Blood pressure lowering in diabetic patients

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Original article 1253

Effects of intensive blood pres
sure reduction on myocardialinfarction and stroke in diabetes: a meta-analysis in73 913 patientsGianpaolo Reboldia, Giorgio Gentilea, Fabio Angelib, Giuseppe Ambrosioc,Giuseppe Manciad and Paolo Verdecchiae
Objective Guidelines generally recommend intensive

lowering of blood pressure (BP) in patients with type 2

diabetes. There is uncertainty about the impact of this

strategy on case-specific events. Thus, we generated

estimates of the effects of BP reduction on the risk of

myocardial infarction (MI) and stroke in diabetic patients.

Methods We selected studies which compared different

BP-lowering agents and different BP intervention strategies

in patients with diabetes. Outcome measures were MI and

stroke. We abstracted information about study design,

intervention, population, outcomes, and methodological

quality for a total of 73 913 patients with diabetes (295 652

patient-years of exposure) randomized in 31 intervention

trials.

Results Overall, experimental treatment reduced the risk of

stroke by 9% (P U 0.0059), and that of MI by 11%

(P U 0.0015). Allocation to more-tight, compared with less-

tight, BP control reduced the risk of stroke by 31% [relative

risk (RR) 0.61, 95% confidence interval (CI) 0.48–0.79],

whereas the reduction in the risk of MI approached, but did

not achieve, significance [odds ratio (OR) 0.87, 95% CI

0.74–1.02]. In a meta-regression analysis, the risk of stroke

decreased by 13% (95% CI 5–20, P U 0.002) for each 5-

mmHg reduction in SBP, and by 11.5% (95% CI 5–17,

P < 0.001) for each 2-mmHg reduction in DBP. In contrast,

the risk of MI did not show any association with the extent of

BP reduction (SBP: P U 0.793; DBP: P U 0.832).

opyright © Lippincott Williams & Wilkins. Unauth

0263-6352 � 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Conclusion In patients with diabetes, protection from

stroke increases with the magnitude of BP reduction. We

were unable to detect such a relation for MI. J Hypertens

29:1253–1269 Q 2011 Wolters Kluwer Health | Lippincott

Williams & Wilkins.

Journal of Hypertension 2011, 29:1253–1269

Keywords: cardiovascular risk, diabetes, hypertension, meta-analysis,myocardial infarction, stroke

Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes;ACEIs, angiotensin-converting enzyme-inhibitors; ARBs, angiotensinreceptor antagonists; BP, blood pressure; BPLTTC, Blood PressureLowering Treatment Trialists’ Collaboration; CCBs, calcium channelsblockers; CIs, confidence intervals; MI, myocardial infarction; ONTARGET,Ongoing Telmisartan Alone and in Combination With Ramipril GlobalEndpoint Trial; PRISMA, Preferred Reporting Items for SystematicReviews and Meta-Analysesx; QUORUM, Quality of Reporting ofMeta-analyses; RRs, relative risks; UKPDS, United Kingdom ProspectiveDiabetes Study

aDepartment of Internal Medicine, University of Perugia, bDepartment ofCardiology, Hospital ‘Santa Maria della Misericordia’, cDepartment of Cardiology,University of Perugia, dDepartment of Medicine, University of Milano-Bicocca,Milan and eDepartment of Medicine, Hospital of Assisi, Assisi, Italy

Correspondence to Paolo Verdecchia, MD, FACC, FAHA, FESC, Department ofMedicine, Hospital of Assisi, Via Valentin Muller 1, 06081 Assisi, ItalyTel: +39 075 8139336; 39 075 8139272; fax: +39 075 8139301;e-mail: [email protected]

Received 26 August 2010 Revised 4 March 2011Accepted 9 March 2011

See editorial comment on page 1283

IntroductionControl of blood pressure (BP) plays a central role in the

management of patients with diabetes mellitus. These

patients are at high risk of cardiovascular disease at any

level of BP [1,2], and their prevalence of hypertension

can reach 70% or more [3]. Although numerous outcome

trials have been conducted in patients with diabetes,

several important questions regarding the levels of BP

that should be targeted by treatment are still unanswered.

In this respect, guidelines consistently recommend to

begin or to intensify drug treatment in diabetic patients

also when BP is below 140/90 mmHg, with the aim to

reduce BP to less than 130/80 mmHg [4–6]. Recently,

however, a critical analysis of available trials has shown

that such recommendation is not supported by solid

evidence [7]. This position has been subsequently

endorsed by a consensus document of the European

Society of Hypertension, which emphasizes that although

lowering BP to less than 140/90 mmHg is unquestionably

protective in diabetic patients, the beneficial effects of a

tighter BP control is still inconclusive [8]. This contro-

versy has not been solved by the recently published

Action to Control Cardiovascular Risk in Diabetes

(ACCORD) trial [9], which compared a more tight

(<120 mmHg) with a less tight (<140 mmHg) SBP goal

in patients with diabetes. The incidence of the primary

endpoint (a composite of fatal and nonfatal cardiovascular

events) did not differ between the two groups, nor did the

incidence of myocardial infarction (MI). In contrast, the

incidence of stroke was lower in the more intensively as

compared to the less intensively treated patients [9]. In

ACCORD, however, the number of strokes was relatively

small, which did not allow the evidence to be regarded

as conclusive.

orized reproduction of this article is prohibited.

DOI:10.1097/HJH.0b013e3283469976

mailto:[email protected]

http://dx.doi.org/10.1097/HJH.0b013e3283469976

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1254 Journal of Hypertension 2011, Vol 29 No 7

Given the uncertainty surrounding the optimal level of

BP reduction to achieve in diabetic patients to protect

against stroke and MI, we undertook a meta-analysis of

available outcome-based studies which had either specifi-

cally addressed patients with diabetes, or in which a

diabetic subgroup had been identified. The primary

aim of our overview was to define the relation, if any,

between the magnitude of BP reduction and the risk of

stroke and MI in patients with diabetes. The secondary

aim was to investigate whether there is reliable evidence

in the cumulative literature favouring a specific interven-

tion or strategy in these patients.

MethodsStudy selection, data sources and searchesWe extracted data from prospective controlled trials with

a parallel design, which met the following selection

criteria: comparison between various BP-lowering

agents: angiotensin-converting enzyme (ACE)-inhibi-

tors, angiotensin receptor antagonists (ARBs), calcium

channel blockers (CCBs), diuretics, b-blockers, alone or

in combination, vs. placebo or another active treatment;

publication before 1 April 2010; inclusion of patients

with diabetes mellitus at baseline (representing either

the whole trial population or a subgroup reported sep-

arately); stroke and/or MI as prespecified endpoints; SBP

values both at baseline and at follow-up, in all groups

included in the trial; duration of follow-up of at least

1 year.

opyright © Lippincott Williams & Wilkins. Unautho

Table 1 Main characteristics of selected studies

Acronym Study typeStudypopulation

Trialdesign

Multiarmedtrial

Tyco

ABCD-H DM Primary Study DM RCT Yes ACABCD-N DM Primary Study DM RCT Yes ACACCORD DM Primary Study DM RCT No STADVANCE DM Primary Study DM RCT No PLATLANTIS DM Primary Study DM RCT Yes PLDETAIL DM Primary Study DM RCT No ACDIABHYCAR DM Primary Study DM RCT No PLFACET DM Primary Study DM RCT No ACIDNT DM Primary Study DM RCT Yes ACRENAAL DM Primary Study DM RCT No PLUKPDS38 DM Primary Study DM RCT No STUKPDS39 DM Primary Study DM RCT No ACACTION DM Sub-Study CAD RCT No PLEUROPA DM Sub-Study CAD RCT No PLMERIT-HF DM Sub-Study CHF RCT No PLHOPE DM Sub-Study HR RCT No PLALLHAT DM Sub-Study HTN RCT Yes ACASCOT DM Sub-Study HTN PROBE No ACCAPPP DM Sub-Study HTN PROBE No ACHOT-DM DM Sub-Study HTN PROBE No STINSIGHT DM Sub-Study HTN RCT No ACINVEST DM Sub-Study HTN PROBE No ACJMIC-B DM Sub-Study HTN PROBE No ACLIFE DM Sub-Study HTN RCT No ACMOSES DM Sub-Study HTN PROBE No ACNORDIL DM Sub-Study HTN PROBE No ACSHEP DM Sub-Study HTN RCT No PLSTOP2 DM Sub-Study HTN PROBE Yes ACSYST-EUR DM Sub-Study HTN RCT No PLPROFESS DM Sub-Study STR RCT No PLPROGRESS DM Sub-Study STR RCT No PL

MDoctoral thesis; available at http://publishing.eur.nl/ir/repub/asset/10627/071026_W

Data extraction and quality assessmentWe searched (see below section for search strategies)

for eligible studies through Medline and the

Cochrane Library using research Methodology Filters

[10]. No language restriction was applied to avoid

discriminating papers not written in the English

language (‘tower of Babel bias’) [11]. Reference lists

from identified trials and review articles were further

screened along with hand-searching of doctoral disser-

tations, conference proceedings, pharmaceutical indus-

try files and personal communication to experts in

the field [12] to identify any other relevant study

(Table 1).

