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Titre: Impact of More Restrictive Blood Transfusion Strategies on Clinical Outcomes: A Meta-analysis and Systematic Review
Auteur: Shelley R. Salpeter MD

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CLINICAL RESEARCH STUDY

Impact of More Restrictive Blood Transfusion Strategies on
Clinical Outcomes: A Meta-analysis and Systematic Review
Shelley R. Salpeter, MD,a Jacob S. Buckley,b Saurav Chatterjee, MDc
a
Stanford University School of Medicine, Stanford, Calif; bBrown University, Providence, RI; cSt Luke’s e Roosevelt Hospital Center,
New York, NY.

ABSTRACT
BACKGROUND: There is accumulating evidence that restricting blood transfusions improves outcomes, with
newer trials showing greater benefit from more restrictive strategies. We systematically evaluated the
impact of various transfusion triggers on clinical outcomes.
METHODS: The MEDLINE database was searched from 1966 to April 2013 to find randomized trials
evaluating a restrictive hemoglobin transfusion trigger of <7 g/dL, compared with a more liberal trigger.
Two investigators independently extracted data from the trials. Outcomes evaluated included mortality,
acute coronary syndrome, pulmonary edema, infections, rebleeding, number of patients transfused, and
units of blood transfused per patient. Extracted data also included information on study setting, design,
participant characteristics, and risk for bias of the included trials. A secondary analysis evaluated trials
using less restrictive transfusion triggers, and a systematic review of observational studies evaluated more
restrictive triggers.
RESULTS: In the primary analysis, pooled results from 3 trials with 2364 participants showed that a
restrictive hemoglobin transfusion trigger of <7 g/dL resulted in reduced in-hospital mortality (risk ratio
[RR], 0.74; confidence interval [CI], 0.60-0.92), total mortality (RR, 0.80; CI, 0.65-0.98), rebleeding
(RR, 0.64; CI, 0.45-0.90), acute coronary syndrome (RR, 0.44; CI, 0.22-0.89), pulmonary edema (RR,
0.48; CI, 0.33-0.72), and bacterial infections (RR, 0.86; CI, 0.73-1.00), compared with a more liberal
strategy. The number needed to treat with a restrictive strategy to prevent 1 death was 33. Pooled data
from randomized trials with less restrictive transfusion strategies showed no significant effect on
outcomes.
CONCLUSIONS: In patients with critical illness or bleed, restricting blood transfusions by using a hemoglobin trigger of <7 g/dL significantly reduces cardiac events, rebleeding, bacterial infections, and total
mortality. A less restrictive transfusion strategy was not effective.
Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 124-131
KEYWORDS: Clinical outcomes; Meta-analysis; Mortality; Systematic review; Transfusion
SEE RELATED EDITORIAL p. 103

Red blood cell transfusions have been the standard of care
for treating anemia for more than 100 years now, with little
evidence that they improve clinical outcomes.1-3 By the

Funding: None.
Conflict of Interest: None.
Authorship: All authors had access to the data and played a role in
writing this manuscript.
Requests for reprints should be addressed to Shelley Salpeter, MD,
34 North San Mateo Drive, Suite 1, San Mateo, CA 94401.
E-mail address: salpeter@stanford.edu
0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2013.09.017

early 1900s, blood transfusion was considered to be “a
procedure of such simple and harmless character” that no
clinical indication was needed, “the mere possibility of
benefitting a condition by the addition of blood being
considered sufficient warrant.”1 The practice was based on
the assumption that anemia is tolerated poorly and that red
blood cell transfusions improve outcomes.1,4,5 Researchers
did not begin to question the evidence behind the practice
until the 1980s and 1990s, when the first randomized trials
were performed.6-12 By that time, the practice of blood
transfusion was so ingrained in our medical framework that

