new england

The
journal of medicine
established in 1812 december 29, 2011 vol. 365 no. 26

Liberal or Restrictive Transfusion in High-Risk Patients

after Hip Surgery
Jeffrey L. Carson, M.D., Michael L. Terrin, M.D., M.P.H., Helaine Noveck, M.P.H., David W. Sanders, M.D.,
Bernard R. Chaitman, M.D., George G. Rhoads, M.D., M.P.H., George Nemo, Ph.D., Karen Dragert, R.N.,
Lauren Beaupre, P.T., Ph.D., Kevin Hildebrand, M.D., William Macaulay, M.D., Courtland Lewis, M.D.,
Donald Richard Cook, B.M.Sc., M.D., Gwendolyn Dobbin, C.C.R.P., Khwaja J. Zakriya, M.D., Fred S. Apple, Ph.D.,
Rebecca A. Horney, B.A., and Jay Magaziner, Ph.D., M.S.Hyg., for the FOCUS Investigators*

A bs t r ac t

Background
The hemoglobin threshold at which postoperative red-cell transfusion is warranted The authors’ affiliations are listed in the
is controversial. We conducted a randomized trial to determine whether a higher Appendix. Address reprint requests to
Dr. Carson at the Department of Medicine,
threshold for blood transfusion would improve recovery in patients who had under- University of Medicine and Dentistry of
gone surgery for hip fracture. New Jersey, Robert Wood Johnson Medi-
cal School, 125 Paterson St., New Bruns-
wick, NJ 08903, or at carson@umdnj.edu.
Methods
We enrolled 2016 patients who were 50 years of age or older, who had either a his- * Investigators in the Transfusion Trigger
tory of or risk factors for cardiovascular disease, and whose hemoglobin level was Trial for Functional Outcomes in Cardio-
vascular Patients Undergoing Surgical
below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients Hip Fracture Repair (FOCUS) are listed
to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a in the Supplementary Appendix, avail-
restrictive transfusion strategy (symptoms of anemia or at physician discretion for able at NEJM.org.

a hemoglobin level of <8 g per deciliter). The primary outcome was death or an in- This article (10.1056/NEJMoa1012452)
ability to walk across a room without human assistance on 60-day follow-up. was published on December 14, 2011, at
NEJM.org.
Results N Engl J Med 2011;365:2453-62.
A median of 2 units of red cells were transfused in the liberal-strategy group and Copyright © 2011 Massachusetts Medical Society.

none in the restrictive-strategy group. The rates of the primary outcome were 35.2%
in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio
in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for
an absolute risk difference of 0.5 percentage points (95% CI, −3.7 to 4.7). The rates
of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively
(absolute risk difference, −0.9%; 99% CI, −3.3 to 1.6), and rates of death on 60-day
follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI,
−1.9 to 4.0). The rates of other complications were similar in the two groups.

Conclusions
A liberal transfusion strategy, as compared with a restrictive strategy, did not re-
duce rates of death or inability to walk independently on 60-day follow-up or reduce
in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the
National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number,
NCT00071032.)

n engl j med 365;26 nejm.org december 29, 2011 2453

The New England Journal of Medicine
Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

I
n the United States, more than 17 mil- more per deciliter; current tobacco use; or a cre-
lion red-cell units are collected annually, and atinine level of more than 2.0 mg per deciliter.6
15 million units are transfused.1 Blood trans- We excluded patients if they were unable to
fusions are frequently given to surgical patients walk without human assistance before hip frac-
and to the elderly.2,3 Yet, the indications for post- ture, declined blood transfusions, had multiple
operative transfusion have not been adequately trauma (defined as having had or planning to
evaluated and remain controversial. Most clinical undergo surgery for non–hip-related traumatic
trials have been small.4 One adequately powered injury), had a pathologic hip fracture associated
trial involving adults in intensive care units showed with cancer, had a history of clinically recognized
a nonsignificant decrease in 30-day mortality with acute myocardial infarction within 30 days be-
a restrictive transfusion strategy, as compared fore randomization, had previously participated
with a liberal strategy (18.7% vs. 23.3%).5 How- in the trial with a contralateral hip fracture, had
ever, the effect of a restrictive approach on func- symptoms associated with anemia (e.g., ischemic
tional recovery or risk of myocardial infarction in chest pain), or were actively bleeding at the time
patients with cardiac disease has not been stud- of potential randomization.
ied.4 We performed the Transfusion Trigger Trial The institutional review board or ethics com-
for Functional Outcomes in Cardiovascular Patients mittee at all 47 participating clinical sites approved
Undergoing Surgical Hip Fracture Repair (FOCUS) the protocol (available with the full text of this
to test the hypothesis that a higher threshold for article at NEJM.org). An independent data and
blood transfusion (a hemoglobin level of 10 g per safety monitoring board also approved the proto-
deciliter) would improve functional recovery and col and monitored the trial. Written informed
reduce morbidity and mortality, as compared with consent was obtained from patients or their des-
a more restrictive transfusion strategy (a hemo- ignated representatives. Methods were reported
globin level of <8 g per deciliter or symptoms). in detail previously.6