Search strategies

MEDLINE records: 35398 (on 31 March 2010).

(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((‘Antihyper-

tensive Agents’ Intensive OR ‘Angiotensin II Type 1

Receptor Blockers’[Mesh]) OR ‘Receptors, Angioten-

sin’[Mesh]) OR ‘Losartan’[Mesh]) OR ‘valsartan ‘[Sub-

stance Name]) OR ‘irbesartan ‘[Substance Name]) OR

‘candesartan ‘[Substance Name]) OR ‘candesartan cilex-

etil ‘[Substance Name]) OR ‘telmisartan ‘[Substance

Name]) OR ‘eprosartan ‘[Substance Name]) OR ‘olme-

sartan ‘[Substance Name]) OR ‘tasosartan ‘[Substance

Name]) OR ‘Angiotensin-Converting Enzyme Inhibi-

tors’[Mesh]) OR ‘Captopril’[Mesh]) OR ‘Ramipril’[-

Mesh]) OR ‘Fosinopril’[Mesh]) OR ‘Lisinopril’[Mesh])

OR ‘Cilazapril’[Mesh]) OR ‘Perindopril’[Mesh]) OR

rized reproduction of this article is prohibited.

pe ofmparator

Publicationyear

Patientsrandomized

F/Uyears Risk of bias

TIVE/STRATEGY 2000 470 5.3 Intermediate biasTIVE/STRATEGY 2002 480 5.3 Intermediate biasRATEGY 2010 4733 4.7 High biasACEBO 2007 11 140 4.3 Intermediate biasACEBO 2000 134 2 Low biasTIVE 2004 250 5 Intermediate biasACEBO 2004 4912 4 Low biasTIVE 1998 380 3 High biasTIVE 2003 1715 2.6 Low biasACEBO 2001 1513 3.4 Intermediate biasRATEGY 1998 1148 8.4 High biasTIVE 1998 758 8.4 Intermediate biasACEBO 2007M 1113 4.8 High biasACEBO 2005 1502 4.3 Intermediate biasACEBO 2005 985 1 Intermediate biasACEBO 2000 3577 4.5 Intermediate biasTIVE 2005 13 101 4.9 Low biasTIVE 2008 5137 5.5 High-BiasTIVE 2001 572 6.1 High biasRATEGY 2001 1501 3.8 High biasTIVE 2003 1302 3.5 High biasTIVE 2004 6400 2.7 High biasTIVE 2004 372 3 High biasTIVE 2002 1195 3 Low biasTIVE 2006 498 2.5 High biasTIVE 2000 727 4.5 High biasACEBO 1996 583 4.5 Low biasTIVE 2000 719 5 High biasACEBO 1999 492 2 High biasACEBO 2008 5743 2.5 High biasACEBO 2004 761 3.9 Intermediate bias

agener,%20Gilbert.pdf.

http://publishing.eur.nl/ir/repub/asset/10627/071026_Wagener,%2520Gilbert.pdf

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Effects of BP reduction on MI and stroke in diabetes Reboldi et al. 1255

Set Search

1 antihypertensive agent/2 angiotensin 1 receptor antagonist/3 angiotensin receptor/4 LOSARTAN/5 VALSARTAN/6 IRBESARTAN/7 CANDESARTAN HEXETIL/ or CANDESARTAN/8 TELMISARTAN/9 EPROSARTAN/10 OLMESARTAN/11 TASOSARTAN/12 angiotensin-converting enzyme inhibitors.mp.13 CAPTOPRIL/14 RAMIPRIL/15 FOSINOPRIL/16 LISINOPRIL/17 CILAZAPRIL/18 PERINDOPRIL/19 ZOFENOPRIL/20 BENAZEPRIL/21 QUINAPRIL/22 SPIRAPRIL/23 temocapril/24 IMIDAPRIL/25 MOEXIPRIL/26 beta adrenergic receptor blocking agent/27 ATENOLOL/28 CARVEDILOL/29 METOPROLOL/30 PROPRANOLOL/31 OXPRENOLOL/32 PINDOLOL/33 calcium channel blocking agent/34 AMLODIPINE/35 FELODIPINE/36 LACIDIPINE/37 MEPIRODIPINE/38 NIFEDIPINE/39 NISOLDIPINE/40 NITRENDIPINE/41 VERAPAMIL/42 DILTIAZEM/43 diuretic agent/44 HYDROCHLOROTHIAZIDE/45 CHLOROTHIAZIDE/46 chlorthalidone/47 AMILORIDE/48 TRIAMTERENE/49 INDAPAMIDE/50 BENDROFLUMETHIAZIDE/51 METHYCLOTHIAZIDE/52 hydrochlorothiazide and triamterene/53 spironolactone/54 or/1–5355 randomized controlled trial/56 controlled clinical trial/57 or/55–5658 and/54,5759 child/60 retrospective study/61 meta analysis/62 editorial/63 ‘review’/64 or/59–6365 58 not 64

‘zofenopril ‘[Substance Name]) OR ‘benazepril

‘[Substance Name]) OR ‘quinapril ‘[Substance Name])

OR ‘spirapril ‘[Substance Name]) OR ‘temocapril hydro-

chloride ‘[Substance Name]) OR ‘imidapril ‘[Substance

Name]) OR ‘moexipril ‘[Substance Name]) OR ‘Adre-

nergic beta-Antagonists’[Mesh]) OR ‘Atenolol’[Mesh])

OR ‘Carvedilol’[ Substance Name]) OR (’Metoprolol’

[Mesh]) OR ‘Propranolol’[Mesh]) OR ‘Oxprenolol’

[Mesh]) OR ‘Pindolol’[Mesh]) OR ‘Calcium Channel

Blockers’[Mesh]) OR ‘Amlodipine’[Mesh]) OR ‘Felodi-

pine’[Mesh]) OR ‘lacidipine ‘[Substance Name]) OR

‘mepirodipine ‘[Substance Name]) OR ‘Nifedipine’

[Mesh]) OR ‘Nisoldipine’[Mesh]) OR ‘Nitrendipine’

[Mesh]) OR ‘Verapamil’[Mesh]) OR ‘Diltiazem’[Mesh])

OR ‘Diuretics’[Mesh]) OR ‘Hydrochlorothiazide’

[Mesh]) OR ‘Chlorothiazide’[Mesh]) OR ‘Chlorthalido-

ne’[Mesh]) OR ‘Amiloride’[Mesh]) OR ‘Triamterene’

[Mesh]) OR ‘Indapamide’[Mesh]) OR ‘Bendroflumethia-

zide’[Mesh]) OR ‘Methyclothiazide’[Mesh]) OR ‘hydro-

chlorothiazide-triamterene ‘[Substance Name]) OR

‘hydrochlorothiazide-spironolactone ‘[Substance Name])

OR ‘Furosemide’[Mesh]) OR ‘Placebos’[Mesh]) AND

((’Randomized Controlled Trial ‘[Publication Type]) OR

‘Controlled Clinical Trial ‘[Publication Type])) NOT

‘Child’[Mesh]) NOT ‘Retrospective Studies’[Mesh])

NOT ‘Meta-Analysis ‘[Publication Type]) NOT

‘Review ‘[Publication Type]) NOT ‘Editorial ‘[Publi-

cation Type]

CENTRAL records: 36887 (on 31 March 2010). (antihy-

pertensive agents ):kw or (angiotensin II type 1 receptor

blockers ):kw or (receptors, angiotensin ):kw or (losar-

tan):kw or (valsartan):kw or (irbesartan):kw or (cande-

sartan):kw or (candesartan cilexetil):kw or (telmisar-

tan):kw or (eprosartan):kw or (olmesartan):kw or

(tasosartan):kw or (angiotensin-converting enzyme inhi-

bitors):kw or (captopril):kw or (ramipril):kw or (fosino-

pril):kw or (lisinopril):kw or (perindopril):kw or (zofeno-

pril):kw or (benazepril):kw or (quinapril):kw or

(spirapril):kw or (temocapril hydrochloride):kw or (imi-

dapril):kw or (moexipril):kw or (adrenergic beta-antag-

onists):kw or (atenolol):kw or (carvedilol):kw or (meto-

prolol):kw or (propranolol):kw or (oxprenolol):kw or

(pindolol):kw or (calcium channel blockers):kw or

(amlodipine):kw or (felodipine):kw or (lacidipine):kw

or (mepirodipine):kw or (nifedipine):kw or (nisoldipi-

ne):kw or (nitrendipine):kw or (verapamil):kw or

(diltiazem):kw or (diuretics):kw or (hydrochloro-

thiazide):kw or (chlorothiazide):kw or (chlorthalido-

ne):kw or (amiloride):kw or (triamterene):kw or

(indapamide):kw or (bendroflumethiazide):kw or

(methyclothiazide):kw or (hydrochlorothiazide-

triamterene):kw or (hydrochlorothiazide-spironolacto-

ne):kw or (furosemide):kw or (placebos):kw and

((randomized clinical trials):kw or (controlled clinical

trials):kw)

EMBASE records: 15980 (on 31 March 2010).


