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1

OPEN ACCESS

thebmj BMJ2015;350:h1354 doi: 10.1136/bmj.h1354

Department o Intensive Care, Copenhagen UniversityHospital, Rigshospitalet,Blegdamsvej , DK-Copenhagen, DenmarkCopenhagen Trial Unit, Centreor Clinical InterventionResearch , CopenhagenUniversity Hospital,Rigshospitalet, Copenhagen,Denmark

Correspondence to: L B [email protected]

Additional material is publishedonline only. To view please visitthe journal online ( http://dx.doi.org/./BMJ.h)

Cite this as: BMJ;:hdoi: ./bmj.h

Accepted: February

Restrictive versus liberal transfusion strategy for red blood

cell transfusion: systematic review of randomised trials with

meta-analysis and trial sequential analysis

Lars B Holst,Marie W Petersen,Nicolai Haase,Anders Perner,Jrn Wetterslev

ABSTRACT

OBJECTIVE

To compare the benefit and harm of restrictive versus

liberal transfusion strategies to guide red blood cell

transfusions.

DESIGN

Systematic review with meta-analyses and trial

sequential analyses of randomised clinical trials.

DATA SOURCES

Cochrane central register of controlled trials,

SilverPlatter Medline ( to date), SilverPlatter

Embase ( to date), and Science Citation IndexExpanded ( to present). Reference lists of

identified trials and other systematic reviews were

assessed, and authors and experts in transfusion were

contacted to identify additional trials.

TRIAL SELECTION

Published and unpublished randomised clinical trials

that evaluated a restrictive compared with a liberal

transfusion strategy in adults or children, irrespective

of language, blinding procedure, publication status, or

sample size.

DATA EXTRACTION

Two authors independently screened titles and

abstracts of trials identified, and relevant trials wereevaluated in full text for eligibility. Two reviewers then

independently extracted data on methods,

interventions, outcomes, and risk of bias from

included trials. random effects models were used to

estimate risk ratios and mean differences with %

confidence intervals.

RESULTS

trials totalling randomised patients were

included. The proportion of patients receiving red

blood cells (relative risk ., % confidence interval

. to ., patients, trials) and the number

of red blood cell units transfused (mean difference

., % confidence interval . to .) were

lower with the restrictive compared with liberal

transfusion strategies. Restrictive compared with

liberal transfusion strategies were not associated with

risk of death (., . to ., patients, nine

lower risk of bias trials), overall morbidity (., .to ., patients, six lower risk of bias trials), or

fatal or non-fatal myocardial infarction (., . to

., patients, seven lower risk of bias trials).

Results were not affected by the inclusion of trials with

unclear or high risk of bias. Using trial sequential

analyses on mortality and myocardial infarction, the

required information size was not reached, but a %

relative risk reduction or increase in overall morbidity

with restrictive transfusion strategies could be

excluded.

CONCLUSIONS

Compared with liberal strategies, restrictive

transfusion strategies were associated with a

reduction in the number of red blood cell units

transfused and number of patients being transfused,

but mortality, overall morbidity, and myocardial

infarction seemed to be unaltered. Restrictive

transfusion strategies are safe in most clinical

settings. Liberal transfusion strategies have not been

shown to convey any benefit to patients.

TRIAL REGISTRATION

PROSPERO CRD.

Introduction

Transusion o red blood cells are ofen used to treat

anaemia or bleeding in a variety o patient groups.Recent results o randomised clinical trials have

avoured restrictive transusion strategies and eluci-

dated potential harm with liberal transusion strate-

gies. Data rom several newly published randomised

controlled trialswarrant an up to date review o the

available evidence comparing the effects o different

transusion thresholds to inorm on the benefits and

harms o transusion strategies guiding red blood cell

transusion. A Cochrane review identiied ran-

domised controlled trials including patients.

