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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 VerdecchiaeObjective 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
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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.
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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).
opyright © Lippincott Williams & Wilkins. Unauth
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
orized reproduction of this article is prohibited.
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1256 Journal of Hypertension 2011, Vol 29 No 7
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-
opyright © Lippincott Williams & Wilkins. Unautho
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
rized reproduction of this article is prohibited.
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Effects of BP reduction on MI and stroke in diabetes Reboldi et al. 1257
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
opyright © Lippincott Williams & Wilkins. Unauth
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
orized reproduction of this article is prohibited.
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1258 Journal of Hypertension 2011, Vol 29 No 7
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
opyright © Lippincott Williams & Wilkins. Unautho
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
rized reproduction of this article is prohibited.
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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Effects of BP reduction on MI and stroke in diabetes Reboldi et al. 1259
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
opyright © Lippincott Williams & Wilkins. Unauth
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
orized reproduction of this article is prohibited.
C
1260 Journal of Hypertension 2011, Vol 29 No 7
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
opyright © Lippincott Williams & Wilkins. Unautho
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
rized reproduction of this article is prohibited.
C
Effects of BP reduction on MI and stroke in diabetes Reboldi et al. 1261
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
FEM subtotal (I2=0.0%, p=0.573)
REM overall
REM subtotal
IDNT/CCB−PLB
FEM subtotal (I2=56.6%, p=0.004)
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
opyright © Lippincott Williams & Wilkins. Unauth
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
orized reproduction of this article is prohibited.
C
1262 Journal of Hypertension 2011, Vol 29 No 7
Fig. 6
Heterogeneity between subgroups: p = 0.050
FEM overall (I2=13.8%, P = 0.283)
ALLHAT/ACE−CCB
LIFE
ARB
FEM subtotal (I2=47.2%, P = 0.128)REM subtotal
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
Heterogeneity between subgroups: p = 0.065
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
FEM subtotal (I2=52.5%, P = 0.122)REM subtotal
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
opyright © Lippincott Williams & Wilkins. Unautho
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
rized reproduction of this article is prohibited.
C
Effects of BP reduction on MI and stroke in diabetes Reboldi et al. 1263
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
opyright © Lippincott Williams & Wilkins. Unauth
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
orized reproduction of this article is prohibited.
C
1264 Journal of Hypertension 2011, Vol 29 No 7
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
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 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.
opyright © Lippincott Williams & Wilkins. Unautho
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%
rized reproduction of this article is prohibited.
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
Effects of BP reduction on MI and stroke in diabetes Reboldi et al. 1265
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
opyright © Lippincott Williams & Wilkins. Unauth
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
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
−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
orized reproduction of this article is prohibited.
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
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
−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
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1266 Journal of Hypertension 2011, Vol 29 No 7
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
opyright © Lippincott Williams & Wilkins. Unautho
Fig. 11
APHIS, a priori heterogenity-adjusted information sizeRRR, relative risk reduction
-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.
rized reproduction of this article is prohibited.
-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.
Effects of BP reduction on MI and stroke in diabetes Reboldi et al. 1267
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
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Cu
mu
lati
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Fav
ors
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BF
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par
ato
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mu
lati
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-8
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0
2
4
6
80 70000600005000040000300002000010000
-8
-6
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-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
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Stroke)b()a(
)d()c(
(f))e(
Myocardial infarction
APHIS, a priori heterogenity-adjusted information sizeRRR, relative risk reduction
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
1268 Journal of Hypertension 2011, Vol 29 No 7
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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