Data synthesisOn the basis of the above criteria, we identified 31 trials

(Table 2) corresponding to 40 arms of treatment, for a

total of 73 913 diabetic patients and 295 652 patient-years

of exposure [13–41]. Five additional trials [22,42–45], for

a total of 3705 diabetic patients, were excluded for the


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Table 2 Number of patients and outcome events reporting in the selected randomized comparisons

Study/armType ofcomparator

Number randomized inexperimental arm

Number randomizedin control arm

Strokereported

AMIreported

ABCD/HYP ACTIVE 235 235 Yes YesABCD/Norm ACTIVE 234 246 Yes YesALLHAT/ACE-CCB ACTIVE 3510 3597 Yes NoALLHAT/ACE-D ACTIVE 3510 5994 Yes NoALLHAT/CCB-D ACTIVE 3597 5994 Yes NoASCOT ACTIVE 2565 2572 Yes YesCAPPP ACTIVE 309 263 Yes YesDETAIL ACTIVE 120 130 Yes YesFACET ACTIVE 189 191 Yes YesIDNT/ARB-CCB ACTIVE 579 567 Yes YesINSIGHT ACTIVE 649 653 Yes NoINVEST ACTIVE 3169 3231 Yes YesJMIC-B ACTIVE 199 173 Yes YesLIFE ACTIVE 586 609 Yes YesMOSES ACTIVE 245 253 Yes NoNORDIL ACTIVE 351 376 Yes YesSTOP2/ACE-BB ACTIVE 235 253 Yes YesSTOP2/ACE-CCB ACTIVE 236 231 Yes YesSTOP2/CCB-BB ACTIVE 231 253 Yes YesUKPDS39 ACTIVE 400 358 Yes YesACTION PLACEBO 567 546 Yes YesADVANCE PLACEBO 5569 5571 Yes YesATLANTIS/1.25 PLACEBO 44 46 No YesATLANTIS/5 PLACEBO 44 46 No YesDIABHYCAR PLACEBO 2443 2469 Yes YesEUROPA PLACEBO 721 781 Yes YesHOPE PLACEBO 1808 1769 Yes YesIDNT/ARB-PLACEBO PLACEBO 579 569 Yes YesIDNT/CCB-PLACEBO PLACEBO 567 569 Yes YesMERIT-HF PLACEBO 495 490 No YesPROFESS PLACEBO 2840 2903 Yes NoPROGRESS PLACEBO 393 368 Yes NoRENAAL PLACEBO 752 761 Yes YesSHEP PLACEBO 283 300 Yes NoSYST-EUR PLACEBO 252 240 Yes NoABCD-H More vs. Less STRATEGY 237 233 Yes YesABCD-N More vs. Less STRATEGY 237 243 Yes YesACCORD STRATEGY 2362 2371 Yes YesHOT-DM More vs. Less STRATEGY 499 1002 Yes YesUKPDS38 STRATEGY 758 390 Yes Yes

absence of data on stroke or MI. Data extraction was done

independently by two reviewers (G.G. and F.A.) on the

basis of an intention-to-treat approach, and inconsisten-

cies were discussed and resolved in conference. Refer-

ence treatment refers to placebo, active control, or a less

tight BP-lowering strategy. Experimental treatment

refers to any of the five antihypertensive drug classes

mentioned above used alone or in combination, or to a

more tight BP-lowering strategy.

The methodological quality of trials was assessed with

the methods recommended by the Cochrane Collabor-

ation for assessing the risk of bias [46]. The criteria used

for quality assessment were sequence generation of allo-

cation, allocation concealment, masking of participants,

personnel, and outcome assessors, incomplete outcome

data, selective outcome reporting, and other sources of

bias. We classified studies with high risk for bias in any of

the above components as lower-quality studies.

Figure 1 shows the flow diagram with information about

the selected, included and excluded trials. The flow

diagram was prepared according to the Preferred Report-


ing Items for Systematic Reviews and Meta-Analyses

(PRISMA) statement [47].

Data analysisWe calculated relative risks (RRs) and 95% confidence

intervals (CIs) for each endpoint for each trial separately,

and for combination of studies according to fixed and

random-effects models. For multiarm trials, we analysed

only the preplanned comparisons, as defined in the

original study design [48]. The null hypothesis of hom-

ogeneity across individual trials was tested by using the

Q-test. Pooled estimates were assessed for heterogeneity

by using the I2 statistics. Publication bias was tested by

visual inspection of the funnel plot and, more formally,

with a weighted regression test [46].

Heterogeneity was explored by conducting the analysis

in the following subgroups: trial quality score, trial popu-

lation (only diabetics or diabetic subgroup), type of

comparator (placebo or active treatment or BP-lowering

strategy), baseline SBP and DBP tertiles, final SBP and

DBP tertiles, baseline-corrected differences in achieved


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Fig. 1

Search for potentially relevant trials from electronic databases MEDLINE: 35 398 records CENTRAL: 36 887 records EMBASE: 15 980 records

Additional records identified through other sources: 9

Records screened (after duplicates removed) n = 45 626

Excluded (n = 45 456) for: • Studies in animals (n = 291) • Non-cardiovascular studies (n = 45 135) • No control group (n = 30)

Full-text articles assessed for eligibility n = 170

Excluded (n = 134) for: • no data in diabetic patients

Studies identified: Diabetes mellitus primary studies (n = 15)

Diabetes mellitus substudies (n = 21) n = 36

Final selection n = 31

Excluded (n = 5) for: • No data regarding either stroke or myocardial infarction

Criteria for selection of trials.

SBP and DBP (follow-up minus baseline) between

experimental and reference treatment, and meta-

regression analysis [49]. The potential effect modifiers,

as identified from the exploratory fixed-effect subgroup

analysis, were further evaluated by random-effect meta-

regressions. The fit of the model was assessed using the

proportion of the between-study variance explained by

the covariates (adjusted r2), along with a significance test

for each covariate. To control for false-positive findings

(type I error), when performing meta-regression with

multiple covariates, we used the model F value and its

statistical significance to assess whether there was evi-

dence for an association of any of the covariates with the

outcome, and a test based on random permutations to

calculate multiplicity adjusted P values [50]. We also

calculated the 95% prediction intervals around the fitted

line to illustrate the uncertainty about the effect we might

predict in a future study with a given value of the covari-

ates. Assumptions of linear associations between differ-

ences in follow-up BP levels and log relative risk were

tested with standard graphical methods [51].

Analytical meta-analyses, that is those aimed at estimat-

ing a ‘common’ effect, can be used to investigate the

association between the magnitude of BP reduction and

the risk of adverse cardiovascular events by pooling


several trials independently of time. Conversely, a cumu-

lative sequential analysis can establish if and when firm

evidence favouring a specific intervention has been

reached in the literature collected so far [52,53]. To

investigate the conclusiveness of available evidence

favouring specific interventions we defined three main

study domains: active drugs vs. placebo, tight vs. less

tight BP-lowering strategy, and studies selectively com-

paring CCBs/ACE-i/ARBs vs. other active compounds.

Cumulative sequential analysis requires a prespecified

and clinically relevant intervention effect as well as an

overall risk of type I error to be maintained [53]. We

deemed an a priori specified relative risk reduction

(RRR) of 15 and 20% to be clinically relevant, and we

set alpha at 5% (two-sided) being the standard in most

meta-analyses and systematic reviews [46]. With this

information, we calculated the required information size

(i.e. the number of participants in the meta-analysis

required to accept or reject the specific intervention

effect) with adjustment for between-trial heterogeneity

when present (i.e. I2 >0). Then, we constructed the

adjacent two-sided sequential monitoring boundaries

(SMBs) for 15 or 20% RRR based on the Lan-DeMets

alpha-spending function to control the overall type I error

as statistical tests were repeated throughout the accumu-

lation of studies [53,54]. We constructed the cumulative


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Z-curve (i.e. Z-statistics after each trial) for each cumu-

lative random-effects meta-analysis and assessed its cross-

ing of the conventional significance level and the monitor-

ing boundaries. The monitoring boundaries should be

crossed by the cumulative Z-curve to obtain firm evidence

for an intervention effect. Crossing of Z¼ 1.96 provides a

‘conventionally’ significant result, whereas crossing of the

monitoring boundary denotes firm evidence adjusted for

random error risk. Cumulative Z-curves not crossing

Z¼ 1.96 indicate absence of evidence if the information

size is not reached or lack of the specific intervention effect

if the information size is reached.