Me thods Treatment Assignment and Follow-up

We randomly assigned patients to the liberal-
Patients strategy group or the restrictive-strategy group
From July 19, 2004, through February 28, 2009, using an automated telephone randomization
we enrolled patients at 47 clinical sites in the system. Staff members at the data coordinating
United States and Canada. Telephone follow-up center prepared randomization schedules for
ended on May 4, 2009. Patients 50 years of age or each site using randomly ordered block sizes of
older who were undergoing primary surgical re- two, four, six, or eight. After randomization,
pair of a hip fracture and who had clinical evi- clinical-site staff members, clinicians, and pa-
dence of or risk factors for cardiovascular disease tients were aware of study-group assignments.
were eligible if they had a hemoglobin level of Patients in the liberal-strategy group received
less than 10 g per deciliter within 3 days after 1 unit of packed red cells and additional blood as
surgery. According to the original protocol, only needed to maintain a hemoglobin level of 10 g or
patients with cardiovascular disease (a history of more per deciliter. An assessment of the hemo-
ischemic heart disease, electrocardiographic evi- globin level after transfusion was required, and
dence of previous myocardial infarction, a his- an additional unit of blood was transfused if the
tory or presence of congestive heart failure or patient’s hemoglobin level was below 10 g per
peripheral vascular disease, or a history of stroke deciliter.
or transient ischemic attack) were eligible. In De- Patients in the restrictive-strategy group were
cember 2005, eligibility criteria were expanded to permitted to receive transfusions if symptoms or
enhance recruitment by including patients with signs of anemia developed or at the discretion of
any of the following cardiovascular risk factors: their physicians if the hemoglobin level fell below
a history of or treatment for hypertension, diabe- 8 g per deciliter. Symptoms or signs that were
tes mellitus, or hypercholesterolemia; a cholesterol considered indications for transfusion were chest
level of 200 mg or more per deciliter or a low- pain that was deemed to be cardiac in origin,
density lipoprotein cholesterol level of 130 mg or congestive heart failure, and unexplained tachy-

2454 n engl j med 365;26 nejm.org december 29, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 Liber al or Restrictive Tr ansfusion in High-Risk Patients