Salpeter et al

Restrictive Transfusion Strategies and Clinical Outcomes

125

the approach has been to march slowly down on the transprotocol shown in Appendix Tables 1 and 2, online). We
fusion trigger instead of addressing whether transfusions
included trials of adults or children, including neonates,
are beneficial at all.
involving surgical or medical conditions. Trials that used a
The standard transfusion trigger for many years had
restrictive transfusion trigger more than 7 g/dL were evalbeen a hemoglobin of 10 g/dL or even higher.6,9,12,13 This
uated separately as a “less restrictive” strategy. Additional
arbitrary trigger has been lowered gradually to a hemoglobin
searches of related articles were done to perform a syslevel of 6 to 8 g/dL because studies
tematic review of the impact of
showed that blood transfusions are
various transfusion strategies.
CLINICAL SIGNIFICANCE
associated with worse outcomes in
patients with anemia due to illness
Pooled randomized trial data show that
Data Extraction and Quality
or bleeding, compared with simple
blood transfusions increase in-hospital
Assessment
supportive measures such as hymortality, total mortality, rebleeding,
6,9,12-20
Two investigators (SS, JB) exdration.
However, a liberal
acute coronary syndrome, pulmonary
tracted data from the trials,
transfusion practice is still comedema, and bacterial infections.
reconciling differences by conmon, especially for those with
sensus. In addition, selected incoronary artery disease who are
When a restrictive hemoglobin transvestigators were contacted for
thought to benefit more from blood
fusion trigger of <7 g/dL is used in
additional information. Clinical
transfusions.21 There have been
patients with critical illness or bleed, the
outcomes evaluated included inmany challenges inherent in the
number needed to treat to prevent 1
hospital mortality, 30-day mortalstudy of our transfusion practices,
death is 33.
ity, total mortality, acute coronary
such as the broad patient base
syndrome, pulmonary edema,
Observational data indicate that hemoincluded in the analyses, the mulbacterial infections, rebleeding,
tiple indications for blood transglobin levels of 5 to 6 g/dL are well
number of patients receiving any
fusions, and the confounding by
tolerated in normovolemic patients
blood transfusion, and units of
indication in observational studies.
without affecting oxygen delivery.
blood transfused per patient.
We have found no randomized
Extracted data also included inclinical trials comparing transformation
on
study
setting,
design, participant characterfusion with no transfusion. Instead, the available trials
istics,
and
risk
for
bias
for
the included trials (detailed
have compared more or less restrictive transfusion strastudy
protocol
shown
in
Appendix,
online).24
tegies using different transfusion triggers. A previous
meta-analysis pooled data from randomized trials that
evaluated restrictive hemoglobin transfusion triggers
Data Synthesis and Analysis
ranging from 7 to 10 g/dL and found that restricting
The results were reported as a risk ratio (RR) and risk diftransfusions significantly reduced in-hospital mortality but
ference for dichotomous outcomes, for the restrictive strathad no effect on other clinical outcomes.22 We have
egy compared with the liberal strategy, with the confidence
chosen a different approach to evaluate the available evinterval (CI) set at 95% significance. For the amount of
idence. We now update the meta-analysis through April
blood transfused per patient, the results were reported as a
2013 to include a subsequent trial23 and restrict the primean difference, with 95% CIs for the restrictive compared
mary analysis to those trials with a transfusion trigger of
with the liberal strategy. To test for inter-study heteroge<7 g/dL. Trials that evaluated less restrictive strategies
neity, the chi-square value was calculated; statistical sigwere evaluated in a separate analysis. We also provide a
nificance was indicated by P < .1. The fixed-effects method
systematic review of observational studies that evaluated
was chosen to report the results because minimal heteroclinical outcomes related to other more restrictive transgeneity was seen in most of the analyses.25 When heterofusion strategies.
geneity was noted, the random-effects method was used.26

MATERIALS AND METHODS
Data Sources and Study Selection
We conducted a comprehensive search of the MEDLINE
database from 1966 to April 2013 using the terms blood
transfusion and clinical trial, and scanned selected journals
and references of identified articles. Studies of any language
were included in the primary analysis if they were randomized controlled trials that evaluated a restrictive blood
transfusion strategy using a transfusion trigger of <7 g/dL,
compared with a more liberal strategy (detailed study

In a secondary analysis, the pooled results from trials using a less restrictive strategy were evaluated and compared
with the trials in the primary analysis using the test for
interaction.27 The analyses were performed using Review
Manager, Version 5.2, Copenhagen: The Nordic Cochrane
Centre, The Cochrane Collaboration, 2012.