Analyses were performed using Stata, version 11.1

(StataCorp LP, College Station, Texas, USA), and R

version 2.12.1 (R Foundation for Statistical Computing,

Vienna, Austria).

ResultsTable 2 summarizes the 31 trials that satisfied all the

inclusion criteria. We extracted stroke data from 29 trials

(corresponding to 37 arms of treatment) and MI data from

24 trials (corresponding to 31 arms of treatment).

The linear regression tests of funnel plot asymmetry

(Fig. 2) yielded P values of 0.292 and 0.3614 for stroke

and MI, respectively, consistent with no statistical evi-

dence for publication bias.

The overall RR of stroke was significant (RR¼ 0.91, 95%

CI 0.86–0.97, P¼ 0.0059; I2 33.1%; Fig. 3) and consistent

across subgroups (Fig. 4) defined by the trial population

(studies exclusively conducted in diabetic patients vs.

ad-hoc analyses of diabetic patients in studies which

included nondiabetic individuals), baseline SBP and


Fig. 2

0.1 0.2 0.5 1.0 2.0 5.0

2

4

6

8

10

Relative risk

Inve

rse

of s

tan

dar

d e

rro

r

2

4

6

8

10

Stroke

Test offunnel plotasymmetryP = 0.292

Funnel plots for publication bias of studies reporting stroke (left) and myocar(RR)] on the horizontal axis and its precision (inverse of the standard error)

DBP (tertiles), and achieved SBP and DBP at follow-

up (tertiles). On the contrary, the estimated benefit

showed a significant heterogeneity in subgroups defined

by type of comparator (P¼ 0.003), and by tertiles of

the difference in achieved SBP (P¼ 0.013) and DBP

(P¼ 0.001). The overall estimate for the risk of MI

(RR¼ 0.89, 95% CI 0.83–0.96, P¼ 0.0015, I2 37.5%;

Fig. 5) was also significant, with no heterogeneity across

subgroups. In studies comparing active treatments

(Fig. 6) CCBs were more protective for stroke

(RR¼ 0.88, 95% CI 0.78–0.99, P¼ 0.036) than other

active comparators, whereas ACEi and ARBs did not

significantly differ. Conversely, ACEi reduced the risk

of MI by some 30% at the point estimate, though without

reaching formal statistical significance (P¼ 0.094) and

with large between-trial heterogeneity

Figure 7 shows the results on stroke and MI in studies

that directly compared different BP goals. Compared

with a less tight BP control, allocation to a tighter BP

control significantly reduced the risk of stroke by 39%

(RR 0.61, 95% CI 0.48–0.79, P< 0.001) (Fig. 7a). In

contrast, the risk of MI was reduced by only 13% (RR

0.87, 95% CI 0.74–1.02, P¼ 0.084), with the upper con-

fidence limit crossing the identity line (Fig. 7b).

Meta-regression analysisStratified analyses can be used to investigate the possibility

that treatment effects vary between predefined sub-

groups. However, comparisons between subgroups can

be more suitably performed by meta-regression analysis

when within-subgroup heterogeneity is moderate or

large (I2> 50%) [50]. We used separate random-effect

meta-regression models to investigate the role of potential


0.1 0.2 0.5 1.0 2.0 5.0

Relative risk

Myocardial Infarction

Test offunnel plotasymmetryP = 0.361

dial infarction (right). Each study is plotted by its effect size [relative riskon the vertical axis.

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Fig. 3

Heterogeneity between subgroups: p=0.003

FEM overall (I2=33.1% [0%; 55.3%], P = 0.029)

RENAAL

DIABHYCAR

INVEST

REM overall

ABCD−H more vs less

SHEP

ALLHAT/ACE−CCB

REM subtotal

UKPDS−38

REM subtotal

SYST−EUR

ADVANCE

ALLHAT/ACE−D

ACCORD BP

UKPDS−39

NORDIL

ASCOT

IDNT/CCB−PLB

STOP2/CCB−BB

HOPE

CAPPP

Less tight BP control

ACTIVE control

PROFESS

FEM subtotal (I2= 35.6%, P = 0.105)

JMIC−B

ACTION

INSIGHT

EUROPA

LIFE

PLACEBO controlIDNT/ARB−PLB

HOT−DM more vs less

ABCD/HYP

ABCD−N more vs less

FEM subtotal (I2=13.8%, P = 0.283)

STOP2/ACE−CCB

STOP2/ACE−BB

FACETIDNT/ARB−CCB

MOSES

ABCD/Norm

FEM subtotal (I2=0.0%, P = 0.523)REM subtotal

DETAIL

ALLHAT/CCB−D

PROGRESS

1

Favors controlFavors experimental

0.50.2 5

Studyacronym

ARB

ACE

CCB

DBP 75 mmHg

Diur

ACE

SBP/DBP <150/85 mmHg

CCB

ACE+Diur

ACE

SBP <120 mmHg

ACE

CCB

CCB

CCB

CCB

ACE

ACE

ARB

CCB

CCB

CCB

ACE

ARB

ARB

DBP <80 mmHg

CCB

DBP 10 mmHg below baseline

ACE

ACE

ACEARB

ARB

CCB

ARB

ACE

ACE

Experimentaldrug

Placebo

Placebo

Conv Treat

DBP 80−89 mmHg

Placebo

CCB

SBP/DBP <180/105 mmHg

Placebo

Placebo

Diur

SBP <140 mmHg

BB

BB/Diur

BB

Placebo

BB/Diur

Placebo

BB/Diur

Placebo

ACE

Placebo

Diur

Placebo

BB

Placebo

DBP <85−90 mmHg

ACE

DBP 80−89 mmHg

CCB

BB/Diur

CCBCCB

CCB

ACE

ACE

Diur

Placebo

Controldrug

0.91 (0.86, 0.97)

0.95 (0.65, 1.40)

1.03 (0.80, 1.32)

0.83 (0.56, 1.23)

0.90 (0.83, 0.97)

0.61 (0.48, 0.79)

0.98 (0.40, 2.43)

0.74 (0.45, 1.19)

1.16 (0.95, 1.42)

0.97 (0.88, 1.06)

0.58 (0.37, 0.90)

0.88 (0.78, 1.00)

0.32 (0.12, 0.86)

0.99 (0.82, 1.19)

1.06 (0.89, 1.26)

0.58 (0.39, 0.88)

1.11 (0.59, 2.06)

1.07 (0.59, 1.96)

0.76 (0.59, 0.98)

0.58 (0.31, 1.08)

0.81 (0.52, 1.27)

0.69 (0.52, 0.92)

1.03 (0.57, 1.85)

0.98 (0.85, 1.13)

0.91 (0.84, 0.99)

0.58 (0.17, 2.02)

1.22 (0.67, 2.19)

0.90 (0.47, 1.72)

0.85 (0.46, 1.56)

0.82 (0.58, 1.16)

1.06 (0.63, 1.78)

0.80 (0.41, 1.56)

1.57 (0.62, 3.98)

0.32 (0.10, 0.95)

0.97 (0.90, 1.05)

1.15 (0.73, 1.83)

0.94 (0.61, 1.43)

0.40 (0.13, 1.27)1.83 (0.99, 3.39)

0.83 (0.59, 1.16)

1.93 (0.72, 5.13)

0.61 (0.48, 0.79)

1.08 (0.36, 3.27)

0.91 (0.76, 1.09)

0.69 (0.49, 0.98)

Strokerelative risk

(95% CI)

FEM Fixed effect modelREM random effect model

Relative risk of stroke for patients with diabetes in randomized controlled trials. Solid squares represent the relative risk in individual trials, with a sizeproportional to the inverse of variance. Bars and diamond denote the 95% confidence intervals for individual trials and pooled estimates, respectively.

effect modifiers on residual between-trial variance (see

Methods section). Larger differences in achieved SBP and

DBP predicted greater reductions in the risk of stroke,

but not in the risk of MI (Tables 3 and 4). For each

5-mmHg reduction in SBP, and 2-mmHg reduction in

DBP, there was a 13 and 11.5% reduction, respectively, in

the risk of stroke, the P values being statistically significant

also when adjusted for multiplicity. On the contrary, for

each 5-mmHg reduction in SBP, reduction in the risk of

MI was not significant, this being the case also for each

2 mmHg reduction in DBP (Table 4).