cardia or hypotension unresponsive to fluid re- markers that were performed in hospitals for clin­
placement. Blood was administered 1 unit at a ical indications were also collected. Samples were
time, and the presence of symptoms or signs was analyzed at the core laboratory of the Minneapolis
reassessed. Patients with clinically diagnosed de- Medical Research Foundation of Hennepin County
mentia received transfusions when the hemoglo- Medical Center for troponin I (Access 2 Immuno-
bin level fell below 8 g per deciliter because they assay System, Beckman Coulter) with the use of
might not be able to report their symptoms. a threshold of 0.06 μg per liter (1.5 times the
Hemoglobin levels were measured during hos- 99th percentile [0.04 μg per liter] for healthy pa-
pitalization on days 1, 2, 4, and 7 after randomiza- tients). We used the Universal Definition of Myo-
tion. Additional hemoglobin determinations were cardial Infarction criteria7,8 to define myocardial
made as clinically indicated. The assigned trans- infarction and unstable angina on the basis of
fusion strategy was to be followed until discharge review of clinical status, central interpretation of
or up to 30 days, whichever came first. Transfu- electrocardiograms at Saint Louis University, and
sion was permitted at any time without measur- results of core laboratory and clinical cardiac bio-
ing a hemoglobin level if the patient was bleeding markers (see the Supplementary Appendix, avail-
and emergency transfusion was considered nec- able at NEJM.org). Study investigators who classi-
essary by the treating physician. fied cardiovascular outcomes and those who did
Nurses at the clinical coordinating center who follow-up telephone assessments were unaware
were not involved with study implementation and of study-group assignments.
were unaware of study-group assignments tele- Other secondary outcomes that were deter-
phoned patients or proxies at or close to 30 days mined on telephone follow-up at or close to 30 days
and 60 days after randomization to ascertain out- and 60 days after randomization included current
comes after hospital discharge. They spoke di- residence, survival, functional measures (lower-
rectly to patients who were accessible by tele- extremity physical and instrumental activities of
phone or to proxies if patients were cognitively daily living), and fatigue. These outcomes were
impaired or could not talk on the telephone. ascertained with the use of methods described
previously.6
Primary Outcome
The primary outcome was death or an inability to Tertiary Study Outcomes
walk 10 ft (or across a room) without human as- We evaluated in-hospital morbidity up to 30 days
sistance at the 60-day follow-up. We hypothesized after randomization, including pneumonia, wound
that an increased hemoglobin level would allow infection, thromboembolism, stroke or transient
patients to participate more actively in rehabilita- ischemic attack, and clinically recognized myocar-
tion and therefore increase the proportion who dial infarction.6 We prespecified two composite
were walking independently 60 days after ran- outcomes: death, myocardial infarction, or pneu-
domization. monia; and death, myocardial infarction, pneumo-
nia, thromboembolism, or stroke.
Secondary Outcomes
Secondary outcomes included a combined out- Vital Status and Walking Confirmation
come of in-hospital myocardial infarction, unstable We validated the vital status of patients in the
angina, or death for any reason; each of these out- United States by searching the online Social Se-
comes was assessed individually. curity Database. When discrepancies were identi-
Electrocardiography was performed before sur- fied between telephone reports and this database,
gery, before randomization, and on day 4 after we verified deaths using hospital records or pub-
randomization (or at the time of discharge if be- lished obituaries. We validated the vital status of
fore day 4). Blood (plasma or serum) specimens Canadian patients by searching hospital medical
were collected for measurement of the cardiac records, vital-status records, and outpatient med-
troponin I level before surgery, before random- ical records. We validated vital status in 95.9% of
ization, and on days 1 and 4 after randomization patients (99.0% in the United States and 91.2% in
or before discharge (if before day 4). Electrocar- Canada). Of 1934 vital-status confirmations, we
diograms and results of testing of cardiac bio- found 7 discrepancies (0.4%) between telephone re-

n engl j med 365;26 nejm.org december 29, 2011 2455

The New England Journal of Medicine
Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

ports and vital-status records; in these cases, we R e sult s

used vital-status records. We assessed the reli-
ability of the self-report of walking status in a Study Population
subgroup of 814 patients for whom we had both We screened 14,438 patients and randomly as-
self-report and proxy report and found high re- signed 2016 to either the liberal-strategy group
liability (kappa = 0.90) between these reports.9 (1007 patients) or the restrictive-strategy group
(1009) (see the Supplementary Appendix). There
Adherence Definitions were 14 withdrawals, 2 losses to follow-up, and
We defined major protocol violations as a lack 1 incomplete follow-up ascertainment; follow-up
of receipt of a transfusion or hospital discharge for the primary analysis was obtained in 99.2%
with a hemoglobin level of less than 10 g per of the patients. Of the 1999 patients included in
deciliter in the liberal-strategy group and as the the primary analysis, we directly interviewed 1075
receipt of transfusion with a hemoglobin level (53.8%) and obtained data on 923 (46.2%) by
of 8 g per deciliter or more in the absence of proxy; the source of information was missing for
symptoms in the restrictive-strategy group. 1 patient.
The mean age of the study population was
Statistical Analysis 81.6 years (range, 51 to 103), and cardiovascular
According to the original study design, we de- disease was present in 62.9%. Baseline charac-
termined that a sample size of 2600 patients teristics were similar in the two study groups
would provide a power of 90% and an experi- (Table 1).
ment-wise alpha level of 0.05 allowing for in-
terim analyses (four were performed by the data Hemoglobin Levels and Transfusion
and safety monitoring board) and a level of The average hemoglobin level before transfusion
0.048 for the final comparison to detect an ab- was 1.3 g per deciliter higher in the liberal-strat-
solute between-group difference of 7 percent- egy group than in the restrictive-strategy group
age points in the primary outcome (odds ratio, (P<0.001) (Table 2). The median number of units
0.75). In September 2007, the data and safety transfused was 2.0 (interquartile range, 1 to 2) in
monitoring board approved a reduction of re- the liberal-strategy group and 0 (interquartile
cruitment goal to 2000 patients. This change range, 0 to 1) in the restrictive-strategy group;
resulted in an absolute change of approximately 59.0% of patients in the restrictive-strategy group
1 percentage point in the between-group differ- did not receive a transfusion after randomiza-
ence in the primary outcome that could be ex- tion. Figure 1 shows the average daily lowest he-
cluded with a power of 90%. moglobin levels in the two groups.
We used the Mantel–Haenszel method10 to Violations in the transfusion protocol occurred
conduct the primary analysis, taking into ac- in 9.0% of patients in the liberal-strategy group
count different clinical sites. We prespecified and in 5.6% of those in the restrictive-strategy
tests for interaction of the primary outcome11,12 group. Symptoms leading to transfusion are listed
with sex, age, race, and cardiovascular-disease in Table 2.
status (known cardiovascular disease vs. risk fac-
tors only) without adjustment of the alpha level. Outcomes
Tests for interaction and differences in outcomes The rates of death or an inability to walk without
are presented without adjustment for clinical human assistance at 60-day follow-up were simi-
site. The primary outcome analysis is presented lar in the liberal-strategy group and the restric-
as a Mantel–Haenszel odds ratio with 95% con- tive-strategy group (35.2% vs. 34.7%, P = 0.90)
fidence intervals. For secondary and tertiary (Table 3). The odds ratio for the primary outcome
analyses, we used standard methods for the associated with the liberal strategy versus the re-
comparison of proportions and means without strictive strategy was 1.01 (95% confidence inter-
adjustment for clinical site, using an alpha val [CI], 0.84 to 1.22), for an absolute risk differ-
level of 0.01 (with 99% confidence intervals). ence of 0.5 percentage points (95% CI, −3.7 to 4.7).
Analyses were performed with the use of SAS There was a significant interaction according to
software, version 9.2. patients’ sex (P = 0.03), with an odds ratio associ-

