.Theyarepresentedherebecauseexclusionsbasedofriskofbiasweredonebeforeselectiononbloodpressuredata.

Page 54 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



26

eTable 2 - Absolute risk of MACE in primary preventive trials StudyID Pts(n) MACE(n) Follow-up(y) 10-year

MACE-rate(%)*

ACTIVEI 9016 1926 4.1 52ALTITUDE 8561 1129 2.7 49BCAPS 793 18 3.0 7.6DREAM 5269 56 3.0 3.5HOPE-3 12705 539 5.6 7.6Lewis-93 409 - 3.0 -NAVIGATOR 9306 752 6.5 12PHARAO 1008 13 3.0 4.3PREVEND-IT 864 42 3.8 13ROADMAP 4447 - 3.2 -Ravid-98 194 - 6.0 -VA-NEPHRON 1448 270 2.2 85Pts=participants.MACE=majorcardiovascularevents.*10-yearMACE-ratewascalculatedas(MACE/Pts)x(10/duration).

Page 55 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



27

eTable 3 - Risk of bias table

Studyacronym Randomsequencegeneration

Allocationconcealment

Blindingofparticipantsandpersonnel

Blindingofoutcomeassessors

Incompleteoutcomedata

Selectivereporting

Othersourcesofbias

ACTION14 Low Low Low Unclear Low Low LowACTIVEI15 Low Low Low Low Low Low LowALTITUDE16 Low Low Low Low Unclear Low HighBCAPS17 Unclear Unclear Unclear Unclear Low Low LowDREAM18 Low Low Low Low Unclear Low LowEUROPA19 Unclear Unclear Low Unclear Low Low UnclearHOPE20 Low Low Low Low Low Low HighHOPE-321 Low Low Unclear Low Low Low LowLewis-9322 Low Low Low Low Low High LowNAVIGATOR23 Low Low Low Low Unclear Low LowPART-224 Low Low Low Unclear Low Low LowPEACE25 Low Low Low Unclear Low Low LowPHARAO26 Low Low Unclear Low Low Low LowPREVEND-IT27 Low Low Low Low Unclear Low LowRavid-9828 Low Low Low Low Unclear Low LowROADMAP29 Low Low Low Unclear Low Low LowSCAT30 Unclear Unclear Unclear Unclear Low Low LowVA-NEPHRON31 Low Low Low Unclear Unclear Low Low

Page 56 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



28

eTable 4 - Hypotension-related adverse events Study ID Pts (n) Events (n) RR for hypotension --------------------------------------------------------------------------------------------------------NAVIGATOR 8 401 3 644 1.17 ACTION 7 305 558 1.20 HOPE 9 297 158 1.26 VA NEPHRON 1 409 19 1.38 ALTITUDE 8 339 876 1.47 HOPE-3 12 592 347 1.67 ACTIVE I 8 976 191 1.98 EUROPA 12 215 77 3.53 ROADMAP 4 341 64 9.56 Note:theapparentasymmetryinthefunnelplotsisnotprimarilyduetosmallerstudieshavingextremeresults;ratherstudieswithfeweventsshowlargerrelativerisks.Thisshouldbeinterpretedcautiously,butmightrepresentdifferentthresholdsforreportingadverseeventsindifferenttrials,withlargerrelativerisksformoresevereevents.

Page 57 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



29

eResults - Risk of bias assessment and description Risk of bias was judged as low when we found a clear description that fulfilled the criteria for low risk of bias according to Cochrane Collaborations risk of bias assessment tool. Risk of bias was judged as unclear if we could not find an adequate description, or if the described methods did not fulfil the criteria for either low or high risk of bias. High risk of bias was assigned when we found a description of a study characteristic of methodological feature known to be associated with biased effect estimates. All included studies were described as randomized double-blind placebo-controlled trials. Studies judged be at unclear risk of bias for the first three domains generally provided no further description of how randomization and/or blinding was achieved, yet we have no reason to believe it failed. Trials judged to be at unclear risk of bias in the forth domain generally described that outcomes were assessed by a separate committee, but did not explicitly describe this committee as blinded. Several trials were judged to be at unclear risk of bias for incomplete outcome data. We used this label when attrition was small and asymmetric (ALTITUDE), or when loss to follow-up-rates were higher than event-rates (others). None of the included trials had large and asymmetric loss to follow-up. Lewis -93 reported myocardial infarction, stroke, and heart failure for both groups combined, and is therefore judged to be at high risk of bias for these outcomes. This is not likely to affect overall results, however, because Lewis -93 was a small study with very few events compared to overall analyses. We assessed early termination, changes in protocol and sponsor involvement as other potential sources of bias. In EUROPA, the definition of the primary outcome changed during follow-up. Although this might affect the interpretation of the study findings, outcomes used in our analyses where based on pre-defined criteria and not on whether they were primary or secondary in individual studies. Thus it should have little impact on our analyses. ALTITUDE and HOPE were stopped pre-term due to interim findings. ALTITUDE was stopped due to an increased risk of stroke in the intervention group, whereas HOPE was stopped due to decreased risk of major cardiovascular events in the intervention group. To test the impact of these trials on overall results, we performed ad-hoc sensitivity analyses where they were excluded. Exclusion of ALTITUDE from the primary preventive stroke analysis moved the estimate slightly more towards benefit (relative risk 0.83, 95 % confidence interval 0.68-1.01, compared to 0.89, 0.73-1.09 when ALTITUDE was included). Exclusion of HOPE from the MACE analysis for CAD trials moved the estimate slightly towards neutrality (0.88, 0.78-0.99, compared to 0.85, 0.77-0.94 when HOPE was included).

Page 58 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



30

eReferences 1. Bilous R, Chaturvedi N, Sjolie AK, et al. Effect of Candesartan on Microalbuminuria and Albumin Excretion Rate in Diabetes Three Randomized Trials. Ann Int Med 2009; 151(1): 11-U27. 2. Tillin T, Orchard T, Malm A, Fuller J, Chaturvedi N. The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study. J Hypertens 2011; 29(7): 1457-62. 3. Chaturvedi N, Stevenson J, Fuller JH, et al. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997; 349(9068): 1787-92. 4. Langford HG, Stamler J, Wassertheilsmoller S, Prineas RJ. All-cause mortality in the Hypertension Detection and Follow-up Program - findings for the whole cohort and for persons with less severe hypertension, with and without other traits related to risk of mortality. Prog Cardiovasc Dis 1986; 29(3): 29-54. 5. Sun M, Zhou H, Jia Z. Prevention and treatment of stroke after hypertension for ten years in Hunan Province. Zhonghua Nei Ke Za Zhi 1997; 36(5): 312-4. 6. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S, Deckers JW. Retardation of angiographic progression of coronary-artery disease by nifedipine - results of the international nifedipine trial on antiatherosclerotic therapy (INTACT). Lancet 1990; 335(8698): 1109-13. 7. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary-protein restriction and blood-pressure control on the progression of chronic renal-disease. N Engl J Med 1994; 330(13): 877-84. 8. Dens JA, Desmet WJ, Coussement P, et al. Long term effects of nisoldipine on the progression of coronary atherosclerosis and the occurrence of clinical events: the NICOLE study. Heart 2003; 89(8): 887-92. 9. Liu L, Wang Z, Gong L, et al. Blood pressure reduction for the secondary prevention of stroke: a Chinese trial and a systematic review of the literature. Hypertens Res 2009; 32(11): 1032-40. 10. Gong LS, Zhang WZ, Zhu YJ, et al. Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 1996; 14(10): 1237-45. 11. Suzuki H, Kanno Y, Sugahara S, 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): 501-6. 12. Liu LS, Wang JG, Gong LS, Liu GZ, Staessen JA, Systolic Hypertension China C. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens 1998; 16(12): 1823-9. 13. Smith WM. Treatment of mild hypertension - results of a 10-year intervention trial. Circ Res 1977; 40(5): 98-105. 14. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364(9437): 849-57. 15. Yusuf S, Healey JS, Pogue J, et al. Irbesartan in Patients with Atrial Fibrillation. N Engl J Med 2011; 364(10): 928-38. 16. Parving HH, Brenner BM, McMurray JJV, et al. Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes. N Engl J Med 2012; 367(23): 2204-13. 17. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation 2001; 103(13): 1721-6. 18. Bosch J, Yusuf S, Gerstein HC, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355(15): 1551-62. 19. Fox KM, Investigators EtOrocewPiscAd. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362(9386): 782-8. 20. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342(3): 145-53. 21. Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med 2016. 22. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The Effect Of Angiotensin-Converting Enzyme-Inhibition On Diabetic Nephropathy. N Engl J Med 1993; 329(20): 1456-62. 23. McMurray JJ, Holman RR, Haffner SM, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362(16): 1477-90. 24. MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol 2000; 36(2): 438-43.

Page 59 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



31

25. Braunwald E, Pfeffer MA, Domanski M, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351(20): 2058-68. 26. Luders S, Schrader J, Berger J, et al. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure - a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens 2008; 26(7): 1487-96. 27. Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110(18): 2809-16. 28. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus - A randomized, controlled trial. Ann Intern Med 1998; 128(12): 982-+. 29. Haller H, Ito S, Izzo JL, et al. Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes. N Engl J Med 2011; 364(10): 907-17. 30. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis - The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000; 102(15): 1748-54. 31. Fried LF, Emanuele N, Zhang JH, et al. Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy. N Engl J Med 2013; 369(20): 1892-903.

Page 60 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist

Section/topic # Checklist item Reported on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

2-4

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 6-7

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

7

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

7

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. 7-8

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

8 + Suppl.

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

8 + Suppl.

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis). 8 + Suppl.

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

8

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

8

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

8-9

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 9

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis.

9-10

Page 61 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960





Page 1 of 2


Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

10

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating

which were pre-specified. 10

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Suppl.

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

Table 1

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Suppl.

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Fig. 1 & 2

Suppl.

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 11-12

Fig. 1 & 2

Table 2

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 13 +

Suppl.

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 12-13 +

Suppl.

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

14

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

14-15

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 15-19

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

20

Page 62 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960





From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.

Page 2 of 2

Page 63 of 63


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



For peer review onlyBenefits and harms of lower blood pressure treatment

targets – systematic review and meta-analysis of randomized placebo-controlled trials

Journal: BMJ Open

Manuscript ID bmjopen-2018-026686.R1

Article Type: Original research

Date Submitted by the Author: 08-Mar-2019


<b>Primary Subject Heading</b>: Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine, Evidence based practice, General practice / Family practice



BMJ Open on O


http://bmjopen.bm

j.com/

BM



ber 2019. Dow

nloaded from



1



controlled trials






[email protected]

+46733693182


SE-901 87 Umeå

Sweden

3 539 words

2 figures

2 tables



Page 1 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from

mailto:[email protected]



2

Abstract

Objectives


pressure range.