Role of Funding Source
The investigators received no funding for the study. No
sponsor had a role in any aspect of the study, including its
design and conduct, data extraction and analysis, and
preparation of the manuscript.

126

The American Journal of Medicine, Vol 127, No 2, February 2014

-

Potentially relevant studies
identified and screened for
retrieval (n = 4500)

Studies excluded:
Not trials of transfusion triggers (n = 4369)
Studies used for systematic review

Trials of transfusion triggers
In anemia (n = 32)

Trials excluded:
Not randomized (n = 2)

Randomized trials of transfusion
triggers in anemia (n = 30)

Trials excluded from primary analysis:
Used less-restrictive trigger (n = 19)
(16 trials used in secondary analysis)
Did not provide clear trigger (n = 4)
Duplicate data from other trials (n = 4)

Primary analysis:
Randomized controlled trials of a
restrictive transfusion strategy using
a hemoglobin trigger of < 7 g/dL,
compared with a more liberal
strategy (n = 3)
Figure 1

Flow chart of trials search for meta-analysis.

RESULTS
Primary Meta-analysis
Search Results. The search identified approximately 4500
studies, of which 32 were potentially relevant trials evaluating transfusion triggers (Figure 1). Of these, 3 trials met
inclusion criteria for the primary analysis.12,23,28 One
study provided unpublished information.23 Studies were
excluded for the following reasons: Two were not randomized, 19 used a less-restrictive hemoglobin transfusion
trigger of >7 g/dL, 4 did not provide a clear transfusion
trigger, and 4 provided duplicate data on participants
included in another trial. Of the 19 trials evaluating a

less-restrictive strategy, 16 provided data on clinical outcomes and were evaluated separately.6-11,21,29-37
Trial Characteristics. The primary analysis included 3
trials, with a total of 2364 participants followed for mean
trial duration of 45 days. The characteristics of the included
trials, including their risk of bias, are shown in Appendix
Figure 1 (online). The mean study size was 788 participants (range, 637-889), with a mean participant age of 45.7
years (standard deviation, 16 years). Transfusion strategies
were evaluated in the setting of adult critical care,12 pediatric critical care,28 and acute upper gastrointestinal
bleeding.23

Salpeter et al

Restrictive Transfusion Strategies and Clinical Outcomes

127

Table 1 Outcomes for Restrictive Transfusion Strategy, with Hemoglobin Transfusion Trigger <7 g/dL, Compared with a More
Liberal Strategy
Outcome
Mortality
Hospital mortality
30-d mortality
Total mortality
Cardiac events
Acute coronary syndrome
Pulmonary edema
Other outcomes
Rebleeding
Bacterial infections
Blood transfusions
Patients exposed to blood
Units transfused per patient

Trials

Patients

RR or MD

RD

No. Needed
to Treat

2
3
3

1727
2364
2364

RR, 0.74 [CI, 0.60-0.92]
RR, 0.81 [CI, 0.61-0.96]
RR, 0.80 [CI, 0.65-0.98]

RD, 0.04 [CI, 0.04 to 0.00]
RD, 0.02 [CI, 0.04 to 0.00]
RD, 0.03 [CI, 0.05 to 0.00]

25
50
33

2
3

1727
2364

RR, 0.44 [CI, 0.22-0.89]
RR, 0.48 [CI, 0.33-0.73]

RD, 0.02 [CI, 0.03 to 0.00]
RD, 0.03CI, 0.05 to 0.01

50
33

1
3

889
2364

RR, 0.64 [CI, 0.45-0.90]
RR, 0.86 [CI, 0.73-1.00]

RD, 0.06 [CI, 0.10 to 0.01]
RD, 0.03 [CI, 0.06 to 0.00]

17
33

3
3

2364
2364

RR, 0.57 [CI, 0.46-0.70]
MD 1.98 [CI, 3.22 to 0.74]

RD, 0.41 [CI, 0.52 to 0.29]

2

CI ¼ confidence interval; MD ¼ mean difference; RD ¼ risk difference; RR ¼ risk ratio.