Most o the data on mortality were rom the Transusion

Requirements in Critical Care (TRICC) trial(%) and

Transusion Trigger Trial or Functional Outcomes inCardiovascular Patients Undergoing Surgical Hip

WHAT IS ALREADY KNOWN ON THIS TOPIC

Red blood cells are commonly used in the treatment of haemorrhage and anaemia,

but recent trials have shown potential harm with this intervention

Recent meta-analysis indicates no harm with the use of a restrictive transfusion

strategy

WHAT THIS STUDY ADDS

This review includes new data from five recently published randomised trials of

restrictive versus liberal transfusion strategies and includes data from more than

patients

Pooled analyses did not show harm with restrictive transfusion strategies (no

increased risk of mortality, overall morbidity, or acute myocardial infarction) but the

number of units and number of patients transfused were reduced compared with

liberal strategies

Liberal strategies have possible associations with harm (risk of infectious

complications)

Further large trials with lower risk of bias are needed to establish firm evidence to

guide transfusion in subgroups of patients
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Fracture Repair (FOCUS) trial (%),underlining the

somewhat limited evidence base or guiding the use o

red blood cells.

We carried out a systematic review including data

rom the latest published randomised controlled trials

and used conventional meta-analysis to compare the

effects o different transusion strategies on important

outcomes in various patient groups. We were particu-

larly interested to examine whether the evidence sup-

ported a restrictive strategy without harm to patients.

Methods

Our systematic review was conducted according to the

protocol previously published in the PROSPERO regis-

ter (www.crd.york.ac.uk/PROSPERO). The methodology

and reporting were based on recommendations rom

the Cochrane Collaborationand the preerred report-

ing items or systematic reviews and meta-analyses

statement, and evaluated according to the GRADE

(grading o recommendations assessment, develop-

ment, and evaluation) guidelines.

Eligibility criteria

We considered prospective randomised controlled trials

to be eligible or inclusion i red blood cell transusions

were administered on the basis o a clear transusion

trigger or threshold, defined as a specific haemo-

globin or haematocrit level. Comparator group patients

were required to be either transused at higher haemo-

globin or haematocrit levels than the intervention

group or transused in accordance with current transu-

sion practices. We considered or inclusion trials that

included surgical or medical patients and adults or chil-

dren, but excluded trials conducted on neonates andchildren with low birth weight.

All randomised controlled trials were eligible irre-

spective o language, blinding, publication status or

date, or sample size. We excluded quasirandomised tri-

als or assessment o benefit but considered them or

inclusion or assessment o harm.

Search strategy

We identified relevant randomised controlled trials

through an up to date systematic search strategy used

in a published Cochrane review;in the Cochrane cen-

tral register o controlled trials, SilverPlatter Medline

( to October ), SilverPlatter Embase ( toOctober ), and Science Citation Index Expanded

( to October ). To identiy any planned, unre-

ported, or ongoing trials we contacted the main authors

o included trials and experts in this discipline. We

reviewed the reerences o included trials to identiy

additional trials. Moreover, we identified ongoing clini-

cal trials and unpublished trials through Current Con-

trolled Trials, ClinicalTrials.gov, and www.centerwatch.

com (see supplementary appendix or detailed inor-

mation on the search strategy).

Trial selection

Authors (LB, MWP, and NH) independently reviewed alltitles and abstracts identified through the systematic

search. They excluded trials that did not ulfil the eligi-

bility criteria and evaluated the remaining trials in ull

text. Disagreements were resolved with JW.

Data extraction

The researchers were not masked to the author, institu-

tion, and publication source o trials at any time. Using

preprepared extraction orms the researchers (LBH,

NH, or MWP) independently extracted the characteris-

tics o the trials (single or multicentre, country), base-

line characteristics o the patients (age, sex, disease

severity), inclusion and exclusion criteria, the descrip-

tion o intervention (thresholds, duration), and out-

comes. When inormation was unclear or missing we

contacted the corresponding authors o the relevant

trials.