Design


Information sources


browsed for clinical trials. PubMed and CENTRAL were searched for trials directly in

February 2018.












Page 2 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



3

Results












Conclusion




Registration


Page 3 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



4

Article Summary





benefits and harms





bias.

Page 4 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



5

Introduction

















randomized trials comparing different treatment goals.8






Page 5 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



6










previous ones. Because the ACC/AHA systematic review was restricted to non-blinded

target trials and this review is restricted to placebo-controlled trials of different agents,

our analyses serves as validation of the ACC/AHA systematic review findings in a

different population with theoretically more robust methods.

Methods








Page 6 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



7

agent against placebo, with mean baseline SBP ≥ 130 mm Hg and < 140 mm Hg. The

1000 patient-year cut-off was chosen to reduce the risk of small-study bias. Target-





because several antihypertensive agents are thought to affect on clinical outcomes

through blood pressure-independent mechanisms, like reduced preload, reduced

afterload and sympathetic inhibition, in these settings.12,13

We used one of our recent, more comprehensive systematic reviews, assessing

treatment effect of antihypertensive treatment across blood pressure levels in a wide

range of patient categories, for study selection.14 Search strategies for the previous

review are presented in the online supplement (eMethods). In addition, we searched

PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) from the date of

the previous search until February 2018, using search terms ("blood pressure lowering"

OR "blood-pressure lowering" OR "blood pressure-lowering" OR antihypertensive) AND

(mortality OR myocardial OR stroke). Titles were screened by M.B. and apparently

irrelevant publications were removed. Two authors judged abstracts separately, after

which final decision on eligibility was reached through discussion (eFigure 1).





Page 7 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



8










lack of data, rather than biased data, may produce biased overall results.9, 15














Page 8 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



9
























Page 9 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



10






STATA v12.

Patient involvement






Results






preventive. Mean baseline SBP in primary preventive trials was 138 mm Hg, mean

follow-up SBP was 132 mm Hg respectively 135 mm Hg with active treatment versus

placebo, with a weighted mean difference between groups of 3.4 mm Hg. Six

trials18,23,24,28,29,34, including 38 547 participants, were classified as CAD trials; mean

Page 10 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



11

baseline SBP was 137 mm Hg, mean follow-up SBP was 130 mm Hg in the active

treatment group, 134 mm Hg in the placebo group, with 4.2 mm Hg difference between

groups.


















significant (1.30, 1.06 to 1.58).

Page 11 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



12











cardiovascular risk and diabetes mellitus were non-significant. Both sensitivity analyses

and metaregression analyses should be interpreted carefully due to small number of

trials. Of note, the absolute 10-years risk of MACE was well above the 10% threshold for

recommending treatment in the ACC/AHA guidelines, with an average risk across

studies of 26 % (eTable 2); subgroup analyses of primary preventive trials stratified by

10-year cardiovascular event-rate found no interaction between risk of MACE and

treatment effect (eFigure 13).







Page 12 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



13



Funnel plots showed no signs of asymmetry (eFigure 17-25), although such analyses

should be interpreted carefully due to the small number of trials. The possible exception

was hypotension-related adverse events where interaction was borderline significant

despite low statistical power (p=0.06). When we explored this further, we found that

treatment effect correlated with number of events but not study size (eTable 4). The

frequency of hypotension-related AEs varied by a factor of 50 between trials,

presumably representing different thresholds for reporting. Thus, the observed

association between number of adverse events and the relative risk of adverse events

might represent a stronger association between treatment and severe events compared

to less severe events.

Discussion





to discontinuation. In people with previous CAD, treatment might be beneficial, though


and wider confidence intervals. While the type of trials included here do not assess SBP

targets by design, they correspond to the clinical situation of adding an extra pill to

Page 13 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



14

patients with a SBP between 130 and 140 mm Hg. Overall, the results presented here do

not support such treatment, except for in patients with established CAD.















be explored further in individual-patient data meta-analyses. Thirdly, additional

possible effect modifiers like age, sex, and other comorbidities would also require

individual-patient data and were therefore not assessed. Fourthly, SBP was only






Page 14 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



15

narrow around the null effect. Fifthly, all but two of the included trials assessed the

effect of renin-angiotensin-aldosterone system (RAAS) inhibitors. Whereas the

generalizability of our findings to other drugs therefore could be questioned, previous

meta-analyses have found no clinically meaningful difference between RAAS inhibitors

and other first-line agents for hypertension control.



















Page 15 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



16























studies.

Page 16 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



17























the current analysis does not. If treatment benefit hinges on these assumptions, results

are simply not robust enough to change guidelines for hundreds of millions of people

Page 17 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



18

worldwide. Meta-analyses using non-standardized methods have consistently found that

the effects of antihypertensive treatment are attenuated at lower BP levels.14,40-42 In a

recent paper, we found 22 % reduced risk of MACE if baseline SBP was > 160 mm Hg, 12

% reduced risk in the 140-159 mm Hg SBP range, whereas in trials with baseline SBP

below 140 mm Hg treatment effect was neutral for all efficacy outcomes. These results

are well in line with the third Heart Outcomes Prevention Evaluation (HOPE-3) study,

where 12 705 participants with average baseline BP 138/82 mm Hg were randomized

to candesartan/hydrochlorothiazide combination therapy or matching placebo.25 In fact,

HOPE-3 is the only mega-trial aiming to assess the effect of antihypertensive treatment

against double-blind placebo in mostly treatment naïve normotensive primary

preventive patients. Neither the primary combined endpoints nor individual

cardiovascular outcomes were reduced by treatment. However, there was a significant

interaction between baseline SBP and treatment effect on MACE, with treatment benefit

in the highest SBP tertile but a tendency towards harm in the lowest SBP tertile.











Page 18 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



19








Page 19 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



20

Acknowledgements



Author Contributions: MB and BC contributed equally to the planning, conduct and















publication.

Page 20 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from

http://www.icmje.org/coi_disclosure.pdf



21





Data sharing: All data relevant to the study are included in the article or uploaded as

supplementary information











Page 21 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from

http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013.doc



22

References

1. Pfeffer MA, McMurray JJ. Lessons in Uncertainty and Humility - Clinical Trials Involving Hypertension. N Engl J Med 2016; 375(18): 1756-66.2. Weber MA, Schiffrin EL, White WB, et al. Clinical Practice Guidelines for the Management of Hypertension in the Community A Statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens 2014; 32(1): 3-15.3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for themanagement of arterial hypertension The Task Force for the management ofarterial hypertension of the European Society ofHypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31(7): 1281-357.4. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5): 507-20.5. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017.6. Williams B, Mancia G, et al. 2018 ESC/ESH Hypertension Guidelines. J Hypertens; 2018 (in press).7. Wright JT, Williamson JD, Whelton PK, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015; 373(22): 2103-16.8. Reboussin DM, Allen NB, Griswold ME, et al. Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017.9. Higgins JPT, Green S, Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Chichester, West Sussex ; Hoboken NJ: Wiley-Blackwell; 2008.10. Savović J, Jones HE, Altman DG, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med 2012; 157(6): 429-38.11. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: 37.12. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33(14): 1787-847.13. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33(20): 2569-619.

Page 22 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



23

14. Brunström M, Carlberg B. Association of Blood Pressure Lowering With Mortality and Cardiovascular Disease Across Blood Pressure Levels: A Systematic Review and Meta-analysis. JAMA Intern Med 2018; 178(1): 28-36.15. Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343.16. Brunström M, Carlberg B. Standardization according to blood pressure lowering in meta-analyses of antihypertensive trials: comparison of three methodological approaches. J Hypertens 2018; 36(1): 4-15.17. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med 2006; 25(20): 3443-57.18. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364(9437): 849-57.19. Yusuf S, Healey JS, Pogue J, et al. Irbesartan in Patients with Atrial Fibrillation. N Engl J Med 2011; 364(10): 928-38.20. Parving HH, Brenner BM, McMurray JJV, et al. Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes. N Engl J Med 2012; 367(23): 2204-13.21. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation 2001; 103(13): 1721-6.22. Bosch J, Yusuf S, Gerstein HC, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355(15): 1551-62.23. Fox KM, Investigators EtOrocewPiscAd. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362(9386): 782-8.24. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342(3): 145-53.25. Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med 2016.26. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The Effect Of Angiotensin-Converting Enzyme-Inhibition On Diabetic Nephropathy. N Engl J Med 1993; 329(20): 1456-62.27. McMurray JJ, Holman RR, Haffner SM, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362(16): 1477-90.28. MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol 2000; 36(2): 438-43.29. Braunwald E, Pfeffer MA, Domanski M, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351(20): 2058-68.30. Luders S, Schrader J, Berger J, et al. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure - a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens 2008; 26(7): 1487-96.

Page 23 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



24

31. Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110(18): 2809-16.32. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus - A randomized, controlled trial. Ann Intern Med 1998; 128(12): 982-+.33. Haller H, Ito S, Izzo JL, et al. Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes. N Engl J Med 2011; 364(10): 907-17.34. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis - The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000; 102(15): 1748-54.35. Fried LF, Emanuele N, Zhang JH, et al. Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy. N Engl J Med 2013; 369(20): 1892-903.36. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387(10022): 957-67.37. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 7. Effects of more vs. less intensive blood pressure lowering and different achieved blood pressure levels - updated overview and meta-analyses of randomized trials. J Hypertens 2016; 34(4): 613-22.38. Rosendorff C, Lackland DT, Allison M, et al. Treatment of Hypertension in Patients With Coronary Artery Disease. J Am Coll Cardiol 2015; 65(18): 1998-2038.39. Sipahi I, Tuzcu EM, Schoenhagen P, et al. Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. J Am Coll Cardiol 2006; 48(4): 833-8.40. Brunström M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ 2016; 352: i717.41. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood Pressure Targets in Subjects With Type 2 Diabetes Mellitus/Impaired Fasting Glucose Observations From Traditional and Bayesian Random-Effects Meta-Analyses of Randomized Trials. Circulation 2011; 123(24): 2799-+.42. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood Pressure Lowering in Type 2 Diabetes A Systematic Review and Meta-analysis. JAMA 2015; 313(6): 603-15.43. Beddhu S, Greene T, Boucher R, et al. Intensive systolic blood pressure control and incident chronic kidney disease in people with and without diabetes mellitus: secondary analyses of two randomised controlled trials. Lancet Diabetes Endocrinol 2018; 6(7): 555-63.44. Rocco MV, Sink KM, Lovato LC, et al. Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention Trial (SPRINT). Am J Kidney Dis 2018; 71(3): 352-61.