Data Synthesis. The restrictive transfusion strategy was
associated with a statistically significant reduction of inhospital mortality (RR, 0.74; CI, 0.60-0.92), 30-day mortality (RR, 0.77; CI, 0.61-0.96), and total mortality (RR,
0.80; CI, 0.65-0.98), compared with the liberal strategy
(Table 1, Figure 2). The risk difference for total mortality
was 0.03 for the restrictive strategy compared with
the liberal strategy (mean duration of included trials,
45 days), with a number needed to treat of 33 to save 1
life. In addition, the restrictive strategy resulted in a
reduced incidence of acute coronary syndrome (RR, 0.44;
CI, 0.22-0.89), pulmonary edema (RR, 0.48; CI, 0.330.72), rebleeding (RR, 0.64; CI, 0.45-0.90), and bacterial
infections (RR, 0.86; CI, 0.73-1.00), compared with the
liberal strategy (Table 1, Figure 3, Appendix, online).

Figure 2

The results for bacterial infections were of nominal
significance.
In pooled trial data, 55% of the participants in the
restrictive group received a blood transfusion, compared
with 94% in the liberal group (RR, 0.57; CI, 0.46-0.70
and risk difference, 0.41; CI, 0.52 to 0.29). The
restrictive strategy resulted in a significant reduction in
the mean number of units transfused, with a mean difference of 1.98 units (CI, 3.22 to 0.74 units) per
patient.
No evidence for inter-study heterogeneity was found in
any of the clinical outcomes analyzed (P > .25, for chisquare test). There was evidence for significant heterogeneity in the analyses of exposure to blood transfusions and
the mean number of units transfused (P < .00001).

Restrictive transfusion strategy and mortality. CI ¼ confidence interval.

128

The American Journal of Medicine, Vol 127, No 2, February 2014

Figure 3

Restrictive transfusion strategy and cardiac events. CI ¼ confidence interval.

Secondary Meta-analysis

Systematic Review

Randomized Trials Using Less-Restrictive Transfusion
Triggers. Nineteen of the trials excluded from the primary
analysis evaluated hemoglobin triggers of 7.5 to 10 g/dL in
the restrictive strategy group, and 16 of those provided data
on clinical outcomes.6-11,21,29-37 When the data from these
trials were pooled, with a total of 4572 participants, the
restrictive strategy significantly reduced the exposure to
blood transfusions (RR, 0.60; CI, 0.48-0.75) and amount of
blood transfused (mean difference, 0.80 units; CI, 1.24
to 0.37 units), compared with a more liberal strategy, but
this had no significant effect on in-hospital mortality (RR,
0.65; CI, 0.37-1.15), total mortality (RR, 1.03; CI, 0.811.31), acute coronary syndrome (RR, 1.46; CI, 0.96-2.20),
pulmonary edema (RR, 1.02; CI, 0.67-1.56), rebleeding
(RR, 0.68; CI, 0.34-1.34), or bacterial infections (RR, 0.80;
CI, 0.64-1.02).
When the pooled results for the trials from the primary
analysis (hemoglobin trigger <7 g/dL) were compared with
the results from the less restrictive trials (hemoglobin trigger
7.5-10 g/dL) using the test for interaction, the more
restrictive strategy was associated with a greater reduction in
acute coronary syndrome (P ¼ .004), pulmonary edema
(P ¼ .002), and amount of blood transfused (P ¼ .01),
compared with the less restrictive strategy.
When all 19 trials from the primary and secondary analyses were pooled together, with a total of 6936 participants,
the restrictive strategy was still associated with a significant
reduction in hospital mortality (RR, 0.73; CI, 0.59-0.89),
30-day mortality (RR, 0.83; CI, 0.69-0.99), pulmonary
edema (RR, 0.68; CI, 0.51-0.90), bacterial infections
(RR, 0.84; CI, 0.73-0.95), and rebleeding (RR, 0.64; CI,
0.47-0.88).