Predefined primary outcomes were mortality and

overall morbidity, defined by authors as one or more

complications, overall complications, or any adverse

event (i not reported, we included the most common

complication). Secondary outcomes were adverse

events (transusion reactions, cardiac eventsor

example, myocardial inarction, cardiac arrest, acute

arrhythmia, angina), renal ailure, thromboembolic

events, inections, haemorrhagic events, stroke, or

transitory cerebral ischaemia. We also registered the

proportion o patients transused with allogeneic or

autologous red blood cells, and the number o alloge-

neic and autologous blood units transused. Haemoglo-

bin or haematocrit levels during intervention and

length o hospital stay were regarded as process vari-

ables and thus reported as trial characteristics.

Risk of bias assessmentAccording to recommendations rom the Cochrane Col-

laboration we reviewed the major domains o bias

(random sequence generation, allocation concealment,

blinding o participants and staff, blinding o outcome

assessors, incomplete outcome data, selective outcome

reporting, baseline imbalance, sponsor bias (bias

related to unding source), and academic (whether

authors had published other trials in the same field o

research) in all trials. We categorised trials with low risk

o bias as those with a lower risk o bias in all domains

except blinding because blinding o trigger guided

transusion is generally not easible. All other trials

were categorised as unclear or at high risk o bias.

Grading quality of evidence

We assessed the quality o evidence or mortality, over-

all morbidity, and atal and non-atal myocardial inarc-

tion according to GRADE methodologyor risk o bias,

inconsistency, indirectness, imprecision, and publica-

tion bias; classified as very low, low, moderate, or high.

Statistical analysis

All statistical analyses were perormed using Review

Manager (RevMan) version .. (Nordic Cochrane Cen-

tre, Cochrane Collaboration) and trial sequential analy-

sis program version . beta (www.ctu.dk/tsa).For allincluded trials we report relative risks (% confidence

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intervals) or dichotomous outcomes and mean differ-

ences (% confidence intervals) or continuous out-

comes. We pooled these measures in meta-analyses.

I data rom two or more trials were included in anal-

ysis o an outcome, we used random effectsand fixed

effect modelsor meta-analyses. We report the results

rom both models i there was discrepancy between the

two; otherwise we report results rom the random

effects model. Heterogeneity among trials was quanti-

fied with inconsistency actor (I) or (D) statisticsand

by test, with significance set at a P value o .. We

did sensitivity analyses by applying continuity adjust-

ment in trials with zero events.

For risk o bias we perormed predefined subgroup

analyses (lower versus high or unclear risk) and we

emphasise the results rom the trials with lower risk o

bias,patient populations (adults versus children; sur-

gical versus medical), length o ollow-up ( days

versus > days), and transusion product (leucocyte

reduced versus non-leucocyte reduced red blood cell

suspensions). Only subgroup analyses showing a statis-

tically significant test o interaction (P

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regardless o risk o bias (relative risk ., % confi-

dence interval . to .; P=.; I=%).

Fatal or non-fatal myocardial infarction

Seven trials assessing atal or non-atal myocardial

inarction including patients were defined as trials

with lower risk o bias. Restrictive transu-

sion strategies were not associated with a relative risk

reduction or relative risk increase in atal or non-atal

myocardial inarction (relative risk ., % confi-

dence interval . to .; P=.; I=%) (fig ) and

the trial sequential analysis adjusted % confidence

interval was . to . (fig ). The GRADE quality o

evidence was judged to be very low (table ). A total o

trials with randomised patients were included

in the meta-analysis o atal or non-atal myocardialinarction regardless o risk o bias (., . to .;

P=.; I=%); the GRADE quality o evidence was

judged to be low (table ).

Other adverse events

A total o eight trials deined as lower risk o bias

with patients were included in the meta-analy-

sis on inectious complications. Our analysis showed

an association in avour o using a restrictive trans-

usion strategy (relative risk ., % conidence

interval . to ., P=., I=%) (see supple-

mentary appendix ). The inclusion o

all trials ( patients) regardless o risk o

bias did not alter the result (., . to .,

P=., I=%). Our analysis

showed no association o restrictive versus liberal

transusion with other adverse events (cardiac com-plications, renal ailure, thromboembolic stroke or

Table |Summary of reported blinding procedure in included trials to supplement ROB table (figure ) on blinding procedure, not assessed in overallevaluation of trial bias domains owing to feasibility issues