Page 24 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



25


Acronym(year)

Participants (n, age, sex)

Co-morbidity

Intervention/ Control

Baseline SBP/DBP (mm Hg)

SBP/DBP difference (mm Hg)

ACTION(2004)

766563 years21 % female

100 % CAD 14 % DM

Nifedipine 60 mgvs. placebo

137.5/ 79.8

5.7/ 3.0

ACTIVE I(2011)


36 % CAD20 % DM100 % AF

Irbesartan 300 mgvs. placebo

138.3/82.4

2.9/ 1.9

ALTITUDE(2012)


26 % CAD100 % DM98 % CKD

Aliskiren 300 mgvs. placebo

137.3/ 74.2

1.3/ 0.6

BCAPS(2001)


4 % CAD3 % DMAll had carotid plaques

Metoprolol CR/XL 25 mgvs. placebo

138.9/ 84.7

1.3/ -

DREAM(2006)


0 % CAD0 % DMAll had IGT/IFG

Ramipril 15 mgvs. placebo

136/83.4

4.3/ 2.7

EUROPA(2003)

12 21860 years15 % female

100 % CAD12 % DM

Perindopril 8 mg vs. placebo

137/ 82 5/ 2

HOPE(2000)


81 % CAD 38 % DM

Ramipril 10 mg vs. placebo

139/ 79 3/ 2*

HOPE-3(2016)


0 % CAD6 % DM

Candesartan/ HCTZ 16/12.5 mg vs. placebo

138.1/ 81.9

6/ 3

Lewis(1993)


100 % DM(type 1) All with nephropathy

Captopril 75 mgvs. placebo

138.5/ 85.5

1.5/ 2.5

NAVIGATOR(2010)


24 % CAD0 % DM100 % IGT

Valsartan 160 mgvs. placebo

139.7/ 82.6

2.8/ 1.4

PART-2(2000)


68 % CAD (100 % CVD)9 % DM

Ramipril 5-10 mgvs. placebo

133/ 79 5.5/ 4

PEACE(2004)


100 % CAD17 % DM

Trandolapril 4 mgvs. placebo

133/ 78 3.0/ 1.2

PHARAO (2008)


6 % CAD13 % DM


134.4/ 83.6

2.8/ 0.9

Page 25 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



26

PREVEND-IT(2004)


3 % CAD3 % DM

Fosinopril 20 mgvs. placebo

130/ 76 3/ 3

Ravid(1998)


0 % CAD100 % DM

Enalapril 10 mgvs. placebo

MAP 97 -/ -

ROADMAP(2011)


25 % CAD100 % DM

Olmesartan 40 mgvs. placebo

136.5/ 80.5

3.1/ 1.9

SCAT(2000)


100 % CAD11 % DM

Enalapril10 mgvs. placebo

130/ 77.5 5.2/ 3.3

VA-NEPHRON(2013)

144865 years0.3 % female

23 % CAD100 % DMwith nephro-pathy

Losartan/ lisinopril 100/10-40 mgvs. losartan 100 mg

137.0/ 72.7

1.5/ 1.0







Page 26 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



27



Primary prevention trials Coronary artery disease trialsTrials/

participants/events (n)

RR (95 % CI) I2 (%)Trials/


RR (95 % CI) I2 (%)

Efficacy outcomes

Cardiovascular mortality 8 / 49 685 / 2390 1.07 (0.95-1.21) 27.3 5 / 37 589 / 1802 0.86 (0.74-1.00) 55.7

Myocardial infarction 8 / 46 682 / 1092 1.03 (0.91-1.15) 0.0 5 / 29 893 / 2367 0.83 (0.72-0.97) 60.0

Stroke 9 / 47 546 / 1536 0.89 (0.73-1.09) 52.9 6 / 38 049 / 943 0.79 (0.66-0.94) 36.6

Heart failure 6 / 44 881 / 1903 0.90 (0.81-1.00) 17.7 5 / 37 589 / 957 0.76 (0.67-0.86) 0.0Safety outcomes

Hypotension-related AEs 6 / 44 058 / 5141 1.71 (1.32-2.22) 90.3 3 / 28 817 / 793 1.63 (1.01-2.63) 85.9

Renal impairment 8 / 49 627 / 992 1.20 (0.93-1.55) 71.6 1 / 12 215 / 36 1.25 (0.65-2.41) -

Page 27 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



28

Figure legends





Page 28 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from




Page 29 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from




Page 30 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



ONLINESUPPLEMENT


controlledtrials





Page 31 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



2



Page 32 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



3






analyses:18


review:220



trials:0




Page 33 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



4




.

.

Primary prevention

ACTIVE I

ALTITUDE

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT

ROADMAP



ACTION

EUROPA

HOPE

PART-2

PEACE


acronym

Study

666

246

12

155

128

0

5

15

178

215

282

8

146

treated

deaths

CV

4498

4151

2571

6291

4194

505

431

2182

3644

6107

4645

308

4092

treated (n)

Participants

646

215

10

170

116

0

3

3

177

249

377

18

152

control

deaths

CV

4478

4188

2593

6301

4207

503

433

2159

3661

6108

4652

308

4064

control (n)

Participants

1.03 (0.93, 1.13)

1.15 (0.97, 1.38)

1.21 (0.52, 2.80)

0.91 (0.74, 1.13)

1.11 (0.86, 1.42)

1.00 (0.02, 50.10)

1.67 (0.40, 6.96)

4.95 (1.43, 17.06)

1.07 (0.95, 1.20)

1.01 (0.82, 1.24)

0.86 (0.72, 1.03)

0.75 (0.65, 0.87)

0.44 (0.20, 1.01)

0.95 (0.76, 1.19)

0.86 (0.74, 1.00)

Risk (95% CI)

Relative

38.29

23.73

1.86

18.91

15.60

0.09

0.66

0.87

100.00

22.73

25.08

28.25

3.05

20.90

100.00

Weight

%

1.03 (0.93, 1.13)

1.15 (0.97, 1.38)

1.21 (0.52, 2.80)

0.91 (0.74, 1.13)

1.11 (0.86, 1.42)

1.00 (0.02, 50.10)

1.67 (0.40, 6.96)

4.95 (1.43, 17.06)

1.07 (0.95, 1.20)

1.01 (0.82, 1.24)

0.86 (0.72, 1.03)

0.75 (0.65, 0.87)

0.44 (0.20, 1.01)

0.95 (0.76, 1.19)

0.86 (0.74, 1.00)

Risk (95% CI)

Relative

38.29

23.73

1.86

18.91

15.60

0.09

0.66

0.87

100.00

22.73

25.08

28.25

3.05

20.90

100.00

Weight

%



Page 34 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



5




.

.

Primary prevention

ACTIVE I

ALTITUDE

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

VA NEPHRON



ACTION

EUROPA

HOPE

PART-2

SCAT


acronym

Study

143

147

3

13

52

138

4

52

267

320

459

22

8

treated

MI

4498

4151

396

2571

6291

4194

505

704

3644

6107

4645

308

229

treated (n)

Participants

135

142

5

11

62

140

5

40

257

418

570

33

13

control

MI

4478

4188

397

2593

6301

4207

503

705

3661

6108

4652

308

231

control (n)

Participants

1.05 (0.84, 1.33)

1.04 (0.83, 1.31)

0.60 (0.14, 2.50)

1.19 (0.53, 2.66)

0.84 (0.58, 1.21)

0.99 (0.78, 1.25)

0.80 (0.22, 2.95)

1.30 (0.87, 1.94)

1.03 (0.91, 1.15)

1.04 (0.88, 1.23)

0.77 (0.66, 0.88)

0.81 (0.72, 0.91)

0.67 (0.40, 1.12)

0.62 (0.26, 1.47)

0.83 (0.72, 0.97)

Risk (95% CI)

Relative

25.49

26.61

0.67

2.13

10.15

25.56

0.80

8.59

100.00

27.34

30.01

32.86

6.98

2.81

100.00

Weight

%

1.05 (0.84, 1.33)

1.04 (0.83, 1.31)

0.60 (0.14, 2.50)

1.19 (0.53, 2.66)

0.84 (0.58, 1.21)

0.99 (0.78, 1.25)

0.80 (0.22, 2.95)

1.30 (0.87, 1.94)

1.03 (0.91, 1.15)

1.04 (0.88, 1.23)

0.77 (0.66, 0.88)

0.81 (0.72, 0.91)

0.67 (0.40, 1.12)

0.62 (0.26, 1.47)

0.83 (0.72, 0.97)

Risk (95% CI)

Relative

25.49

26.61

0.67

2.13

10.15

25.56

0.80

8.59

100.00

27.34

30.01

32.86

6.98

2.81

100.00

Weight

%



Page 35 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



6




.

.

Primary prevention

ACTIVE I

ALTITUDE

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT

VA NEPHRON



ACTION

EUROPA

HOPE

PART-2

PEACE

SCAT


acronym

Study

379

147

1

4

75

105

3

1

18

77

98

156

7

71

2

treated

Stroke

4498

4151

396

2571

6291

4194

505

431

704

3644

6107

4645

308

4092

229

treated (n)

Participants

411

122

7

8

94

132

1

10

18

99

102

226

4

92

9

control

Stroke

4478

4188

397

2593

6301

4207

503

433

705

3661

6108

4652

308

4064

231

control (n)

Participants

0.92 (0.80, 1.05)

1.22 (0.96, 1.54)

0.14 (0.02, 1.16)

0.50 (0.15, 1.67)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

2.99 (0.31, 28.63)

0.10 (0.01, 0.78)

1.00 (0.53, 1.91)

0.89 (0.73, 1.09)

0.78 (0.58, 1.05)

0.96 (0.73, 1.27)

0.69 (0.57, 0.84)

1.75 (0.52, 5.92)

0.77 (0.56, 1.04)

0.22 (0.05, 1.03)

0.79 (0.66, 0.94)

Risk (95% CI)

Relative

26.99

21.55

0.90

2.59

18.17

20.67

0.78

0.94

7.41

100.00

21.56

23.25

31.15

2.11

20.56

1.37

100.00

Weight

%

0.92 (0.80, 1.05)

1.22 (0.96, 1.54)

0.14 (0.02, 1.16)

0.50 (0.15, 1.67)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

2.99 (0.31, 28.63)

0.10 (0.01, 0.78)

1.00 (0.53, 1.91)

0.89 (0.73, 1.09)

0.78 (0.58, 1.05)

0.96 (0.73, 1.27)

0.69 (0.57, 0.84)

1.75 (0.52, 5.92)

0.77 (0.56, 1.04)

0.22 (0.05, 1.03)

0.79 (0.66, 0.94)

Risk (95% CI)

Relative

26.99

21.55

0.90

2.59

18.17

20.67

0.78

0.94

7.41

100.00

21.56

23.25

31.15

2.11

20.56

1.37

100.00

Weight

%


Stroke

Page 36 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



7




.