Observational Studies Evaluating More Restrictive
Transfusion Strategies. Recent recommendations to
further restrict blood transfusions have been based on
studies showing the tolerability and safety of anemia under
controlled normovolemic conditions, which involve the
administration of fluids, oxygen, and beta-adrenergic
blockers.14,15,38-45 A meta-analysis of randomized trials
in the perioperative setting showed that normovolemic
hemodilution, in which blood is removed and replaced
with crystalloid or colloid solution, resulted in significantly
less total blood loss and allogenic blood transfusions,
compared with standard care.46 A systematic review found
consistent evidence that normovolemic anemia is associated with a reduction in systemic vascular resistance and an
increase in cardiac output, coronary and cerebral blood
flow, and synthesis of 2,3-diphosphoglycerate in red blood
cells, resulting in maintenance of oxygen delivery and
extraction.39 Observational studies have shown that hemoglobin levels of 5 to 6 g/dL in the setting of surgery,
critical illness, and acute bleeds generally are well tolerated
when standard supportive measures are given, without
evidence of cardiac ischemia or decrease in oxygen
extraction until the hemoglobin decreases to less than 3
to 4 g/dL.47-56

DISCUSSION
Pooled data from randomized controlled trials show that
restricting blood transfusions to patients whose hemoglobin
decreases to less than 7 g/dL results in a significant reduction in total mortality, acute coronary syndrome, pulmonary
edema, rebleeding, and bacterial infection, compared with a

Salpeter et al

Restrictive Transfusion Strategies and Clinical Outcomes

more liberal transfusion strategy. The number needed to
treat to save 1 life was 33. This strategy resulted in a 40%
reduction in the number of patients receiving a blood
transfusion, with an average of 2 units less per person;
however, more than one half of patients still received a
transfusion. In an analysis of trials that used a less restrictive
strategy, with hemoglobin triggers of 7.5 to 9 g/dL, no
significant reduction in morbidity or mortality was seen.
With the available evidence from observational studies,
an even more restrictive transfusion strategy using a hemoglobin trigger of <6 g/dL has been recommended in
some settings.14,15 Observational studies have consistently
shown that transfusions are associated with an increased risk
for adverse events after controlling for potential confounding variables, even when using a restrictive transfusion
strategy.56-63 The increased risk seems to be directly proportional to the amount of blood transfused and the length
of storage of the transfused red blood cells, and may be due
to an inflammatory response to the transfused blood product.58,64-66 Systematic reviews also have evaluated the effect
of blood transfusions on oxygen transport variables in
anemic patients in the setting of surgery, critical illness, and
bleed, and found no significant improvement in oxygen
delivery or use compared with supportive care, despite an
increase in oxygen content.5,57,58 This inability to improve
oxygen uptake in vital organs is due to the hemodynamic
response to increased blood viscosity and the loss of red
cell function during preservation and storage.5,57,58,67-71
Conversely, there is evidence that normovolemic anemia
with hemoglobin levels of 5 to 6 g/dL is well tolerated in
cardiovascular or critical illness and may have beneficial
hemodynamic effects.39,42,47,51
It has been the traditional teaching that patients with
cardiac ischemia should have a more liberal transfusion
strategy to maintain oxygenation, but pooled observational
studies on transfusion in myocardial infarction found that the
rates of subsequent myocardial infarction and all-cause
mortality were significantly higher in patients receiving
blood transfusions compared with standard supportive
measures, after adjustment for possible confounding variables.72 Multivariate meta-regression analysis of the pooled
data revealed that the increased risk was independent of
the baseline or nadir hemoglobin level.72 Subgroup analysis
of a large critical care trial included in the primary analysis
found that in patients with coronary ischemia, a transfusion
trigger of <7 g/dL may be associated with improved clinical
outcomes.12,73 Two small trials included in the secondary
analysis evaluated a restrictive trigger of <8 g/dL in patients
with symptomatic coronary artery disease; pooled results
from these 2 trials showed no significant effect on cardiac
events or mortality using this less restrictive strategy.21,30
This meta-analysis found that restricting transfusions
using a hemoglobin trigger of <7 g/dL reduced mortality in
critical illness or bleed, with a number needed to treat of 33
to save 1 life. With millions of blood transfusions given
yearly over the past century, it would be hard to calculate
how many deaths may have been caused by transfusions.