Reference Patient Clinical/trial staff Outcome assessor

Almeida Not available Not available Not available

Blair Not available Not available Not available

Bracey Not blinded Not blinded Not blinded

Bush Not available Surgeons/anaesthesiologists notblinded; clinical staff not available

Not available

Carson Not available Not available Study nurses obtaining subjective (unctional status, place o residence) andobjective outcomes ( day survival status) were blinded or intervention duringollow-up by telephone

Carson Not blinded Not blinded Study nurses obtaining subjective (unctional status, place o residence) andobjective outcomes ( day survival status) were blinded or intervention duringollow-up by telephone

Carson Not available Not available Composite outcome o death and myocardial inarction; study nurses obtainingsubjective (unctional status, place o residence) and objective outcomes(myocardial inarction, unstable angina, day sur vival status) were blinded orintervention during ollow-up by telephone

Cholette Not blinded Operation staff blinded per ioperatively ;clinical staff not blinded postoperatively

Outcome assessor not available; data and saety monitoring committee blinded

Cooper Not blinded Not blinded Not available

Fortune Not available Not available Not available

Foss Blinded Not available Physiotherapist assessing ambulation blinded

De Gast-Bakker

Not blinded Not blinded Not blinded

Gregersen Not available Not available Not available

Grover Blinded Surgeons/anaesthesiologists notblinded; clinical staff not available

Holter monitor assessor blinded

Hajjar Blinded A naesthesiolog ist s/intensi ve care u nitclinicians blinded; surgeons not available

Outcome assessor blinded; data and saet y monitoring committee not available

Hbert Not blinded Not blinded Not available

Hbert Not blinded Not blinded Outcome assessor not available; data and saety monitoring committee blinded

Holst Not blinded Not blinded Outcome assessor; statisticians and data and saety monitoring committee blinded

Johnson Not available Surgeons/anaesthesiologists notblinded; clinical staff not available

Not available

Lacroix Not blinded Not blinded Outcome assessor not available; statisticians and data and saety monitoringcommittee blinded

Lotke Not available Not available Blinded

Parker Not available Not available Study nurses assessing mobility score blinded

Prick Not available Not available Not available

Robertson Not available Not blinded Trial investigators not blinded; outcome assessors blinded

Shehata Not available Not available Not available

So-Osman Not b linded S ur geons/c lin ic ians not b linded Assessor and s tudy inves tigator s b linded; s tudy nur ses not b linded

Villanueuva Not blinded Not blinded Not blinded

Walsh Blinded Not blinded Not available

Webert Not blinded Not blinded Study staff assessing bleeding and adjudication committee blinded

Wu Not available Not available Not available

Zygun Not available Not available Not available

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transitory ischaemic insult, or haemorrhage) (see

supplementary appendices and ).

Number of patients and units transfused

A total o trials with patients were included inthe meta-analysis o the proportion o patients receiv-

ing red blood cells (relative risk ., % confidence

interval . to .; P

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that uture trials will show overall harm with restrictive

transusion strategies. Regarding overall morbidity, we

ound no association with benefit or harm between

groups, but the trial sequential analysis indicated it

would be utile to obtain more trial data on this outcome.We ound that the trial sequential analysis o pooled risk

o atal or non-atal myocardial inarction was inconclu-

sive, because only % o the required inormation size

was obtained. Regarding inectious complications, our

analysis indicated a possible association between a

restrictive transusion strategy and reduced rates oinection across the different clinical settings.

Table | Summary of findings including GRADE quality assessment of evidence trials with lower risk of bias

Variable s

No ofparticipants(No of studies)

No with event/No in group (%)

Relative risk (% CI) A bsolu te effec t

Quality ofthe evidence(GRADE) Qual ity a ss ess me nt doma in s

Restrictivetransfusiongroup

Liberaltransfusiongroup

All cause mortality,longest ollow-up,low risk o biastrials

() / (.) / (.) Random effects . (. to.); I=%; trial sequentialanalysis adjusted % CI. to .

ewer per (rom ewer to more)

Low; criticalimportance

Inconsistency: not serious*;indirectness: not serious;imprecision: serious;reporting bias: reporting bias