.

Primary prevention

ACTIVE I

ALTITUDE

DREAM

HOPE-3

NAVIGATOR

VA NEPHRON



ACTION

EUROPA

HOPE

PART-2

PEACE


acronym

Study

482

205

12

21

91

89

86

63

141

7

115

treated

failure

Heart

4498

4151

2571

6291

4194

704

3644

6107

4645

308

4092

treated (n)

Participants

551

219

4

29

94

106

121

103

160

9

152

control

failure

Heart

4478

4188

2593

6301

4207

705

3661

6108

4652

308

4064

control (n)

Participants

0.87 (0.78, 0.98)

0.94 (0.78, 1.14)

3.03 (0.98, 9.37)

0.73 (0.41, 1.27)

0.97 (0.73, 1.29)

0.84 (0.65, 1.09)

0.90 (0.81, 1.00)

0.71 (0.54, 0.94)

0.61 (0.45, 0.84)

0.88 (0.71, 1.10)

0.78 (0.29, 2.06)

0.75 (0.59, 0.95)

0.76 (0.67, 0.86)

Risk (95% CI)

Relative

44.53

24.51

0.90

3.54

12.30

14.23

100.00

21.50

16.47

32.21

1.68

28.13

100.00

Weight

%

0.87 (0.78, 0.98)

0.94 (0.78, 1.14)

3.03 (0.98, 9.37)

0.73 (0.41, 1.27)

0.97 (0.73, 1.29)

0.84 (0.65, 1.09)

0.90 (0.81, 1.00)

0.71 (0.54, 0.94)

0.61 (0.45, 0.84)

0.88 (0.71, 1.10)

0.78 (0.29, 2.06)

0.75 (0.59, 0.95)

0.76 (0.67, 0.86)

Risk (95% CI)

Relative

44.53

24.51

0.90

3.54

12.30

14.23

100.00

21.50

16.47

32.21

1.68

28.13

100.00

Weight

%


Heart failure

Page 37 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



8




.

.

Primary prevention

ACTIVE I

ALTITUDE

HOPE-3

NAVIGATOR

ROADMAP

VA NEPHRON



ACTION

EUROPA

HOPE


acronym

Study

127

519

217

1964

58

11

304

60

88

treated

Hypotension

4498

4151

6291

4194

2182

704

3644

6107

4645

treated (n)

Participants

64

357

130

1680

6

8

254

17

70

control

Hypotension

4478

4188

6301

4207

2159

705

3661

6108

4652

control (n)

Participants

1.98 (1.47, 2.66)

1.47 (1.29, 1.67)

1.67 (1.35, 2.07)

1.17 (1.12, 1.23)

9.56 (4.14, 22.12)

1.38 (0.56, 3.40)

1.71 (1.32, 2.22)

1.20 (1.02, 1.41)

3.53 (2.06, 6.04)

1.26 (0.92, 1.72)

1.63 (1.01, 2.63)

Risk (95% CI)

Relative

18.54

23.11

20.98

24.26

6.92

6.19

100.00

38.71

26.75

34.53

100.00

Weight

%

1.98 (1.47, 2.66)

1.47 (1.29, 1.67)

1.67 (1.35, 2.07)

1.17 (1.12, 1.23)

9.56 (4.14, 22.12)

1.38 (0.56, 3.40)

1.71 (1.32, 2.22)

1.20 (1.02, 1.41)

3.53 (2.06, 6.04)

1.26 (0.92, 1.72)

1.63 (1.01, 2.63)

Risk (95% CI)

Relative

18.54

23.11

20.98

24.26

6.92

6.19

100.00

38.71

26.75

34.53

100.00

Weight

%



Page 38 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



9




.

.

Primary prevention

ACTIVE I

ALTITUDE

DREAM

HOPE-3

Lewis -93

NAVIGATOR

ROADMAP

VA NEPHRON



EUROPA


acronym

Study

43

65

99

32

25

136

5

130

20

treated

impairment

Renal

4498

4151

2571

6291

205

4194

2182

704

6107

treated (n)

Participants

24

54

88

20

43

146

2

80

16

control

impairment

Renal

4478

4188

2593

6301

200

4207

2159

705

6108

control (n)

Participants

1.78 (1.08, 2.93)

1.21 (0.85, 1.74)

1.13 (0.86, 1.50)

1.60 (0.92, 2.80)

0.57 (0.36, 0.89)

0.93 (0.74, 1.18)

2.47 (0.48, 12.74)

1.63 (1.26, 2.11)

1.20 (0.93, 1.55)

1.25 (0.65, 2.41)

1.25 (0.65, 2.41)

Risk (95% CI)

Relative

11.33

14.31

16.03

10.21

12.24

17.16

2.16

16.55

100.00

100.00

100.00

Weight

%

1.78 (1.08, 2.93)

1.21 (0.85, 1.74)

1.13 (0.86, 1.50)

1.60 (0.92, 2.80)

0.57 (0.36, 0.89)

0.93 (0.74, 1.18)

2.47 (0.48, 12.74)

1.63 (1.26, 2.11)

1.20 (0.93, 1.55)

1.25 (0.65, 2.41)

1.25 (0.65, 2.41)

Risk (95% CI)

Relative

11.33

14.31

16.03

10.21

12.24

17.16

2.16

16.55

100.00

100.00

100.00

Weight

%



Page 39 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



10



.

.

.

All-cause mortality

DREAM

HOPE-3

PREVEND IT

ROADMAP



DREAM

HOPE-3

PREVEND IT



HOPE-3

PREVEND IT

ROADMAP


acronym

Study

2571

6291

431

2182

2571

6291

431

6291

431

2182

treated

Participants (n)

2593

6301

433

2159

2593

6301

433

6301

433

2159

control

Participants (n)

31

342

5

26

27

260

18

448

58

85

treated

Events (n)

32

349

4

15

29

279

24

346

18

89

control

Events (n)

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

1.26 (0.34, 4.64)

1.72 (0.91, 3.23)

1.01 (0.88, 1.16)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

0.75 (0.42, 1.37)

0.92 (0.79, 1.07)

1.30 (1.13, 1.49)

3.24 (1.94, 5.40)

0.94 (0.71, 1.26)

1.49 (0.92, 2.41)

Risk (95% CI)

Relative

7.57

86.80

1.07

4.56

100.00

8.54

84.94

6.52

100.00

38.30

27.23

34.48

100.00

Weight

%

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

1.26 (0.34, 4.64)

1.72 (0.91, 3.23)

1.01 (0.88, 1.16)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

0.75 (0.42, 1.37)

0.92 (0.79, 1.07)

1.30 (1.13, 1.49)

3.24 (1.94, 5.40)

0.94 (0.71, 1.26)

1.49 (0.92, 2.41)

Risk (95% CI)

Relative

7.57

86.80

1.07

4.56

100.00

8.54

84.94

6.52

100.00

38.30

27.23

34.48

100.00

Weight

%


1.5 2



.

.

.

All-cause mortality

EUROPA

PART-2

PEACE

SCAT



EUROPA

PART-2

PEACE

SCAT



EUROPA

PART-2

PEACE


acronym

Study

6107

308

4092

229

6107

308

4092

229

6107

308

4092

treated

Participants (n)

6108

308

4064

231

6108

308

4064

231

6108

308

4064

control

Participants (n)

375

16

299

8

488

29

396

16

224

31

589

treated

Events (n)

420

25

334

11

603

37

420

30

113

3

264

control

Events (n)

0.89 (0.78, 1.02)

0.64 (0.35, 1.17)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.88 (0.80, 0.97)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.84 (0.73, 0.96)

1.98 (1.59, 2.48)

10.33 (3.19, 33.44)

2.22 (1.93, 2.55)

2.33 (1.70, 3.20)

Risk (95% CI)

Relative

53.22

2.62

42.95

1.21

100.00

45.20

8.07

41.38

5.34

100.00

43.46

6.46

50.08

100.00

Weight

%

0.89 (0.78, 1.02)

0.64 (0.35, 1.17)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.88 (0.80, 0.97)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.84 (0.73, 0.96)

1.98 (1.59, 2.48)

10.33 (3.19, 33.44)

2.22 (1.93, 2.55)

2.33 (1.70, 3.20)

Risk (95% CI)

Relative

53.22

2.62

42.95

1.21

100.00

45.20

8.07

41.38

5.34

100.00

43.46

6.46

50.08

100.00

Weight

%


1.5 2


Page 40 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



11




.

.

.

All-cause mortality

ACTIVE I

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT



ACTIVE I

BCAPS

DREAM

HOPE-3

NAVIGATOR

PHARAO

PREVEND IT



HOPE-3

NAVIGATOR

PREVEND IT


acronym

Study

4498

396

2571

6291

4194

505

431

4498

396

2571

6291

4194

505

431

6291

4194

431

treated

Participants (n)

4478

397

2593

6301

4207

503

433

4478

397

2593

6301

4207

503

433

6301

4207

433

control

Participants (n)

949

4

31

342

295

5

5

963

5

27

260

375

7

18

448

556

58

treated

Events (n)

929

7

32

349

327

2

4

963

13

29

279

377

6

24

346

531

18

control

Events (n)

1.02 (0.94, 1.10)

0.57 (0.17, 1.94)

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

0.90 (0.78, 1.05)

2.49 (0.49, 12.78)

1.26 (0.34, 4.64)

0.99 (0.93, 1.05)

1.00 (0.92, 1.08)

0.39 (0.14, 1.07)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

0.98 (0.92, 1.04)

1.30 (1.13, 1.49)

1.05 (0.94, 1.17)

3.24 (1.94, 5.40)

1.45 (1.03, 2.02)

Risk (95% CI)

Relative

61.45

0.27

1.65

18.92

17.33

0.15

0.23

100.00

61.80

0.37

1.42

14.17

20.81

0.33

1.09

100.00

39.01

39.86

21.13

100.00

Weight

%

1.02 (0.94, 1.10)

0.57 (0.17, 1.94)

0.98 (0.60, 1.60)

0.98 (0.85, 1.13)

0.90 (0.78, 1.05)

2.49 (0.49, 12.78)

1.26 (0.34, 4.64)

0.99 (0.93, 1.05)

1.00 (0.92, 1.08)

0.39 (0.14, 1.07)

0.94 (0.56, 1.58)

0.93 (0.79, 1.10)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

0.98 (0.92, 1.04)

1.30 (1.13, 1.49)

1.05 (0.94, 1.17)

3.24 (1.94, 5.40)

1.45 (1.03, 2.02)

Risk (95% CI)

Relative

61.45

0.27

1.65

18.92

17.33

0.15

0.23

100.00

61.80

0.37

1.42

14.17

20.81

0.33

1.09

100.00

39.01

39.86

21.13

100.00

Weight

%


1.5 2


Page 41 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



12




.