2456 n engl j med 365;26 nejm.org december 29, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 Liber al or Restrictive Tr ansfusion in High-Risk Patients

Table 1. Baseline Characteristics of the Patients.*

Liberal Strategy Restrictive Strategy

Variable (N = 1007) (N = 1009)
Age — yr 81.8±8.8 81.5±9.0
Male sex — no. (%) 250 (24.8) 239 (23.7)
Race — no. (%)†
White 944 (93.7) 947 (93.9)
Black 40 (4.0) 42 (4.2)
Asian 14 (1.4) 13 (1.3)
Other 9 (0.9) 7 (0.7)
Residence in the United States — no. (%) 609 (60.5) 613 (60.8)
Cardiovascular disease — no. (%)
Any 637 (63.3) 631 (62.5)
Coronary artery disease 402 (39.9) 403 (39.9)
Congestive heart failure 184 (18.3) 167 (16.6)
Cerebrovascular disease 249 (24.7) 224 (22.2)
Peripheral vascular disease 117 (11.6) 102 (10.1)
Cardiovascular risk factors — no./total no. (%)
Hypertension 824/1003 (82.2) 821/1005 (81.7)
Diabetes mellitus 252/1003 (25.1) 256/1005 (25.5)
Hypercholesterolemia 347/1002 (34.6) 360/1001 (36.0)
Tobacco use 116/1003 (11.6) 113/1004 (11.3)
Creatinine >2.0 mg/dl 83/1001 (8.3) 86/1003 (8.6)
Chronic lung disease 189/1003 (18.8) 188/1007 (18.7)
History of dementia or confusion 309/1004 (30.8) 325/1008 (32.2)
History of cancer 181/1003 (18.0) 189/1008 (18.8)
Type of hip fracture — no./total no. (%)
Femoral neck 432/1004 (43.0) 422/1008 (41.9)
Intertrochanteric 512/1004 (51.0) 522/1008 (51.8)
Subtrochanteric 88/1004 (8.8) 95/1008 (9.4)
Reverse oblique 13/1004 (1.3) 8/1008 (0.8)
Type of anesthesia — no./total no. (%)
General 543/1005 (54.0) 566/1008 (56.2)
Spinal 457/1005 (45.5) 434/1008 (43.1)
Other 5/1005 (0.5) 8/1008 (0.8)
American Society of Anesthesiology risk score‡ 3.0±0.6 2.9±0.6
Residence — no./total no. (%)
Home or retirement home 892/1005 (88.8) 886/1008 (87.9)
Nursing home 104/1005 (10.3) 110/1008 (10.9)
Other 9/1005 (0.9) 12/1008 (1.2)

* Plus–minus values are means ±SD. There were no significant between-group differences for any of the listed variables.
† Race was self-reported.
‡ Scores range from 1 to 5, with a higher score indicating greater risk. Data in this category were missing for 38 patients
in the liberal-strategy group and 39 in the restrictive-strategy group.