Overall morbidity,lower risk o biastrials

() / (.) / (.) Random effects . (. to.); I=%; trial sequentialanalysis adjusted % CI. to .

ewer per (rom ewer to more)

Very low;criticalimportance

Inconsistency: serious;indirectness: not serious;imprecision: serious;reporting bias: reporting bias

Fatal and non-atalmyocardialinarction in lowerrisk o bias trials

() / (.) / (.) Random effects . (. to.); I=%; trialsequential analysis adjusted% CI . to .

more per (rom ewer to more)

Very low;criticalimportance

Inconsistency: serious**;indirectness: not serious;imprecision: very serious;reporting bias: reporting bias

GRADE Working Group grades o e vidence: low quality=urther research is likely to have an important impact on confidence in estimate o effect and is likely to change the estimate; very lowquality=very uncertain about the estimate.

Quality assessment domains: inconsistency=unexplained heterogeneity o results; indirectness=differences in population, intervention, comparator, and outcome measures;imprecision=relatively ew patients and ew events resulting in wide confidence intervals; reporting bias=publication bias is a systematic under-estimation or over-estimation o underlyingbeneficial or harmul effect owing to selective publication o trial results.*I=%, P=.or heterogeneity, overlap o confidence intervals.Anticipation o % relative risk reduction results in trial sequential analysis adjusted confidence intervals, including >% relative risk reduction or >% relative risk increase. However,

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Relation to other reviews

Well conducted systematic reviews with meta-analysis

on red blood cell transusion have been published.

A Cochrane review indicated that restrictive transusion

strategies were not associated with the rate o adverse

events (that is, mortality, cardiac events, stroke, pneu-

monia, and thromboembolism) compared with liberal

transusion strategies. Restrictive transusion strategies

were associated with a reduction in hospital mortality

(relative risk ., % confidence interval . to .)

but not in day mortality (., . to .).

A review was published in including

patients rom trials assessing the impact o red blood

cell transusion.Pooled data rom three trials (

patients) using restrictive haemoglobin transusion

triggers o g/dL showed reductions in in-hospital mor-

tality (relative risk ., % confidence interval . to

.), total mortality (., . to .), rebleeding

(., . to .), acute coronary syndrome (., .

to .), pulmonary oedema (., . to .), and

Favoursrestrictive

strategy

Favoursliberal

strategy

Cumulative

zsco

re

-

-

-

Requiredinformation

sizeTrial sequential monitoringboundary for benefit

Area of benefit

Conventional boundary for harm P

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bacterial inections (., . to .) compared with

liberal transusion. In contrast, pooled data including

trials with less restrictive transusion thresholds did not

show associations with any o the predefined outcomes.

A recent systematic review with meta-analysis

included randomised controlled trials reporting data

on in-hospital inections.Restrictive transusion strat-

egies were associated with a reduced risk o inectionsamong patients admitted to hospital compared with

liberal transusion strategies (., . to .). Our

analysis showed comparable results, with a possibility

o lowering the rate o inections using restrictive trans-usion strategies. We also included data on non-health-

care associated inections, but our results may be

influenced by multiple testing and sparse data.

We included data rom the recent Transusion Require-

ments In Septic Shock (TRISS) trial, which randomised

patients with septic shock in the intensive care unit,

in which there was no difference in mortality or morbid-

ity with the use o pre-stored leucocyte reduced red blood

cells at a transusion trigger o versus g/dL.In accor-

dance with the Cochrane review we did not find evidence

o harm with the use o restrictive transusion strategies

compared with liberal transusion strategies. However,

our trial sequential analyses were inconclusive or theassessment o mortality and myocardial inarction owing

to insufficient inormation sizes.

Strengths and limitations of this review

Applying Cochrane methodology is a major strength o

this systematic review, comprising a prepublished pro-

tocol, a non-restricted up to date literature search, inde-

pendent data extraction by at least two authors, and risk

o bias assessment leading to GRADE evaluations o

important outcomes. Trial sequential analysis was per-

ormed to explore the risk o random error as a result o

sparse data and repetitive testing in order to increase the

robustness o the meta-analyses and distinguish the cur-rent inormation size rom the required inormation size.