.

.




acronymStudy

396257162912054194505431218291

396257162914194505431

62912054194431218291


397259363012004207503433215993

397259363014207503433

63012004207433215993


431342829555263

527260375718

4483155658853

treatedEvents (n)

7323491432724152

1329279377624

3464653118893

controlEvents (n)

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.90 (0.78, 1.05)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)0.96 (0.87, 1.06)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.87, 1.14)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.96 (0.86, 1.06)

1.30 (1.13, 1.49)0.66 (0.44, 0.99)1.05 (0.94, 1.17)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.16 (0.90, 1.51)


0.664.1047.031.3843.090.370.582.470.32100.00

0.973.7337.1054.490.862.85100.00

24.2915.7824.8312.9919.632.48100.00

Weight%

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.90 (0.78, 1.05)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)0.96 (0.87, 1.06)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.87, 1.14)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.96 (0.86, 1.06)

1.30 (1.13, 1.49)0.66 (0.44, 0.99)1.05 (0.94, 1.17)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.16 (0.90, 1.51)


0.664.1047.031.3843.090.370.582.470.32100.00

0.973.7337.1054.490.862.85100.00

24.2915.7824.8312.9919.632.48100.00

Weight%


1.5 2


Page 42 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



13



.

.

.




acronymStudy

39625716291505431218291

39625716291505431

6291431218291


39725936301503433215993

39725936301503433

6301433215993


43134255263

527260718

44858853

treatedEvents (n)

73234924152

1329279624

34618893

controlEvents (n)

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)1.01 (0.88, 1.16)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.91 (0.78, 1.05)

1.30 (1.13, 1.49)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.45 (0.93, 2.26)


1.197.3984.690.671.044.450.57100.00

2.138.2081.511.906.26100.00

36.1325.0432.246.60100.00

Weight%

0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.23)1.53 (0.26, 8.96)1.01 (0.88, 1.16)

0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.91 (0.78, 1.05)

1.30 (1.13, 1.49)3.24 (1.94, 5.40)0.94 (0.71, 1.26)1.02 (0.21, 4.93)1.45 (0.93, 2.26)


1.197.3984.690.671.044.450.57100.00

2.138.2081.511.906.26100.00

36.1325.0432.246.60100.00

Weight%


1.5 2



.

.

.

All-cause mortality

EUROPA

HOPE

PEACE

SCAT



EUROPA

HOPE

PEACE

SCAT



EUROPA

HOPE

PEACE


acronym

Study

6107

4645

4092

229

6107

4645

4092

229

6107

4645

4092

treated

Participants (n)

6108

4652

4064

231

6108

4652

4064

231

6108

4652

4064

control

Participants (n)

375

482

299

8

488

651

396

16

224

88

589

treated

Events (n)

420

569

334

11

603

826

420

30

113

70

264

control

Events (n)

0.89 (0.78, 1.02)

0.85 (0.76, 0.95)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.87 (0.81, 0.94)

0.81 (0.72, 0.91)

0.79 (0.72, 0.87)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.83 (0.74, 0.92)

1.98 (1.59, 2.48)

1.26 (0.92, 1.72)

2.22 (1.93, 2.55)

1.82 (1.36, 2.43)

Risk (95% CI)

Relative

31.08

43.12

25.09

0.71

100.00

31.96

36.12

28.74

3.17

100.00

33.53

28.19

38.27

100.00

Weight

%

0.89 (0.78, 1.02)

0.85 (0.76, 0.95)

0.89 (0.77, 1.03)

0.73 (0.30, 1.79)

0.87 (0.81, 0.94)

0.81 (0.72, 0.91)

0.79 (0.72, 0.87)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.83 (0.74, 0.92)

1.98 (1.59, 2.48)

1.26 (0.92, 1.72)

2.22 (1.93, 2.55)

1.82 (1.36, 2.43)

Risk (95% CI)

Relative

31.08

43.12

25.09

0.71

100.00

31.96

36.12

28.74

3.17

100.00

33.53

28.19

38.27

100.00

Weight

%


1.5 2


Page 43 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



14



.

.

.

All-cause mortality

ACTIVE I

ALTITUDE

Lewis -93

NAVIGATOR

VA NEPHRON



ACTIVE I

ALTITUDE

NAVIGATOR

VA NEPHRON



ALTITUDE

Lewis -93

NAVIGATOR

VA NEPHRON


acronym

Study

4498

4151

205

4194

704

4498

4151

4194

704

4151

205

4194

704

treated

Participants (n)

4478

4188

200

4207

705

4478

4188

4207

705

4188

200

4207

705

control

Participants (n)

949

376

8

295

63

963

590

375

134

563

31

556

173

treated

Events (n)

929

358

14

327

60

963

539

377

136

437

46

531

115

control

Events (n)

1.02 (0.94, 1.10)

1.06 (0.92, 1.22)

0.56 (0.24, 1.30)

0.90 (0.78, 1.05)

1.05 (0.75, 1.47)

1.00 (0.93, 1.07)

1.00 (0.92, 1.08)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

0.99 (0.80, 1.22)

1.02 (0.97, 1.08)

1.30 (1.16, 1.46)

0.66 (0.44, 0.99)

1.05 (0.94, 1.17)

1.51 (1.22, 1.86)

1.14 (0.92, 1.42)

Risk (95% CI)

Relative

53.38

22.54

0.69

19.18

4.22

100.00

49.89

26.51

16.80

6.80

100.00

29.81

15.12

30.08

24.99

100.00

Weight

%

1.02 (0.94, 1.10)

1.06 (0.92, 1.22)

0.56 (0.24, 1.30)

0.90 (0.78, 1.05)

1.05 (0.75, 1.47)

1.00 (0.93, 1.07)

1.00 (0.92, 1.08)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

0.99 (0.80, 1.22)

1.02 (0.97, 1.08)

1.30 (1.16, 1.46)

0.66 (0.44, 0.99)

1.05 (0.94, 1.17)

1.51 (1.22, 1.86)

1.14 (0.92, 1.42)

Risk (95% CI)

Relative

53.38

22.54

0.69

19.18

4.22

100.00

49.89

26.51

16.80

6.80

100.00

29.81

15.12

30.08

24.99

100.00

Weight

%


1.5 2



.

.

.

All-cause mortality

ACTION



ACTION



ACTION


acronym

Study

3644

3644

3644

treated

Participants (n)

3661

3661

3661

control

Participants (n)

310

444

389

treated

Events (n)

291

458

172

control

Events (n)

1.07 (0.92, 1.25)

1.07 (0.92, 1.25)

0.97 (0.86, 1.10)

0.97 (0.86, 1.10)

2.27 (1.91, 2.70)

2.27 (1.91, 2.70)

Risk (95% CI)

Relative

100.00

100.00

100.00

100.00

100.00

100.00

Weight

%

1.07 (0.92, 1.25)

1.07 (0.92, 1.25)

0.97 (0.86, 1.10)

0.97 (0.86, 1.10)

2.27 (1.91, 2.70)

2.27 (1.91, 2.70)

Risk (95% CI)

Relative

100.00

100.00

100.00

100.00

100.00

100.00

Weight

%



Page 44 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



15



.

.


PHARAO

Lewis -93


ROADMAP

PREVEND IT

acronym


VA NEPHRON

ACTIVE I

NAVIGATOR

10-year risk < 10 %

Ravid -98

DREAM

BCAPS

HOPE-3

ALTITUDE

Study


5

8

26

5

treated

63

949

295

3

31

4

342

376

Deaths

505

205

2182

431

treated (n)

704

4498

4194

91

2571

396

6291

4151

Participants

2

14

15

4

control

60

929

327

2

32

7

349

358

Deaths

503

200

2159

433

control (n)

705

4478

4207

93

2593

397

6301

4188

Participants

1.00 (0.95, 1.06)

2.49 (0.49, 12.78)

0.56 (0.24, 1.30)

0.98 (0.85, 1.13)

1.72 (0.91, 3.23)

1.26 (0.34, 4.64)

Risk (95% CI)

1.01 (0.94, 1.08)

1.05 (0.75, 1.47)

1.02 (0.94, 1.10)

0.90 (0.78, 1.05)

1.53 (0.26, 8.96)

0.98 (0.60, 1.60)

0.57 (0.17, 1.94)

0.98 (0.85, 1.13)

1.06 (0.92, 1.22)

Relative

100.00

0.12

0.44

16.66

0.79

0.18

Weight

83.34

2.77

48.78

13.76

0.10

1.31

0.21

15.02

16.52

%

1.00 (0.95, 1.06)

2.49 (0.49, 12.78)

0.56 (0.24, 1.30)

0.98 (0.85, 1.13)

1.72 (0.91, 3.23)

1.26 (0.34, 4.64)

Risk (95% CI)

1.01 (0.94, 1.08)

1.05 (0.75, 1.47)

1.02 (0.94, 1.10)

0.90 (0.78, 1.05)

1.53 (0.26, 8.96)

0.98 (0.60, 1.60)

0.57 (0.17, 1.94)

0.98 (0.85, 1.13)

1.06 (0.92, 1.22)

Relative

100.00

0.12

0.44

16.66

0.79

0.18

Weight

83.34

2.77

48.78

13.76

0.10

1.31

0.21

15.02

16.52

%




.

.