129

The main goal of blood transfusions is to increase oxygencarrying capacity, but despite increasing oxygen content,
oxygen delivery is not increased.5,57,58 Another indication
for transfusions has been to stabilize bleeding patients,
but in fact transfusions significantly increase the risk for
rebleeding.6,23 So far, there is little trial evidence that
blood transfusions significantly improve oxygen delivery
or clinical outcomes in any setting or with any nadir hemoglobin level.5,57,58,74

Study Limitations
This meta-analysis and systematic review has several limitations. The trials in the primary meta-analysis studied
disparate populations, including both pediatric and adult
patients, and addressed different indications for transfusion,
such as critical illness and gastrointestinal bleed. This has
the potential for introducing bias in the analysis, despite the
fact that we found no evidence for inter-study heterogeneity
in the results. Another potential bias is that there was
incomplete blinding of the participants in the individual
trials because of the nature of the interventions. However,
the hard clinical outcomes studied were unlikely to have
been influenced by this. Another limitation of the study is
that other patient populations, such as those with less lifethreatening illnesses, were not included in the primary
analysis.
The objective of this study was to put together the
available evidence for practicing clinicians to make sense of
it all, but we are left with many unanswered questions. Unfortunately, more than one half of the patients in the restrictive group still received a blood transfusion, so we cannot
directly assess the effect of transfusion versus no transfusion.
At present, there are no randomized trials evaluating lower
transfusion triggers, such as a hemoglobin level of 6 g/dL,
which is what some of the newer guidelines recommend
using on the basis of observational studies.14,15 In addition,
there are no randomized trials evaluating the lower transfusion triggers in acute coronary syndrome, which at present
is considered an indication for the use of a more liberal
trigger. Finally, there is little information on clinical situations or nadir hemoglobin levels for which transfusions are
known to improve oxygen delivery and mortality.

CONCLUSIONS
We have performed an updated meta-analysis of randomized trials that shows that a restrictive transfusion strategy
using a hemoglobin transfusion trigger of <7 g/dL results in
a significant reduction in acute coronary syndrome, pulmonary edema, rebleeding, infections, and total mortality,
compared with a more liberal strategy. At present, there is
no randomized trial evidence that blood transfusions
improve oxygen delivery or clinical outcomes in any setting.
More studies are needed to help guide clinicians in finding
optimal treatment threshold and options in the setting of
anemia and bleed.

130

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131.e1

APPENDIX SUPPLEMENTAL DATA
Study Protocol:
Types of studies:
We included randomized controlled trials with a concurrent control group. Trials were included if the comparison groups were assigned on the basis of a clear transfusion
trigger or threshold of 7 g/dL, described as a hemoglobin
or hematocrit level. Patients in the control group were
required to receive a transfusion of red blood cells at higher
hemoglobin or hematocrit thresholds than the intervention
group.
Types of participants:
We included trials of patients with surgical or medical
conditions, involving adults or children, including neonates.
Types of interventions:
The intervention considered was the use of red blood cell
transfusion thresholds (“triggers”) as a means of providing
insights for rational transfusion practices.
Outcomes assessed:
In-hospital mortality, 30-day mortality, total mortality
over the period of follow-up for individual studies, acute
coronary syndrome, pulmonary edema, bacterial infections,
rebleeding, number of patients receiving any blood transfusion, and units of blood transfused per patient.

The American Journal of Medicine, Vol 127, No 2, February 2014
9. (transfus* adj5 (polic*or practic* or protocol* or
trigger* or threshold* or indicator* or strateg* or criteri* or standard*)).mp.
10. ((Red blood cell* or RBC) adj5 (polic*or practic* or
protocol* or trigger* or threshold*or indicator* or
strateg* or criteri* or standard*)).mp.
11. ((H?emoglobin or h?emocrit or HB or HCT) adj5 (polic*or practic* or protocol* or trigger* or threshold*
or indicator* or strateg* or criteri* or standard*)).mp.
12. (transfus* adj5 (restrict* or liberal*)).mp.
13. ((blood or transfusion*) adj3 (management or
program*)).mp.
14. 8 or 9 or 10 or 11 or 12 or 13
15. randomi?ed.ab,ti.
16. randomized controlled trial.pt.
17. controlled clinical trial.pt.
18. placebo.ab.
19. clinical trials as topic.sh.
20. randomly.ab.
21. trial.ti.
22. 15 or 16 or 17 or 18 or 19 or 20 or 21
23. (animals not (humans and animals)).sh.
24. 22 not 23
25. 24 and 14.