Favoursres

trictive

s

trategy

Favoursliberal

strategy

Cumulative

zscore

-

-

-

Requiredinformation


Area of benefit

Conventional boundary for harm P% relative risk increase. However,

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Our systematic review also has limitations. The ran-

domised controlled trials included in the primary anal-

ysis dealt with different indications or transusion by

randomising a variety o patient groups (or example,

children and adults) in different clinical settings (or

example, elective surgery and critical illness). Thus, the

risk o introducing potentially important heterogeneity

is imminent. To get a clinical applicable result, we

excluded trials o neonates and inants with very lowbirth weight. None o the included trials was blinded, as

this is not easible. This may introduce both peror-

mance and detection bias. However, the primary out-

come o all cause mortality is less prone to be influenced

by lack o blinding. Transusion triggers varied

between trials, with some using a liberal transusion

threshold equal to the restrictive one in other trials,

introducing clinical heterogeneity. Both clinical hetero-

geneity and inadequate ollow-up increase the risk o

type II error. Bias in the included trials, losses to ol-low-up, and incomplete reporting o outcome measures

.. Trauma and acute blood loss

Blair

Zygun

Subtotal

Test for heterogeneity:

=.,

=., df=, P=., I

=%Test for overall effect: z=., P=.

.. Perioperative setting

Almeida

Bush

Carson

Carson

Cholette

Foss

Grover

Hajjar

Parker

Shehata

So-Osman -

Villanueva

Wu

Subtotal

Test for heterogeneity:=., =., df=, P=., I=%

Test for overall effect: z=., P=.

.. Critical care

Carson

Cooper

Hbert

Hbert

Holst

Lacroix

Robertson

Walsh

Subtotal



Total (% CI)



Test for subgroup differences: =., df=, P=., I=%

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .). (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

. (. to .)

/

/

/

/

/

/

/

/

/

/

/

/

/

/

//

/

/

/

/

/

/

/

/

/

/

/

. .

Study or subgroup

Favoursrestrictive strategy

Favoursliberal strategy

Risk ratio M-H torandom (% CI)

Risk of biasRisk ratio M-H torandom (% CI)

Restrictivetransfusion

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

Liberaltransfusion

No of events/total

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Weight(%)

A B C D E F G H I

Randoms

equencegeneration(selectionbias)

Allocationconcealment(selectionbias)

Blind

ingofparticipantsandpersonnel(performancebias)

Blindingofoutcomeassessment(detectionbias)

Incompleteoutcomedata(attritionbias)

Selectivereporting(reportingbias)

Baselineimbalance

Sponsorbias

Academicbias

Fig |Forest plot of mortality in trials stratified by clinical setting. Size of squares for risk ratio reflects weight of trial in pooled analysis. Horizontal barsrepresent % confidence intervals

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are additional limitations in this review. The definitions

o overall morbidity and adverse events were heteroge-

neous and should be taken into account when inter-

preting these data. Finally, or some o the predefined

outcomes, limited trial data could be included in the

meta-analyses resulting in wide confidence intervals

and less certain point estimates.

Unanswered questions

Whether the overall use o red blood cells should be

guided by a restrictive or a liberal transusion strategyis still debatable. Patients with coronary artery disease,

and in particular patients with ongoing cardiac isch-

aemia, might require a higher haemoglobin level to

sustain oxygen delivery to the myocardial cells and to

reduce the sympathetically mediated compensatory

mechanisms o anaemia and reduce myocardial oxy-

gen demand. However, red blood cell transusion couldworsen patient outcome as a result o an increased risk

o circulatory overload and increased thrombogenicity

with higher haematocrit levels. Results rom the FOCUS

trial showed no association with the primary compos-

ite outcome o morbidity and mortality days postop-

eratively or the incidence o coronary syndrome when

comparing two transusion strategies ( g/dL (or symp-

toms o anaemia) versus g/dL). Two small ran-

domised controlled trials evaluating a restrictive

transusion trigger o haemoglobin

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cerebral ischaemic insults because the injured brain

may not compensate or decreased oxygen delivery

associated with anaemia.One randomised controlled

trial using a actorial design compared the effects o

erythropoietin and two different haemoglobin thresh-

olds or red blood cell transusion ( versus g/dL) in

patients with a closed head injury and showed no

difference in neurological outcome at six months.