HOPE-3


Study

DREAM


ALTITUDE

NAVIGATOR

10-year risk < 10 %

PHARAO

PREVEND IT

ACTIVE I

VA NEPHRON

BCAPS

acronym

260

MACE

27

590

375

7

18

963

134

5

treated

6291

Participants

2571

4151

4194

505

431

4498

704

396

treated (n)

279

MACE

29

539

377

6

24

963

136

13

control

6301

Participants

2593

4188

4207

503

433

4478

705

397

control (n)

1.01 (0.96, 1.06)

0.93 (0.79, 1.10)

1.02 (0.97, 1.08)

Relative

0.94 (0.56, 1.58)

0.92 (0.79, 1.07)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

1.00 (0.92, 1.08)

0.99 (0.80, 1.22)

0.39 (0.14, 1.07)

Risk (95% CI)

100.00

10.39

88.02

%

1.06

11.98

23.45

15.12

0.25

0.81

42.41

6.23

0.28

Weight

1.01 (0.96, 1.06)

0.93 (0.79, 1.10)

1.02 (0.97, 1.08)

Relative

0.94 (0.56, 1.58)

0.92 (0.79, 1.07)

1.10 (0.99, 1.23)

1.00 (0.87, 1.14)

1.16 (0.39, 3.43)

0.75 (0.42, 1.37)

1.00 (0.92, 1.08)

0.99 (0.80, 1.22)

0.39 (0.14, 1.07)

Risk (95% CI)

100.00

10.39

88.02

%

1.06

11.98

23.45

15.12

0.25

0.81

42.41

6.23

0.28

Weight



Page 45 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



16


.

.


PREVEND IT



10-year risk < 10 %

HOPE-3


Lewis -93

ROADMAP

Ravid -98

ALTITUDE

VA NEPHRON

NAVIGATOR

acronym

Study

58

448

31

85

3

563

173

556

treated

AEs

431

6291

205

2182

91

4151

704

4194

treated (n)

Participants

18

346

46

89

3

437

115

531

control

AEs

433

6301

200

2159

93

4188

705

4207

control (n)

Participants

1.23 (1.03, 1.47)

3.24 (1.94, 5.40)

1.22 (0.97, 1.52)

1.30 (1.13, 1.49)

1.30 (1.13, 1.49)

0.66 (0.44, 0.99)

0.94 (0.71, 1.26)

1.02 (0.21, 4.93)

1.30 (1.16, 1.46)

1.51 (1.22, 1.86)

1.05 (0.94, 1.17)

Risk (95% CI)

Relative

100.00

7.49

82.49

17.51

17.51

9.57

12.83

1.21

17.97

15.30

18.12

Weight

%

1.23 (1.03, 1.47)

3.24 (1.94, 5.40)

1.22 (0.97, 1.52)

1.30 (1.13, 1.49)

1.30 (1.13, 1.49)

0.66 (0.44, 0.99)

0.94 (0.71, 1.26)

1.02 (0.21, 4.93)

1.30 (1.16, 1.46)

1.51 (1.22, 1.86)

1.05 (0.94, 1.17)

Risk (95% CI)

Relative

100.00

7.49

82.49

17.51

17.51

9.57

12.83

1.21

17.97

15.30

18.12

Weight

%



Page 46 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



17



.

.

.




acronymStudy

45184274396262363562074631505431223297724

45184274396262363564631505431724

427463562074631431223297724


44984287397264663492024675503433221597724

44984287397264663494675503433724

428763492024675433221597724


94937643134282955526363

963590527260375718134

5634483155658853173

treatedEvents (n)

929358732349143272415260

9635391329279377624136

4373464653118893115

controlEvents (n)

1.02 (0.94, 1.10)1.05 (0.92, 1.21)0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.91 (0.78, 1.06)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.24)1.50 (0.26, 8.78)1.05 (0.75, 1.47)1.00 (0.95, 1.06)

1.00 (0.92, 1.08)1.10 (0.98, 1.22)0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.88, 1.15)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.79, 1.22)1.01 (0.96, 1.06)

1.29 (1.15, 1.45)1.29 (1.13, 1.48)0.66 (0.44, 0.99)1.06 (0.95, 1.18)3.24 (1.94, 5.40)0.95 (0.71, 1.27)1.00 (0.21, 4.83)1.50 (1.22, 1.86)1.23 (1.03, 1.46)


48.8316.520.211.3115.040.4413.680.120.180.790.102.77100.00

43.8423.230.261.0110.0614.640.230.775.94100.00

18.0617.589.4918.207.4112.791.1815.30100.00

Weight%

1.02 (0.94, 1.10)1.05 (0.92, 1.21)0.57 (0.17, 1.94)0.98 (0.60, 1.60)0.98 (0.85, 1.13)0.56 (0.24, 1.30)0.91 (0.78, 1.06)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.72 (0.91, 3.24)1.50 (0.26, 8.78)1.05 (0.75, 1.47)1.00 (0.95, 1.06)

1.00 (0.92, 1.08)1.10 (0.98, 1.22)0.39 (0.14, 1.07)0.94 (0.56, 1.58)0.93 (0.79, 1.10)1.00 (0.88, 1.15)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.79, 1.22)1.01 (0.96, 1.06)

1.29 (1.15, 1.45)1.29 (1.13, 1.48)0.66 (0.44, 0.99)1.06 (0.95, 1.18)3.24 (1.94, 5.40)0.95 (0.71, 1.27)1.00 (0.21, 4.83)1.50 (1.22, 1.86)1.23 (1.03, 1.46)


48.8316.520.211.3115.040.4413.680.120.180.790.102.77100.00

43.8423.230.261.0110.0614.640.230.775.94100.00

18.0617.589.4918.207.4112.791.1815.30100.00

Weight%


1.5 2



.

.

.




acronymStudy

3825611046453084158229

3825611046453084158229

3825611046453084158


3840610846523094132231

3840610846523094132231

3840610846523094132


310375482162998

4444886512939616

3892248831589

treatedEvents (n)

2914205692533411

4586038263742030

172113703264

controlEvents (n)

1.07 (0.92, 1.25)0.89 (0.78, 1.02)0.85 (0.76, 0.95)0.64 (0.35, 1.18)0.89 (0.77, 1.03)0.73 (0.30, 1.79)0.90 (0.83, 0.99)

0.97 (0.86, 1.10)0.81 (0.72, 0.91)0.79 (0.72, 0.87)0.79 (0.50, 1.25)0.94 (0.82, 1.07)0.54 (0.30, 0.96)0.85 (0.77, 0.94)

2.27 (1.91, 2.70)1.98 (1.58, 2.48)1.26 (0.92, 1.72)10.37 (3.20, 33.55)2.22 (1.93, 2.55)2.05 (1.62, 2.61)


21.1224.7229.372.0721.750.98100.00

22.3523.3925.794.2321.432.81100.00

25.7823.6719.803.6327.12100.00

Weight%

1.07 (0.92, 1.25)0.89 (0.78, 1.02)0.85 (0.76, 0.95)0.64 (0.35, 1.18)0.89 (0.77, 1.03)0.73 (0.30, 1.79)0.90 (0.83, 0.99)

0.97 (0.86, 1.10)0.81 (0.72, 0.91)0.79 (0.72, 0.87)0.79 (0.50, 1.25)0.94 (0.82, 1.07)0.54 (0.30, 0.96)0.85 (0.77, 0.94)

2.27 (1.91, 2.70)1.98 (1.58, 2.48)1.26 (0.92, 1.72)10.37 (3.20, 33.55)2.22 (1.93, 2.55)2.05 (1.62, 2.61)


21.1224.7229.372.0721.750.98100.00

22.3523.3925.794.2321.432.81100.00

25.7823.6719.803.6327.12100.00

Weight%


1.5 2


Page 47 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



18



.

.

.




acronymStudy

45184274396262363562074631505431223297724

45184274396262363564631505431724

427463562074631431223297724


44984287397264663492024675503433221597724

44984287397264663494675503433724

428763492024675433221597724


969499483407107325576983

983713579325812718154

68651333993581359193


949457785397167952471679

9836381382327845624155

53639448999181457134


1.02 (0.94, 1.10)1.10 (0.97, 1.23)0.57 (0.17, 1.94)0.99 (0.73, 1.33)1.02 (0.90, 1.17)0.61 (0.28, 1.31)0.93 (0.85, 1.02)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.06 (0.77, 1.46)1.50 (0.56, 4.05)1.05 (0.79, 1.40)1.01 (0.96, 1.05)

1.00 (0.92, 1.08)1.12 (1.02, 1.24)0.39 (0.14, 1.07)0.97 (0.72, 1.32)0.99 (0.85, 1.15)0.97 (0.89, 1.06)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.82, 1.21)1.01 (0.95, 1.07)

1.28 (1.16, 1.43)1.30 (1.15, 1.48)0.67 (0.45, 1.00)1.00 (0.93, 1.08)3.24 (1.94, 5.40)0.92 (0.74, 1.16)1.29 (0.50, 3.31)1.44 (1.19, 1.75)1.20 (1.01, 1.43)


36.0115.870.152.5612.680.3926.950.080.132.240.232.69100.00

28.8721.950.313.2911.7325.410.270.897.28100.00

17.2416.769.3617.737.1014.012.8514.94100.00

Weight%

1.02 (0.94, 1.10)1.10 (0.97, 1.23)0.57 (0.17, 1.94)0.99 (0.73, 1.33)1.02 (0.90, 1.17)0.61 (0.28, 1.31)0.93 (0.85, 1.02)2.49 (0.49, 12.78)1.26 (0.34, 4.64)1.06 (0.77, 1.46)1.50 (0.56, 4.05)1.05 (0.79, 1.40)1.01 (0.96, 1.05)

1.00 (0.92, 1.08)1.12 (1.02, 1.24)0.39 (0.14, 1.07)0.97 (0.72, 1.32)0.99 (0.85, 1.15)0.97 (0.89, 1.06)1.16 (0.39, 3.43)0.75 (0.42, 1.37)0.99 (0.82, 1.21)1.01 (0.95, 1.07)

1.28 (1.16, 1.43)1.30 (1.15, 1.48)0.67 (0.45, 1.00)1.00 (0.93, 1.08)3.24 (1.94, 5.40)0.92 (0.74, 1.16)1.29 (0.50, 3.31)1.44 (1.19, 1.75)1.20 (1.01, 1.43)


36.0115.870.152.5612.680.3926.950.080.132.240.232.69100.00

28.8721.950.313.2911.7325.410.270.897.28100.00

17.2416.769.3617.737.1014.012.8514.94100.00

Weight%


1.5 2



.

.