The relation between RR of stroke and MI and the SBP

and DBP difference between the randomized groups

throughout the BP range explored in the trials is reported


in Figs 8 and 9. For stroke, the 95% prediction interval

(which reflects the degree of certainty by which the effect

of a given BP reduction can be predicted including the

random effect) was entirely positioned below unity when

the between-group difference in the BP reduction was at

least 4.8 mmHg in SBP, or at least 1.7 mmHg in DBP. For

MI, the 95% prediction interval was never entirely posi-

tioned below unity for any BP level, indicating that in

diabetic patients the risk of MI is not related to the

difference in achieved BP reduction.

Cumulative sequential analysisPlacebo controlled studies

For the outcome of stroke and MI, the cumulative

Z-curve crossed both the traditional boundary and


C


Fig. 4

0.99 (0.88, 1.13) 0.84 (0.76, 0.93) 0.87 (0.74, 1.02)

0.88 (0.80, 0.98) 0.94 (0.82, 1.08) 0.85 (0.74, 0.98)

0.86 (0.77, 0.95) 0.95 (0.83, 1.08) 0.86 (0.71, 1.05)

0.98 (0.87, 1.11) 0.85 (0.77, 0.94) 0.78 (0.63, 0.96)

0.96 (0.85, 1.10) 0.86 (0.77, 0.96) 0.86 (0.73, 1.01)

0.97 (0.83, 1.13) 0.82 (0.74, 0.92) 0.92 (0.81, 1.04)

1.05 (0.89, 1.23) 0.85 (0.76, 0.94) 0.85 (0.74, 0.97)

0.89 (0.83, 0.96)

57 0 0

0 53 56

0 46 68

47 49 48

55 35 59

67 27 0

70 0 0

1 0.5 1 1.5

Type of comparator Active Placebo More vs less

Baseline SBP tertile

136-147 mmHg 148-160 mmHg 161-196 mmHg

Baseline DBP tertile

76-84 mmHg 85-94 mmHg 95-105 mmHg

F/U SBP tertile

119.3-138.4 mmHg 138.5-144.0 mmHg 144.1-161.8 mmHg

F/U DBP tertile 64-76 mmHg 77-79 mmHg 80-89 mmHg

Difference in achieved SBP -6.4-0.0 mmHg 0.1-4.0 mmHg 4.1-13.8 mmHg

Difference in achieved DBP -2.8-0.0 mmHg 0.1-2.9 mmHg 3.0-8.0 mmHg

Overall

I2 33.1% [0%; 55.3%]] Test of RR = 1 z = 2.8 P = 0.0059

Subgroup

0.97 (0.90, 1.05) 0.91 (0.84, 0.99) 0.61 (0.48, 0.79)

0.97 (0.89, 1.05) 0.86 (0.74, 0.98) 0.82 (0.71, 0.94)

0.94 (0.87, 1.01) 0.81 (0.70, 0.93) 0.91 (0.77, 1.08)

0.87 (0.78, 0.97) 0.98 (0.90, 1.07) 0.85 (0.72, 1.00)

0.97 (0.89, 1.05) 0.82 (0.71, 0.94) 0.86 (0.74, 1.01)

1.01 (0.92, 1.11) 0.85 (0.76, 0.95) 0.82 (0.73, 0.93)

1.01 (0.93, 1.10) 0.88 (0.79, 0.97) 0.69 (0.58, 0.82)

0.91 (0.86, 0.97)

Relative risk(95% CI)

P-valuefor subgroupheterogenity

14 36 0

53 27 0

52 44 0

32 53 0

45 41 0

2 19 48

17 0

22

I2

1 0.5 1 1.5

0.94 (0.85, 1.04) 0.84 (0.76, 0.93)

43 24

Trial population Only diabetics Sub-group

0.93 (0.83, 1.04) 0.92 (0.86, 0.99)

48 21

Stroke Myocardial Infarction

Overall

I2 37.5% [3.4%; 59.6%] Test of RR = 1 z = 3.2 P = 0.0015

0.87 (0.78, 0.96) 0.91 (0.83, 1.00)

0.116

0.623

0.445

0.103

0.354

0.188

0.066

0.003

0.075

0.191

0.146

0.096

0.013

0.001

0.103 0.938

0.489 19 51

Trial methdological quality Low High

0.88 (0.80, 0.97) 0.94 (0.87, 1.01) 0.308

24 26

Favors experimental Favors control Favors experimental Favors control

Relative risk(95% CI)

P-valuefor subgroupheterogenity I2

Consistency of the pooled estimate for stroke and myocardial infarction across predefined subgroups. See text for explanations.

adjacent SMBs, demonstrating reliable evidence for a 15

and 20% RRR in the active treatment group compared

with the placebo group (Fig. 10).

More tight vs. less tight blood pressure control strategies

The cumulative Z-curve crossed the traditional boundary

and the SMBs only for stroke (Fig. 11) but not for MI,

suggesting that firm evidence favouring tighter BP control

strategy has been reached so far only for stroke. The

cumulative Z-curve for MI appears very close to the

conventional boundary though without complete crossing.

Studies comparing CCB, ACE-I, and angiotensin receptor

antagonists with other active drugs

There was lack of firm evidence favouring one specific

drug class over another for both stroke and MI for either

benefit or harm (Fig. 12). The cumulative Z-curve for

CCBs crossed the conventional boundary for stroke


benefit at a point exceeding the required information

size, whereas for MI the Z-curve lies in the lower quad-

rant favouring comparator drugs though without crossing

any boundary. ACE-i cumulative Z-curves moved in the

opposite direction of those of CCBs for stroke and MI,

respectively, although they did not cross any boundary.

The cumulative evidence for ARBs studies appeared well

below the minimum requirements for sequential analysis.

DiscussionThe present analysis of a large number of diabetic

patients included in outcome-based trials provides the

following main results. One, we found a consistent

relationship between BP reduction and prevention of

stroke. Two, our analyses did not disclose a significant

association between the magnitude of BP reduction and

prevention of MI. Three, the relationship between the

degree of BP reduction and the risk of MI was not


C


Fig. 5

Heterogeneity between subgroups: p = 0.116

FEM overall (I2=37.5%[3.4%; 59.6%], p=0.020)

RENAAL

ABCD/HYP

UKPDS−39

PLACEBO control

ASCOTINVEST

LIFENORDIL

Less tight BP controlABCD−H more vs less

DETAIL

ATLANTIS/5

ABCD−N more vs less

REM subtotal

ABCD/norm

STOP2/ACE−CCB

IDNT/ARB−CCB

STOP2/ACE−BB

JMIC−B

ATLANTIS/1.25

ACTIVE control

REM subtotal

MERIT−HF

DIABHYCAREUROPAACTION

STOP2/CCB−BB

HOT−DM more vs less

IDNT/ARB−PLB

HOPEADVANCE

FEM subtotal (I2=0.0%, p=0.582)

CAPPP

FACET

UKPDS−38ACCORD BP


REM overall

REM subtotal

IDNT/CCB−PLB


0.89 (0.83, 0.96)

0.74 (0.52, 1.06)

3.00 (1.44, 6.24)

1.19 (0.83, 1.69)

0.89 (0.68, 1.17)1.04 (0.74, 1.46)

0.85 (0.57, 1.27)1.01 (0.53, 1.93)

1.12 (0.56, 2.25)

1.35 (0.55, 3.32)

1.05 (0.07, 16.20)

1.30 (0.68, 2.49)

0.99 (0.81, 1.22)

1.18 (0.62, 2.26)

0.52 (0.30, 0.91)

1.60 (1.00, 2.54)

0.70 (0.39, 1.26)

0.87 (0.22, 3.42)

2.09 (0.20, 22.25)

0.84 (0.76, 0.93)

1.30 (0.69, 2.46)

0.79 (0.57, 1.10)0.78 (0.56, 1.08)0.88 (0.62, 1.25)

1.35 (0.83, 2.19)

0.64 (0.27, 1.49)

0.94 (0.63, 1.40)

0.79 (0.66, 0.95)1.01 (0.80, 1.27)

0.87 (0.74, 1.02)

0.38 (0.20, 0.73)

0.78 (0.35, 1.73)

0.80 (0.60, 1.05)0.87 (0.69, 1.09)

0.84 (0.76, 0.93)

0.91 (0.82, 1.00)

0.87 (0.74, 1.02)

0.59 (0.37, 0.93)

0.99 (0.88, 1.13)

10.2 0.5 5FEM fixed effect modelREM random effect model

Studyacronym

ARB

CCB

ACE

CCBCCB

ARBCCB

DBP 75 mmHg

ARB

ACE

DBP 10 mmHg below baseline

CCB

ACE

ARB

ACE

CCB

ACE

BB

ACEACECCB

CCB

DBP <80 mmHg

ARB

ACEACE+Diur

ACE

ACE

SBP/DBP <150/85 mmHgSBP <120 mmHg

CCB

Experimentaldrug

Placebo

ACE

BB

BBConv Treat

BBBB/Diur

DBP 80−89 mmHg

ACE

Placebo

DBP 80−89 mmHg

ACE

CCB

CCB

BB/Diur

ACE

Placebo

Placebo

PlaceboPlaceboPlacebo

BB/Diur

DBP <85−90 mmHg

Placebo

PlaceboPlacebo

BB/Diur

CCB

SBP/DBP <180/105 mmHgSBP <140 mmHg

Placebo

Controldrug

Myocardial infarctionrelative risk

(95% CI)

Favors controlFavors experimental

Relative risk of myocardial infarction for patients with diabetes in randomized controlled trials. Solid squares represent the relative risk in individualtrials, with a size proportional to the inverse of variance. Bars and diamond denote the 95% confidence intervals for individual trials and pooledestimates, respectively.