Search methods for identification of studies:
We did not restrict our search for trials by date, language,
or publication status. A comprehensive search of the
MEDLINE database from 1966 to April 2013 was conducted using the following MeSH terms and strings:

Searching other resources:
We contacted authors of published studies for clarification of trial methodology and data. This was provided in 1
instance.21
We searched the reference lists of relevant reviews and
published articles, as well as the reference lists of all
included trials for further studies.

1. *Blood Transfusion/
2. ((Red blood cell* or RBC) adj3 (therap* or
transfus*)).mp.
3. 1 or 2
4. exp Reference Standards/
5. standards.fs.
6. methods.fs.
7. 4 or 5 or 6
8. 3 and 7

Assessment of risk of bias in included studies:
We completed a “risk of bias” table for each study, incorporating a description of the study’s performance against each
of the above domains as follows: “low,” “unclear” (indicating
unclear or unknown risk of bias), and “high” risk of bias.
One investigator (SC) studied the following domains:
sequence generation; allocation concealment; blinding;
incomplete outcome data; selective outcome reporting; other
potential sources of bias.

Salpeter et al

Restrictive Transfusion Strategies and Clinical Outcomes

Appendix Figure 1
confidence interval.

131.e2

Restrictive transfusion strategy and other clinical events. CI ¼

Appendix Table 1 Patient-Level Characteristics of Randomized Controlled Trials Evaluating a Liberal Transfusion Strategy (Hemoglobin
Trigger of <7.0 g/dL) Compared with a More Liberal Strategy
Trial
Trial Characteristics

Hebert et al12

Lacroix et al28

Villanueva et al23*

Setting

Adult Intensive Care Unit

Pediatric Intensive Care Unit

Severe Acute Upper
Gastrointestinal Bleeding

Transfusion strategy

Restrictive Arm

Liberal Arm

Restrictive Arm

Liberal Arm

Restrictive Arm

Liberal Arm

Transfusion trigger (g/dL)
Total (N)
Mean age (y)
Men (%)
Baseline hemoglobin (g/dL)
Mean units of red-cell transfusion
Mean length of storage of
red cells (d [SD])
Cardiovascular disease (N [%])
Infection (N [%])

7.0
418
57.1
64
8.2
2.5
NR

10.0
420
58.1
61
8.2
2.3
NR

7.0
320
2.98
59
8.0
0.9
14.9 [11.8]

9.5
317
3.3
60
8.0
1.7
15.2 [10.6]

7.0
444
64
71
9.55
1.5
15.8 [8]

9.0
445
66
65
9.44
3.7
15.8 [8]

76 [18]
114 [27]

94 [22]
108 [26]

76 [24]
157 [49]

75 [24]
155 [49]

NR
37 [8.3]

NR
44 [9.8]

NR ¼ not reported (in primary publication, as referenced); SD ¼ standard deviation.
*Additional data provided by corresponding author on request.

131.e3
Appendix Table 2

Trial

The American Journal of Medicine, Vol 127, No 2, February 2014
Risk of Bias Assessments for Included Trials
Blinding of
Participants and
Random Sequence Allocation
Researchers
Concealment
Generation
(Selection Bias) (Performance Bias)
(Selection Bias)

Hebert et al12
Low
Lacroix et al28
Low
Villanueva et al23 Low

Low
Low
Low

Low
Low
Low

Blinding of
Selective
Incomplete
Outcome
Other
Outcome Data Reporting
Assessment
(Detection Bias) (Attrition Bias) (Reporting Bias) Bias
Low
Low
Low

Low
Low
Low

Low
Low
Low

Low
Low
Low



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