.




acronymStudy

3825611046453084158229

3825611046453084158229

3825611046453084158


3840610846523094132231

3840610846523094132231

3840610846523094132


491378482163658

6254916512946216

5702278831655


4704205692640211

6376038263848830

351113704332


1.05 (0.93, 1.18)0.90 (0.79, 1.03)0.85 (0.76, 0.95)0.62 (0.34, 1.13)0.90 (0.79, 1.03)0.73 (0.30, 1.79)0.91 (0.83, 1.00)

0.99 (0.89, 1.09)0.81 (0.73, 0.91)0.79 (0.72, 0.87)0.77 (0.48, 1.21)0.94 (0.83, 1.06)0.54 (0.30, 0.96)0.86 (0.77, 0.96)

1.63 (1.44, 1.85)2.01 (1.61, 2.51)1.26 (0.92, 1.72)7.78 (2.78, 21.76)1.96 (1.73, 2.22)1.81 (1.48, 2.22)


25.4322.6526.162.2022.541.03100.00

23.6522.4024.284.7221.823.13100.00

27.8922.7018.043.4827.90100.00

Weight%

1.05 (0.93, 1.18)0.90 (0.79, 1.03)0.85 (0.76, 0.95)0.62 (0.34, 1.13)0.90 (0.79, 1.03)0.73 (0.30, 1.79)0.91 (0.83, 1.00)

0.99 (0.89, 1.09)0.81 (0.73, 0.91)0.79 (0.72, 0.87)0.77 (0.48, 1.21)0.94 (0.83, 1.06)0.54 (0.30, 0.96)0.86 (0.77, 0.96)

1.63 (1.44, 1.85)2.01 (1.61, 2.51)1.26 (0.92, 1.72)7.78 (2.78, 21.76)1.96 (1.73, 2.22)1.81 (1.48, 2.22)


25.4322.6526.162.2022.541.03100.00

23.6522.4024.284.7221.823.13100.00

27.8922.7018.043.4827.90100.00

Weight%


1.5 2


Page 48 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



19




ACTIVE I

acronym

HOPE-3

NAVIGATOR

PREVEND IT

DREAM

VA NEPHRON

Study

BCAPS

PHARAO

379

treated

75

105

1

4

18

Stroke

1

3

4498

treated (n)

6291

4194

431

2571

704

Participants

396

505

411

control

94

132

10

8

18

Stroke

7

1

4478

control (n)

6301

4207

433

2593

705

Participants

397

503

0.83 (0.68, 1.01)

0.92 (0.80, 1.05)

ES (95% CI)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

0.10 (0.01, 0.78)

0.50 (0.15, 1.67)

1.00 (0.53, 1.91)

0.14 (0.02, 1.16)

2.99 (0.31, 28.63)

100.00

38.94

Weight

22.17

26.36

0.88

2.48

7.60

%

0.85

0.73

0.83 (0.68, 1.01)

0.92 (0.80, 1.05)

ES (95% CI)

0.80 (0.59, 1.08)

0.80 (0.62, 1.03)

0.10 (0.01, 0.78)

0.50 (0.15, 1.67)

1.00 (0.53, 1.91)

0.14 (0.02, 1.16)

2.99 (0.31, 28.63)

100.00

38.94

Weight

22.17

26.36

0.88

2.48

7.60

%

0.85

0.73





ACTION

PEACE

SCAT

Study

EUROPA

PART-2

acronym

444

396

16

MACE

488

29

treated

3644

4092

229

Participants

6107

308

treated (n)

458

420

30

MACE

603

37

control

3661

4064

231

Participants

6108

308

control (n)

0.88 (0.78, 0.99)

0.97 (0.86, 1.10)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

ES (95% CI)

100.00

30.13

28.86

3.81

%

31.45

5.75

Weight

0.88 (0.78, 0.99)

0.97 (0.86, 1.10)

0.94 (0.82, 1.07)

0.54 (0.30, 0.96)

0.81 (0.72, 0.91)

0.78 (0.49, 1.24)

ES (95% CI)

100.00

30.13

28.86

3.81

%

31.45

5.75

Weight



Page 49 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



20





0.2

.4.6

.81

SE o

f log

RR

for m

orta

lity



.2.4

.6SE

of L

og R

R fo

r MAC

E



Page 50 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



21





0.2

.4.6

.8SE o

f log

RR

for A

Es le

adin

g to

dis

cont

inua

tion



.51

1.5

2SE

of l

og R

R fo

r CV

mor

talit

y



Page 51 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



22





0.2

.4.6

.8SE

of l

og R

R fo

r myo

card

ial i

nfar

ctio

n



.51

1.5

SE o

f log

RR

for s

troke



Page 52 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



23





0.2

.4.6

SE o

f log

RR

for h

eart

failu

re



.1.2

.3.4

.5SE

of l

og R

R fo

r hyp

oten

sion



Page 53 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



24



0.2

.4.6

.8SE

of l

og R

R fo

r ren

al im

pairm

ent



Page 54 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



25













Page 55 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



26


MACE-rate(%)*


Page 56 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



27







Selectivereporting

Othersourcesofbias


Page 57 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



28


Page 58 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



29


Page 59 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



30


Page 60 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



31


Page 61 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from





TITLE


ABSTRACT


2-4

INTRODUCTION



7

METHODS


7




8 + Suppl.


8 + Suppl.




8


8



8-9




9-10

Page 62 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960





Page 1 of 2



10



RESULTS


Suppl.


Table 1



Fig. 1 & 2

Suppl.


Fig. 1 & 2

Table 2


Suppl.


Suppl.

DISCUSSION


14


14-15


FUNDING


20

Page 63 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960







Page 2 of 2

Page 64 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



For peer review onlyBenefits and harms of lower blood pressure treatment

targets – systematic review and meta-analysis of randomized placebo-controlled trials

Journal: BMJ Open

Manuscript ID bmjopen-2018-026686.R2

Article Type: Original research

Date Submitted by the Author: 10-Jun-2019


<b>Primary Subject Heading</b>: Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine, Evidence based practice, General practice / Family practice



BMJ Open on O


http://bmjopen.bm

j.com/

BM



ber 2019. Dow

nloaded from



1



controlled trials






[email protected]

+46733693182


SE-901 87 Umeå

Sweden

3 539 words

2 figures

2 tables



Page 1 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from

mailto:[email protected]



2

Abstract

Objectives


pressure range.

Design


Information sources


browsed for clinical trials. PubMed and CENTRAL were searched for trials directly in

February 2018.












Page 2 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



3

Results












Conclusion




Registration


Page 3 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



4

Article Summary





benefits and harms





bias.

Page 4 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



5

Introduction

















randomized trials comparing different treatment goals, finding a reduced risk of major

cardiovascular events and stroke in trials comparing a target ≤ 130 mm Hg to any higher

target.8




Page 5 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



6












previous ones. Because the ACC/AHA systematic review was restricted to non-blinded

target trials and this review is restricted to placebo-controlled trials of different agents,

our analyses serves as validation of the ACC/AHA systematic review findings in a

different population with theoretically more robust methods.

Methods






Page 6 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



7



agent against placebo, with mean baseline SBP ≥ 130 mm Hg and < 140 mm Hg. The

1000 patient-year cut-off was chosen to reduce the risk of small-study bias. Target-





because several antihypertensive agents are thought to affect on clinical outcomes

through blood pressure-independent mechanisms, like reduced preload, reduced

afterload and sympathetic inhibition, in these settings.12,13

We used one of our recent, more comprehensive systematic reviews, assessing

treatment effect of antihypertensive treatment across blood pressure levels in a wide

range of patient categories, for study selection.14 Search strategies for the previous

review are presented in the online supplement (eMethods). In addition, we searched

PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) from the date of

the previous search until February 2018, using search terms ("blood pressure lowering"

OR "blood-pressure lowering" OR "blood pressure-lowering" OR antihypertensive) AND

(mortality OR myocardial OR stroke). Titles were screened by M.B. and apparently

irrelevant publications were removed. Two authors judged abstracts separately, after

which final decision on eligibility was reached through discussion (eFigure 1).



Page 7 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



8












lack of data, rather than biased data, may produce biased overall results.9, 15












Page 8 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



9
























Page 9 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



10








STATA v12.

Patient involvement






Results






preventive. Mean baseline SBP in primary preventive trials was 138 mm Hg, mean

follow-up SBP was 132 mm Hg respectively 135 mm Hg with active treatment versus

Page 10 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



11

placebo, with a weighted mean difference between groups of 3.4 mm Hg. Six

trials18,23,24,28,29,34, including 38 547 participants, were classified as CAD trials; mean

baseline SBP was 137 mm Hg, mean follow-up SBP was 130 mm Hg in the active

treatment group, 134 mm Hg in the placebo group, with 4.2 mm Hg difference between

groups.


















significant (1.30, 1.06 to 1.58).

Page 11 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



12











cardiovascular risk and diabetes mellitus were non-significant. Both sensitivity analyses

and metaregression analyses should be interpreted carefully due to small number of

trials. Of note, the absolute 10-years risk of MACE was well above the 10% threshold for

recommending treatment in the ACC/AHA guidelines, with an average risk across

studies of 26 % (eTable 2); subgroup analyses of primary preventive trials stratified by

10-year cardiovascular event-rate found no interaction between risk of MACE and

treatment effect (eFigure 13).






Page 12 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



13




Funnel plots showed no signs of asymmetry (eFigure 17-25), although such analyses

should be interpreted carefully due to the small number of trials. The possible exception

was hypotension-related adverse events where interaction was borderline significant

despite low statistical power (p=0.06). When we explored this further, we found that

treatment effect correlated with number of events but not study size (eTable 4). The

frequency of hypotension-related AEs varied by a factor of 50 between trials,

presumably representing different thresholds for reporting. Thus, the observed

association between number of adverse events and the relative risk of adverse events

might represent a stronger association between treatment and severe events compared

to less severe events.

Discussion





to discontinuation. In people with previous CAD, treatment might be beneficial, though


and wider confidence intervals. While the type of trials included here do not assess SBP

targets by design, they correspond to the clinical situation of adding an extra pill to

Page 13 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



14

patients with a SBP between 130 and 140 mm Hg. Overall, the results presented here do

not support such treatment, except for in patients with established CAD.















be explored further in individual-patient data meta-analyses. Thirdly, additional

possible effect modifiers like age, sex, and other comorbidities would also require

individual-patient data and were therefore not assessed. Fourthly, SBP was only






Page 14 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



15

narrow around the null effect. We cannot exclude that larger SBP reductions with more

ambitious treatment would have resulted in clinical benefit, such as in the SPRINT trial,

although based on our findings it seems unlikely. Fifthly, all but two of the included

trials assessed the effect of renin-angiotensin-aldosterone system (RAAS) inhibitors.

Whereas the generalizability of our findings to other drugs therefore could be

questioned, previous meta-analyses have found no clinically meaningful difference

between RAAS inhibitors and other first-line agents for hypertension control.

