J-shaped, suggesting that a more intensive reduction of

BP, whereas not providing additional benefit, does not

increase the risk of MI. Four, the above findings apply to

both SBP and DBP reductions induced by treatment.

Five, cumulative sequential analysis provided firm evi-

dence for stroke and MI risk reduction in studies com-

paring active treatment with a placebo, but only for stroke

when comparing more vs. less tight treatment target

strategies. There was lack of firm evidence favouring

one specific drug class over another for both stroke and

MI for either benefit or harm.

Our results are consistent with the conclusion of previous

meta-analyses, and individual outcome-based trials, that


for any reduction of BP induced by treatment, protection

against stroke is superior to that against MI [55–58].

However, neither individual trials nor meta-analyses

elucidated the protective role of BP reduction on

cause-specific events such as stroke and MI in the pre-

specified population of patients with diabetes. For

example, in the meta-analysis of the Blood Pressure

Lowering Treatment Trialists’ Collaboration (BPLTTC)

[59], treatment strategies targeting lower BP values led to

a significantly greater reduction in the risk of overall or

fatal total cardiovascular event in patients with diabetes

than in those without diabetes (P¼ 0.03 and 0.02,

respectively, by x2 test of homogeneity). That is, whereas

in patients without diabetes the RR of a total or fatal


C


Fig. 6


FEM overall (I2=13.8%, P = 0.283)

ALLHAT/ACE−CCB

LIFE

ARB


REM subtotal

REM subtotal

INSIGHT

FEM subtotal (I2=0.0%, P = 0.597)

STOP2/ACE−BB

ALLHAT/CCB−D

ABCD/Norm

CAPPP

STOP2/ACE−CCB

IDNT/ARB−CCB

NORDILINVEST

JMIC−B

FEM subtotal (I2=0.0%, P = 0.690)

DETAIL

STOP2/CCB−BB

REM overall

CCB

ALLHAT/ACE−D

MOSES

ASCOT

UKPDS−31FACET

ABCD/HYP

ACE

ACE

ARB

CCB

ACE

ACE

CCB

ACE

ACE

ARB

CCBCCB

CCB

ARB

CCB

ACE

ARB

CCB

ACEACE

CCB

CCB

BB

Diur

BB/Diur

Diur

ACE

BB/Diur

CCB

CCB

BB/DiurConv Treat

ACE

ACE

BB/Diur

Diur

CCB

BB

BBCCB

ACE

0.97 (0.90, 1.05)

1.16 (0.95, 1.42)

0.82 (0.58, 1.16)

0.92 (0.74, 1.15)0.98 (0.70, 1.38)

1.08 (0.96, 1.21)

0.88 (0.78, 0.99)

0.90 (0.47, 1.72)

0.88 (0.78, 0.99)

0.94 (0.61, 1.43)

0.91 (0.76, 1.09)

1.93 (0.72, 5.13)

1.03 (0.57, 1.85)

1.15 (0.73, 1.83)

1.83 (0.99, 3.39)

1.07 (0.59, 1.96)0.83 (0.56, 1.23)

0.58 (0.17, 2.02)

1.08 (0.96, 1.21)

1.08 (0.36, 3.27)

0.81 (0.52, 1.27)

0.97 (0.88, 1.06)

1.06 (0.89, 1.26)

0.83 (0.59, 1.16)

0.76 (0.59, 0.98)

1.11 (0.59, 2.06)0.40 (0.13, 1.27)

1.57 (0.62, 3.98)

Studyacronym

Experimentaldrug

Controldrug

Strokerelative risk

(95% CI)

Favors control Favors experimental 10.3 0.5 2.5


FEM overall (I2=56.6%, P = 0.004)

IDNT/ARB−CCB

INVEST

UKPDS−39

ABCD/HYP

REM overall

ACE

NORDIL

REM subtotal

REM subtotalFEM subtotal (I2=42.9%, P = 0.105)

STOP2/ACE−CCB

FEM subtotal (I2=66.9%, P = 0.017)

STOP2/ACE−BB

CCB

ASCOT

STOP2/CCB−BB

ARB

LIFE


JMIC−B

ABCD/Norm

FACET

CAPPP

DETAIL

ARB

CCB

ACE

CCB

CCB

ACE

ACE

CCB

CCB

ARB

CCB

CCB

ACE

ACE

ARB

CCB

Conv Treat

BB

ACE

BB/Diur

CCB

BB/Diur

BB

BB/Diur

BB

ACE

ACE

CCB

BB/Diur

ACE

1.60 (1.00, 2.54)

1.04 (0.74, 1.46)

1.19 (0.83, 1.69)

3.00 (1.44, 6.24)

1.01 (0.53, 1.93)

0.69 (0.44, 1.07)

1.15 (0.89, 1.50)1.07 (0.90, 1.28)

0.52 (0.30, 0.91)

0.78 (0.62, 0.99)

0.70 (0.39, 1.26)

0.89 (0.68, 1.17)

1.35 (0.83, 2.19)

0.85 (0.57, 1.27)

1.13 (0.85, 1.51)1.18 (0.75, 1.86)

0.87 (0.22, 3.42)

1.18 (0.62, 2.26)

0.78 (0.35, 1.73)

0.38 (0.20, 0.73)

1.35 (0.55, 3.32)

0.99 (0.88, 1.13)0.99 (0.81, 1.22)

10.3 0.5 2.5

FEM fixed effect modelREM random effect model

Studyacronym

Experimentaldrug

Controldrug

Myocardial Infarctionrelative risk

(95% CI)

Favors control Favors experimental

Relative risk of stroke (left) and myocardial infarction (right) for patients with diabetes in randomized trials comparing active treatments. Solid squaresrepresent the relative risk in individual trials, with a size proportional to the inverse of variance. Bars and diamond denote the 95% confidenceintervals for individual trials and pooled estimates, respectively.

cardiovascular event remained unaltered or was even

increased by the tight BP control strategy, in diabetic

patients it was significantly reduced by 25 and 33%,

respectively. However, when in diabetic patients the

cause-specific events were addressed separately, the regi-

mens targeting lower BP values did not show a greater

protective effect than those targeting a less tight BP

control. [59]

In the ACCORD trial (which was specifically designed to

compare two different BP goals) 4733 patients with type 2

diabetes were randomized to a tighter (<120 mmHg) or

less tight (<140 mmHg) SBP goal and followed for

4.7 years [9]. Total and nonfatal stroke was less frequent,

by 47 and 53%, respectively, in the more than in the less

tight strategy group, whereas the incidence of MI did not

show any difference between the groups. [9]

The BPLTTC analysis was based on a small number of

trials on diabetic patients (four trials), whereas in the

ACCORD the total number of strokes was small. In the

Ongoing Telmisartan Alone and in Combination With

Ramipril Global Endpoint Trial (ONTARGET), greater

reductions in SBP were associated with a lesser risk for

stroke, but not for MI. However, patients with diabetes


were only 37% of the total ONTARGET population and

the results were obtained by post-hoc analysis of the data,

that is comparisons were done in nonrandomized groups.

[60]

By providing a quantitative assessment of the relation-

ship between the magnitude of BP reduction by treat-

ment and the prevention of MI and stroke in a large

number of diabetic patients, the present analysis extends

previous available information. In quantitative terms, this

analysis shows that for each 5 mmHg greater reduction in

SBP, the risk of stroke decreases by 13%, whereas the risk

of MI does not change significantly, and that similar

effects are produced for each 2 mmHg greater reduction

in DBP. Thus, a policy of pursuing a more intense BP-

lowering in patients with diabetes may be highly

beneficial against cerebrovascular events, but to a lesser

extent against coronary events. Notably, however, cor-

onary complications did not appear to increase as a result

of a J curve phenomenon, which might imply that such

an intensive BP-lowering policy may be worthy to be

adopted anyway.

