restrictive blood transfusion strategies 2014.pdf

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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.


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
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.

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.