Also in patients with acute brain injury data rom high

quality randomised controlled trials are needed toguide transusion practice.

Conclusions

In conventional meta-analyses restrictive transusion

strategies compared with liberal transusion strategies

were associated with a reduction in the number o red

blood cells used and the number o patients beingtransused but were not associated with benefit or harm

regarding mortality, overall morbidity, and atal or

non-atal myocardial inarction in various clinical set-

tings. However, the required inormation sizes were not

reached except or overall morbidity, where a % rela-

tive risk reduction or increase with restrictive transu-

sion strategies may be reuted. Analyses o all trials,

regardless o risk o bias, showed similar findings. We

ound possible associations between restrictive transu-

sion strategies and a reduced number o inectious com-

plications.

Restrictive transusion strategies are sae in most

clinical settings. Liberal transusion strategies have notbeen shown to coner any benefit to patients but have

the potential or harm.

We thank Sarah Klingenberg, search coordinator or the CochraneHepato-Biliary Group, or perorming the literature search.

Contributors: LBH developed the protocol, was responsible or thesearches, selected trials, extracted data, assessed the risk o bias otrials, did the data analysis, and developed the final review. MWPdeveloped the protocol, selected trials, extracted data, assessed therisk o bias o trials, and developed the final review. NH developed theprotocol, selected trials, extracted data, assessed the risk o bias otrials, and developed the final review. AP developed the protocol,analysed data, and developed the final review. JW developed theinitial idea or the review, developed the protocol, selected trials,advised on statistical methods, analysed data and resolved anydisagreements during data extraction and bias assessment, and

developed the final review. All authors read and approved the finalmanuscript. LBH and JW are the guarantors and affirm that the

Low risk of bias and myocardial infarction

Carson

Cooper

Foss

Hbert

Holst

Lacroix

Walsh

Subtotal

Test for heterogeneity: =., =., df=, P=., I=%


Total (95% CI)

Test for heterogeneity: =., =., df=, P=., I=%


Test for subgroup differences: Not applicable

. (. to .)

. (. to .)

. (. to .)

. (. to .). (. to .)

. (. to .)

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Fig |Forest plot of myocardial infarctions in low risk of bias trials. Size of squares for risk ratio reflects weight of trial in pooled analysis. Horizontal barsrepresent % confidence intervals

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manuscript is an honest, accurate, and transparent account o thestudy being reported; that no important aspects o the study havebeen omitted; and that any discrepancies rom the study as plannedhave been explained.

Funding: This review was unded by the Danish Strategic ResearchCouncil (), supported by Copenhagen University Hospital,Rigshospitalet. The unders had no inluence on the protocol, dataanalyses, or reporting.

Competing interests: All authors have completed the ICMJE uniormdisclosure orm at www.icmje.org/coi_disclosure.pd (available onrequest rom the corresponding author) and declare: AP was principalinvestigator or Transusion Requirements In Septic Shock (TRISS) trialand LBH, NH, and JW were members o the steering committee. AP ishead o research in his intensive care unit, which receives researchgrants rom CSL Behring, Fresenius Kabi, and Cosmed.

Ethical approval: Not required.

Data sharing: No additional data available.

Transparency: The lead authors (LBH and JW) affirm that themanuscript is an honest, accurate, and transparent account o thestudy being reported; that no important aspects o the study havebeen omitted; and that any discrepancies rom the study as planned(and, i relevant, registered) have been explained.

This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC .) license,

which permits others to distribute, remix, adapt, build upon this worknon-commercially, and license their derivative works on differentterms, provided the original work is properly cited and the use isnon-commercial. See: http://creativecommons.org/licenses/by-nc/./.

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