The potential explanations of our findings remain elu-

sive. In patients with diabetes, glucose control is effective


C


Fig. 7

Weights are from random effects analysis

Overall

I2 =0.0%, P = 0.523

Test of RR = 1, z = 3.75 P < 0.001

ACCORD BP

ssel sv eroM MD-TOH

ssel sv eroM H-DCBA

ssel sv eroM N-DCBA

UKPDS 38

119

145

132

128

Final Systolic BP

Tight BP group mmHg

144

14

3

8

7

Difference in achieved systolic BP

mmHg

9

0.61 (0.48, 0.79 )

0.58 (0.39, 0.88 )

)65.1 ,14.0( 08.0

)34.2 ,04.0( 89.0

)59.0 ,01.0( 23.0

StrokeRelative risk

(95% CI)

)09.0 ,73.0( 85.0

99/4094

36/2363

12/499

9/237

4/237

n/N Tight BP control

38/758

148/4239

62/2371

30/1002

9/233

13/243

34/390

Tight control better

Less tight control better

1 0.2 0.5 2.5

10* 129*

n/N Less tight BP

control Study

(a)

(b)

Acronym

Weights are from random effects analysis

Overall I2 = 0.0%, P = 0.582 Test of RR = 1, z = 1.73 P = 0.084

ssel sv eroM N-DCBA

ssel sv eroM H-DCBA

ssel sv eroM MD-TOH

PB DROCCA

83 SDPKU

)20.1 ,47.0( 78.0

)94.2 ,86.0( 03.1

)52.2 ,65.0( 21.1

)94.1 ,72.0( 46.0

)90.1 ,96.0( 78.0

)50.1 ,06.0( 08.0

275/4094

19/237

16/237

7/499

126/2363

107/758

266/4239

15/243

14/233

22/1002

146/2371

69/390

1 0.5 2.5

119

145

132

128

144

14

3

8

7

9

129* 10*

Final Systolic BP

Tight BP group mmHg

Differencein achievedaystolic BP

mmHg

Myocardial infarctionRelative risk

(95% CI) n/N

Tight BP control

n/N Less tight BP

control StudyAcronym

Tight control better Less tight control better

Upper panel: pooled estimate for stroke in trials comparing different blood pressure-lowering strategies. Lower panel: pooled estimate for myocardialinfarction in trials comparing different blood pressure-lowering strategies. �The final weighted SBP mean and difference in achieved is calculated byweighting the observed values in each contributing trial by the number of randomized patients.

for prevention of MI [61,62]. In a meta-analysis of five

prospective trials, an intensive compared with standard

glucose control was associated with a significant 15%

reduction in the risk of MI [61], and similar results

emerged from another meta-analysis [62]. The variable

impact of glucose control on the risk of MI in individual


studies may be difficult to explain, although some poten-

tial effect modifiers including duration and severity of

diabetes differed across the studies. Several basic mech-

anisms including inflammation, endothelial dysfunction,

increased oxidative stress and pro-thrombotic state have

been proposed to link hyperglycaemia with accelerated


C


Fig. 8

DETAIL

ABCD/HYP

ABCD/Norm

JMIC−B

IDNT/ARB−CCB

FACET

MOSES

STOP2/ACE−CCB

ALLHAT/ACE−CCB

ALLHAT/CCB−D

INSIGHT

STOP2/CCB−BB

LIFE

STOP2/ACE−BB

ASCOT

INVEST

UKPDS−39ALLHAT/ACE−D

CAPPPIDNT/ARB−PLB

RENAAL

SHEP

PROGRESS

IDNT/CCB−PLB

ACTION

EUROPA

DIABHYCAR

SYST−EUR

HOPE

ADVANCE ABCD−H More vs Less

ACCORD BPUKPDS−38

HOT−DM More vs Less

ABCD−N More vs Less

0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

2.25

2.50

2.753.00

Rel

ativ

e ri

sk o

f str

oke

−6 −4 −2 0 2 4 6 8 10 12 14 16 18 20

SBP difference between randomized groups (mmHg)

DETAIL

ABCD/HYP

ABCD/Norm

JMIC−B

IDNT/ARB−CCB

FACET

STOP2/ACE−CCB

STOP2/CCB−BB

LIFE

STOP2/ACE−BB

ASCOT

INVEST

UKPDS−39

CAPPP

IDNT/ARB−PLB

RENAAL

IDNT/CCB−PLB

ACTION

EUROPA

DIABHYCARHOPE

ADVANCE

ATLANTIS/5

ATLANTIS/1.25

ABCD−H More vs Less

ACCORD BP

UKPDS−38



0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

2.25

2.50

2.753.00

Rel

ativ

e ri

sk o

f myo

card

ial i

nfa

rcti

on

−6 −4 −2 0 2 4 6 8 10 12 14 16 18 20

SBP difference between randomized groups (mmHg)

Relation between the SBP difference between randomized groups and the relative risk for stroke (left panel) and myocardial infarction (right panel).Circles represent the relative risk in individual trials with a size proportional to the weight in the random-effects model. The dashed lines delimit the95% prediction band.

atherosclerosis and risk of MI [63], [64]. On the contrary,

the impact of BP on the risk of MI in diabetic patients is

weaker. In the epidemiological analysis of United King-

dom Prospective Diabetes Study 23 (UKPDS 23) with

censoring at 10 years, SBP ranked fourth, after low-

density lipoprotein cholesterol, high-density lipoprotein

cholesterol and haemoglobin A1c, in a multivariable

selection model of the major predictors of coronary artery

disease [65]. Overall, these data suggest that BP might

not be a leading determinant of MI in diabetic patients,

which would explain the modest protective impact of its

reduction in these patients.


Table 3 Results of univariable meta-regression analyses for stroke

Covariate Relative risk Standard error

SBP difference (5 mmHg) 0.870 0.039DBP difference (2 mmHg) 0.885 0.030

SBP Model – Intercept: 0.946 (0.872–1.026); residual variation due to heterogeneity, Iresidual variation due to heterogeneity, I2¼12.50%; adj-R2 70.9%. BP, blood pressucalculated for two single covariate meta-regressions.

To the best of our knowledge this is the first time that

cumulative sequential analysis is applied to an overview

of BP-lowering intervention trials to determine whether

the available evidence is reliable and conclusive. Several

considerations suggest that a higher level of scepticism is

appropriate in interpreting a meta-analysis than a single

randomized and rigorously conducted controlled trial

[53]. The question of whether a meta-analysis is defini-

tive and no further studies are needed can be considered

by using the logic of early stopping for a randomized

controlled trial. Our results of cumulative sequential

analysis showed firm and definitive evidence for a 15%


95% CI P value Multiplicty adjusted P valuea

(0.797–0.950) 0.002 0.006(0.828–0.946) <0.001 0.002

2¼18.61%; adj-R2 67.2%. Diastolic BP Model – Intercept: 0.948 (0.879–1.022);re. a Adjusted P values were obtained by Monte Carlo random permutation test

C


Table 4 Results of univariable meta-regression analyses for myocardial infarction

Covariate Relative risk Standard error 95% CI P value Multiplicty adjusted P valuea

SBP difference (5 mmHg) 0.982 0.069 (0.855–1.128) 0.793 0.952DBP difference (2 mmHg) 0.990 0.049 (0.898–1.090) 0.832 0.976

SBP Model – Intercept: 0.911 (0.782 to 1.060); residual variation due to heterogeneity, I2¼41.6%; adj-R2 negative (residual variance unexplained). DBP Model –Intercept: 0. 906 (0.786 to 1.045); residual variation due to heterogeneity, I2¼45.6%; adj-R2 negative (residual variance unexplained). BP, blood pressure. a AdjustedP values were obtained by Monte Carlo random permutation test calculated for two single covariate meta-regressions.