Page 15 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



16
























Page 16 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



17


studies.





















Page 17 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



18



the current analysis does not make. If treatment benefit hinges on these assumptions,

results are simply not robust enough to change guidelines for hundreds of millions of

people worldwide. Meta-analyses using non-standardized methods have consistently

found that the effects of antihypertensive treatment are attenuated at lower BP

levels.14,40-42 In a recent paper, we found 22 % reduced risk of MACE if baseline SBP was

> 160 mm Hg, 12 % reduced risk in the 140-159 mm Hg SBP range, whereas in trials

with baseline SBP below 140 mm Hg treatment effect was neutral for all efficacy

outcomes. These results are well in line with the third Heart Outcomes Prevention

Evaluation (HOPE-3) study, where 12 705 participants with average baseline BP 138/82

mm Hg were randomized to candesartan/hydrochlorothiazide combination therapy or

matching placebo.25 In fact, HOPE-3 is the only mega-trial aiming to assess the effect of

antihypertensive treatment against double-blind placebo in mostly treatment naïve

normotensive primary preventive patients. Neither the primary combined endpoints

nor individual cardiovascular outcomes were reduced by treatment. However, there was

a significant interaction between baseline SBP and treatment effect on MACE, with

treatment benefit in the highest SBP tertile but a tendency towards harm in the lowest

SBP tertile.






Page 18 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



19













Page 19 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



20

Acknowledgements



Author Contributions: MB and BC contributed equally to the planning, conduct and















publication.

Page 20 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from

http://www.icmje.org/coi_disclosure.pdf



21





Data sharing: All data relevant to the study are included in the article or uploaded as

supplementary information











Page 21 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from

http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013.doc



22

References

1. Pfeffer MA, McMurray JJ. Lessons in Uncertainty and Humility - Clinical Trials Involving Hypertension. N Engl J Med 2016; 375(18): 1756-66.2. Weber MA, Schiffrin EL, White WB, et al. Clinical Practice Guidelines for the Management of Hypertension in the Community A Statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens 2014; 32(1): 3-15.3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for themanagement of arterial hypertension The Task Force for the management ofarterial hypertension of the European Society ofHypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31(7): 1281-357.4. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5): 507-20.5. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017.6. Williams B, Mancia G, et al. 2018 ESC/ESH Hypertension Guidelines. J Hypertens; 2018 (in press).7. Wright JT, Williamson JD, Whelton PK, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015; 373(22): 2103-16.8. Reboussin DM, Allen NB, Griswold ME, et al. Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017.9. Higgins JPT, Green S, Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Chichester, West Sussex ; Hoboken NJ: Wiley-Blackwell; 2008.10. Savović J, Jones HE, Altman DG, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med 2012; 157(6): 429-38.11. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: 37.12. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33(14): 1787-847.13. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33(20): 2569-619.

Page 22 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



23

14. Brunström M, Carlberg B. Association of Blood Pressure Lowering With Mortality and Cardiovascular Disease Across Blood Pressure Levels: A Systematic Review and Meta-analysis. JAMA Intern Med 2018; 178(1): 28-36.15. Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343.16. Brunström M, Carlberg B. Standardization according to blood pressure lowering in meta-analyses of antihypertensive trials: comparison of three methodological approaches. J Hypertens 2018; 36(1): 4-15.17. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med 2006; 25(20): 3443-57.18. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364(9437): 849-57.19. Yusuf S, Healey JS, Pogue J, et al. Irbesartan in Patients with Atrial Fibrillation. N Engl J Med 2011; 364(10): 928-38.20. Parving HH, Brenner BM, McMurray JJV, et al. Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes. N Engl J Med 2012; 367(23): 2204-13.21. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation 2001; 103(13): 1721-6.22. Bosch J, Yusuf S, Gerstein HC, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355(15): 1551-62.23. Fox KM, Investigators EtOrocewPiscAd. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362(9386): 782-8.24. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342(3): 145-53.25. Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med 2016.26. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The Effect Of Angiotensin-Converting Enzyme-Inhibition On Diabetic Nephropathy. N Engl J Med 1993; 329(20): 1456-62.27. McMurray JJ, Holman RR, Haffner SM, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362(16): 1477-90.28. MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol 2000; 36(2): 438-43.29. Braunwald E, Pfeffer MA, Domanski M, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351(20): 2058-68.30. Luders S, Schrader J, Berger J, et al. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure - a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens 2008; 26(7): 1487-96.

Page 23 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



24

31. Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110(18): 2809-16.32. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus - A randomized, controlled trial. Ann Intern Med 1998; 128(12): 982-+.33. Haller H, Ito S, Izzo JL, et al. Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes. N Engl J Med 2011; 364(10): 907-17.34. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis - The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000; 102(15): 1748-54.35. Fried LF, Emanuele N, Zhang JH, et al. Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy. N Engl J Med 2013; 369(20): 1892-903.36. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387(10022): 957-67.37. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 7. Effects of more vs. less intensive blood pressure lowering and different achieved blood pressure levels - updated overview and meta-analyses of randomized trials. J Hypertens 2016; 34(4): 613-22.38. Rosendorff C, Lackland DT, Allison M, et al. Treatment of Hypertension in Patients With Coronary Artery Disease. J Am Coll Cardiol 2015; 65(18): 1998-2038.39. Sipahi I, Tuzcu EM, Schoenhagen P, et al. Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. J Am Coll Cardiol 2006; 48(4): 833-8.40. Brunström M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ 2016; 352: i717.41. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood Pressure Targets in Subjects With Type 2 Diabetes Mellitus/Impaired Fasting Glucose Observations From Traditional and Bayesian Random-Effects Meta-Analyses of Randomized Trials. Circulation 2011; 123(24): 2799-+.42. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood Pressure Lowering in Type 2 Diabetes A Systematic Review and Meta-analysis. JAMA 2015; 313(6): 603-15.43. Beddhu S, Greene T, Boucher R, et al. Intensive systolic blood pressure control and incident chronic kidney disease in people with and without diabetes mellitus: secondary analyses of two randomised controlled trials. Lancet Diabetes Endocrinol 2018; 6(7): 555-63.44. Rocco MV, Sink KM, Lovato LC, et al. Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention Trial (SPRINT). Am J Kidney Dis 2018; 71(3): 352-61.

Page 24 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



25


Acronym(year)

Participants (n, age, sex)

Co-morbidity

Intervention/ Control

Baseline SBP/DBP (mm Hg)

SBP/DBP difference (mm Hg)

ACTION(2004)


100 % CAD 14 % DM

Nifedipine 60 mgvs. placebo

137.5/ 79.8

5.7/ 3.0

ACTIVE I(2011)


36 % CAD20 % DM100 % AF

Irbesartan 300 mgvs. placebo

138.3/82.4

2.9/ 1.9

ALTITUDE(2012)


26 % CAD100 % DM98 % CKD

Aliskiren 300 mgvs. placebo

137.3/ 74.2

1.3/ 0.6

BCAPS(2001)


4 % CAD3 % DMAll had carotid plaques

Metoprolol CR/XL 25 mgvs. placebo

138.9/ 84.7

1.3/ -

DREAM(2006)


0 % CAD0 % DMAll had IGT/IFG


136/83.4

4.3/ 2.7

EUROPA(2003)


100 % CAD12 % DM

Perindopril 8 mg vs. placebo

137/ 82 5/ 2

HOPE(2000)


81 % CAD 38 % DM

Ramipril 10 mg vs. placebo

139/ 79 3/ 2*

HOPE-3(2016)


0 % CAD6 % DM

Candesartan/ HCTZ 16/12.5 mg vs. placebo

138.1/ 81.9

6/ 3

Lewis(1993)


100 % DM(type 1) All with nephropathy

Captopril 75 mgvs. placebo

138.5/ 85.5

1.5/ 2.5

NAVIGATOR(2010)


24 % CAD0 % DM100 % IGT

Valsartan 160 mgvs. placebo

139.7/ 82.6

2.8/ 1.4

PART-2(2000)


68 % CAD (100 % CVD)9 % DM

Ramipril 5-10 mgvs. placebo

133/ 79 5.5/ 4

PEACE(2004)


100 % CAD17 % DM

Trandolapril 4 mgvs. placebo

133/ 78 3.0/ 1.2

PHARAO (2008)


6 % CAD13 % DM


134.4/ 83.6

2.8/ 0.9

Page 25 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



26

PREVEND-IT(2004)


3 % CAD3 % DM

Fosinopril 20 mgvs. placebo

130/ 76 3/ 3

Ravid(1998)


0 % CAD100 % DM

Enalapril 10 mgvs. placebo

MAP 97 -/ -

ROADMAP(2011)


25 % CAD100 % DM

Olmesartan 40 mgvs. placebo

136.5/ 80.5

3.1/ 1.9

SCAT(2000)


100 % CAD11 % DM

Enalapril10 mgvs. placebo

130/ 77.5 5.2/ 3.3

VA-NEPHRON(2013)

144865 years0.3 % female

23 % CAD100 % DMwith nephro-pathy

Losartan/ lisinopril 100/10-40 mgvs. losartan 100 mg

137.0/ 72.7

1.5/ 1.0







Page 26 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from



27



Primary prevention trials Coronary artery disease trialsTrials/


RR (95 % CI) I2 (%)Trials/


RR (95 % CI) I2 (%)

Efficacy outcomes

Cardiovascular mortality 8 / 49 685 / 2390 1.07 (0.95-1.21) 27.3 5 / 37 589 / 1802 0.86 (0.74-1.00) 55.7

Myocardial infarction 8 / 46 682 / 1092 1.03 (0.91-1.15) 0.0 5 / 29 893 / 2367 0.83 (0.72-0.97) 60.0

Stroke 9 / 47 546 / 1536 0.89 (0.73-1.09) 52.9 6 / 38 049 / 943 0.79 (0.66-0.94) 36.6

Heart failure 6 / 44 881 / 1903 0.90 (0.81-1.00) 17.7 5 / 37 589 / 957 0.76 (0.67-0.86) 0.0Safety outcomes

Hypotension-related AEs 6 / 44 058 / 5141 1.71 (1.32-2.22) 90.3 3 / 28 817 / 793 1.63 (1.01-2.63) 85.9

Renal impairment 8 / 49 627 / 992 1.20 (0.93-1.55) 71.6 1 / 12 215 / 36 1.25 (0.65-2.41) -

Page 27 of 64


BMJ Open

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960



jopen.bmj.com

/B

MJ O


eptember 2019. D

ownloaded from