RR reduction for both stroke and MI in placebo-

controlled trials. The same held for stroke in more vs.

less tight BP control studies. Conversely, for MI the

cumulative Z-curve, though very close to the conven-

tional Z¼ 1.96 (P< 0.05) boundary, did not cross any of

the adjacent monitoring boundaries. Hence, if the data

included in our meta-analysis were from a single rando-

mized controlled trial at an interim analysis, insufficient

evidence would exist to justify stopping the trial. Finally,

cumulative sequential analysis, also revealed absence

of definitive evidence of a drug-specific intervention

effect because neither the monitoring boundary nor

the conventional Z¼ 1.96 (P< 0.05) was crossed. This


Fig. 9

DETAIL

ABCD/HYP

ABCD/Norm

JMIC−B

IDNT/ARB−CCB

FACET

MOSES

STOP2/ACE−CCB

ALLHAT/ACE−CCB

ALLHAT/CCB−D INSIGHT

STOP2/CCB−BB

LIFE

STOP2/ACE−BB

ASCOT

INVEST

UKPDS−39ALLHAT/ACE−D

CAPPPIDNT/ARB−PLB

RENAAL

SHEPPROGRESS

IDNT/CCB−PLB

ACTION

EUROPA

DIABHYCAR

SYST−EUR

HOPE

ADVANCEABCD−H More vs Less

ACCORD BP

UKPDS−38



0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

2.25

2.50

2.753.00

Rel

ativ

e ri

sk o

f str

oke

−4 −2 0 2 4 6 8 10

DBP difference between randomized groups (mmHg)

Relation between the DBP difference between randomized groups and theCircles represent the relative risk in individual trials with a size proportional95% prediction band.

is likely due to the number of patients randomized to

CCBs, ACEi and ARBs, which was well below the

required information size for most of the randomized

comparisons.

Our literature search procedures were extensive and

included a broad range of information sources (electronic

databases, experts in the field, doctoral dissertations,

etc.). Nonetheless, we recognize that publication bias

may still exist despite our best efforts to conduct a

comprehensive search and despite the lack of statistical

evidence for the existence of bias. Another limitation

common to systematic reviews is the methodological


DETAIL

ABCD/HYP

ABCD/Norm

JMIC−B

IDNT/ARB−CCB

FACET

STOP2/ACE−CCB

STOP2/CCB−BB

LIFE

STOP2/ACE−BB

ASCOT

INVEST

UKPDS−39

CAPPP

IDNT/ARB−PLB

RENAAL

IDNT/CCB−PLB

ACTION

EUROPA

DIABHYCAR

HOPE

ADVANCE

ATLANTIS/5

ATLANTIS/1.25

ABCD−H More vs Less

ACCORD BP

UKPDS−38



0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

2.25

2.50

2.753.00

−4 −2 0 2 4 6 8 10

Rel

ativ

e ri

sk o

f myo

card

ial i

nfa

rcti

on

DBP difference between randomized groups (mmHg)

relative risk for stroke (left panel) and myocardial infarction (right panel).to the weight in the random-effects model. The dashed lines delimit the

C


Fig. 10

APHIS, a priori heterogenity-adjusted information sizeRRR, relative risk reduction

-8

-6

-4

-2

0

2

4

6

8 35000 30000 25000 20000 15000 10000 5000 0

Cumulative sequential analysisstroke in active vs. placebo studies

Cumulative sequential analysisAMI in active vs. placebo studies

Fav

ors

act

ive

Fav

ors

pla

ceb

oC

um

ula

tive

Z-v

alu

e

No. of patients

Conventional0.05

boundary

20% RRRAPHIS17292

15% RRRAPHIS31550

20% RRRAPHIS12208

15% RRRAPHIS21966

No. of patients

-8

-6

-4

-2

0

2

4

6

8 35000 30000 25000 20000 15000 10000 5000 0

Fav

ors

act

ive

Fav

ors

pla

ceb

oC

um

ula

tive

Z-v

alu

e

Conventional0.05

boundary

Conventional0.05

boundary

Conventional0.05

boundary

Cumulative sequential analysis of the effects of BP-lowering agents vs. placebo on stroke (left) and myocardial infarction (right). APHIS, a prioriheterogeneity-adjusted information size; RRR, relative risk reduction.

quality of the original studies. We used the Cochrane

Collaboration’s tool for assessing risk of bias and found no

evidence of heterogeneity between higher and lower

quality trials. We included both primary studies in dia-

betic patients only and sub-studies of diabetic patients to

increase the overall information size of our meta-analysis.

This definitely increases the statistical power but may


Fig. 11


-8

-6

-4

-2

0

2

4

6

8 15000 10000 5000 0 25000 20000

Cumulative sequential analysisstroke in more vs. less intensive BP strategy studies

Fav

ors

mo

re ti

gh

tF

avo

rs le

ss ti

gh

t

20% RRRAPHIS11336

15% RRRAPHIS20318

No. of patients

Conventional0.05

boundary

Conventional0.05

boundary

Cu

mu

lati

ve Z

-val

ue

Cu

mu

lati

ve Z

-val

ue

Cumulative sequential analysis of the effects of tight BP-lowering strategieinfarction (right). RRR indicates relative risk reduction. APHIS, a priori hete

introduce bias. Our analyses, however, showed a consist-

ent effect between trial populations.

In conclusion, the results of our analysis indicate that in

patients with type 2 diabetes the risk of stroke progress-

ively decreases with the magnitude of BP reduction,

whereas such relation is actually not significant for MI.


-8

-6

-4

-2

0

2

4

6

8 10000 5000 0 25000 20000 15000

Cumulative sequential analysisAMI in more vs. less intensive BP strategy studies

20% RRRAPHIS12208

15% RRRAPHIS

21996

No. of patients

Conventional0.05

boundary

Conventional0.05

boundary

Fav

ors

mo

re ti

gh

tF

avo

rs le

ss ti

gh

t

s vs. less tight BP lowering strategies on stroke (left) and myocardialrogeneity-adjusted information size.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


Fig. 12

-8

-6

-4

-2

0

2

4

6

8700006000050000400003000020000100000

No. of patients

Conventional0.05

boundary

20% RRRAPHIS11136

15% RRRAPHIS20318

Conventional0.05

boundary

No. of patients

Conventional0.05

boundary

Conventional0.05

boundary

20% RRRAPHIS36882

15% RRRAPHIS66453

-8

-6

-4

-2

0

2

4

6

8 00007 0 600005000040000300002000010000

Fav

ors

AC

E-i

Fav

ors

co

mp

arat

or

Cu

mu

lati

ve Z

-val

ue

Fav

ors

AC

E-i

Fav

ors

co

mp

arat

or

Cu

mu

lati

ve Z

-val

ue

-8

-6

-4

-2

0

2

4

6

8700006000050000400003000020000100000

-8

-6

-4

-2

0

2

4

6

8700006000050000400003000020000100000

20% RRR APHIS21380

15% RRRAPHIS38522

20% RRRAPHIS11336

15% RRRAPHIS20318

No. of patients

Conventional0.05

boundary

Conventional0.05

boundary

No. of patients

Conventional0.05

boundary

Conventional0.05

boundary

Fav

ors

CC

BF

avo

rs c

om

par

ato

r

Cu

mu

lati

ve Z

-val

ue

Fav

ors

CC

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rs c

om

par

ato

r

Cu

mu

lati

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-val

ue

-8

-6

-4

-2

0

2

4

6

80 70000600005000040000300002000010000

-8

-6

-4

-2

0

2

4

6

80 70000600005000040000300002000010000

No. of patients

Conventional0.05

boundary

15% RRRAPHIS38481

Conventional0.05

boundary

Fav

ors

AR

Bs

Fav

ors

co

mp

arat

or

Cu

mu

lati

ve Z

-val

ue

15% RRRAPHIS46307

No. of patients

Conventional0.05

boundary

Conventional0.05

boundary

20% RRRAPHIS25701

20% RRRAPHIS21091

Fav

ors

AR

Bs

Fav

ors

co

mp

arat

or

Cu

mu

lati

ve Z

-val

ue

Stroke)b()a(

)d()c(

(f))e(

Myocardial infarction


Cumulative sequential analysis of the effects CCB or ACE-i or ARBs vs. active comparators on stroke (left) and myocardial infarction (right). APHIS, apriori heterogeneity-adjusted information size; RRR, relative risk reduction.

C


Additionally, our results remove the potential concern for

an increased risk of MI at low levels of achieved BP,

which implies that these levels can be pursued in clinical

practice because the beneficial effect on one type of

cardiovascular event are unlikely to be neutralized or

exceeded by harmful effects on another event. These

data should be regarded as mainly hypothesis-generating

for further studies specifically designed to test the effi-

cacy of a tight control of BP on the risk of stroke in

patients with diabetes.

AcknowledgementsThe article was supported in part by the no-profit ‘Fon-

dazione Umbra Cuore e Ipertensione – AUCI Onlus’,

Perugia, Italy.

Author contributions: Conception and design: G.R., P.V.;

analysis and interpretation of the data: G.R., P.V., G.M.;

search strategies and data abstraction: G.G., F.A.; drafting

of the article: P.V., G.R., G.M.; critical revision of the

article for important intellectual content: G.R., G.G.,

F.A., G.A., G.M., P.V.; final approval of the article:

G.R., G.G., F.A., G.A., G.M., P.V.; statistical analyses:

G.R., P.V.; collection and assembly of data: G.G., F.A.

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Blood pressure lowering in diabetic patients

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