n engl j med 365;26 nejm.org december 29, 2011 2457

The New England Journal of Medicine
Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Hemoglobin Levels and Transfusions.*

Liberal Strategy Restrictive Strategy

Variable (N = 1007) (N = 1009) P Value
Hemoglobin level — g/dl
Before surgery 11.3±1.5 11.3±1.5 0.70
During eligibility screening 9.0±0.8 9.0±0.8 0.98
Before transfusion 9.2±0.5 7.9±0.6 <0.001
Estimated blood loss during surgery — ml† 209±179 232±257 0.03
Transfusions before randomization
0 units — no./total no. (%) 754/1006 (75.0) 720/1008 (71.4)
≥1 unit — no./total no. (%) 252/1006 (25.0) 288/1008 (28.6) 0.07
Total no. of units 452 531
Transfusions after randomization
0 units — no./total no. (%) 33/1003 (3.3) 594/1007 (59.0)
1 unit — no./total no. (%) 420/1003 (41.9) 246/1007 (24.4)
2 units — no./total no. (%) 346/1003 (34.5) 127/1007 (12.6)
3 units — no./total no. (%) 132/1003 (13.2) 24/1007 (2.4)
≥4 units — no./total no. (%) 72/1003 (7.2) 16/1007 (1.6) <0.001
Total no. of units 1866 652
Storage of units transfused after randomization — days‡ 22.0±9.5 22.1±9.9 0.83
Leukoreduced units transfused after randomization — %§ 90.2 88.6 0.25
Major protocol violation — no./total no. (%)¶ 91/1006 (9.0) 56/1007 (5.6) 0.003
Transfusion because of symptoms — no./total no. (%)‖
Rapid bleeding 5/1006 (0.5) 14/1007 (1.4) 0.04
Chest pain 4/1006 (0.4) 9/1007 (0.9) 0.17
Congestive heart failure 1/1006 (0.1) 10/1007 (1.0) 0.007
Tachycardia or hypotension 43/1006 (4.3) 123/1007 (12.2) <0.001

* Plus–minus values are means ±SD.

† Data on estimated blood loss were missing for 122 patients in the liberal-strategy group and 129 in the restrictive-strat-
egy group.
‡ Data on the length of storage of units were missing for 25 units in the liberal-strategy group and 8 in the restrictive-
strategy group.
§ Data on leukoreduction status were missing for 19 units in the liberal-strategy group and 10 in the restrictive-strategy
group.
¶ In the liberal-strategy group, there were two types of protocol violations: 30 patients (3.0%) did not receive a transfu-
sion, and 61 patients (6.1%) were discharged with a hemoglobin level of less than 10 g per deciliter. In the restrictive-
strategy group, there was only one type of violation: 56 patients (5.6%) who did not have symptoms or rapid bleeding
received transfusions for a hemoglobin level of 8.0 g per deciliter or more.
‖ Patients may have had more than one symptom.

ated with the liberal strategy of 1.45 (95% CI, ference of 0.9 percentage points (99% CI, −1.5 to
1.00 to 2.10) for men versus 0.91 (95% CI, 0.74 to 3.4), and on 60-day follow-up (7.6% in the liberal-
1.13) for women. Interactions according to age, strategy group vs. 6.6% in the restrictive-strategy
race, and cardiovascular-disease status were not group), for an absolute risk difference of 1.0 per-
significant (see the Supplementary Appendix). centage point (99% CI, −1.9 to 4.0) (Table 3). The
There were no significant between-group dif- between-group differences were also not signifi-
ferences in the rates of death on 30-day follow-up cant in the rates of in-hospital acute myocardial
(5.2% in the liberal-strategy group vs. 4.3% in the infarction, unstable angina, or death (4.3% in the
restrictive-strategy group), for an absolute risk dif- liberal-strategy group vs. 5.2% in the restrictive-

2458 n engl j med 365;26 nejm.org december 29, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 Liber al or Restrictive Tr ansfusion in High-Risk Patients

strategy group), for an absolute risk difference of

−0.9 percentage points (99% CI, −3.3 to 1.6). 14
Liberal strategy Restrictive strategy Both strategies
The frequencies of in-hospital clinical events and 13
serious adverse events did not differ signifi-

Lowest Daily Hemoglobin (g/dl)

12
cantly between groups (Table 4). Also similar in
the two groups were the length of hospital stay, 11
scores for lower-extremity physical activities of 10
daily living, instrumental activities of daily liv-
9
ing, and fatigue, as well as rates of residing at
home at 30-day and 60-day follow-up (Table 3). 8

7
Discussion 6

We performed a randomized clinical trial involv- 0

0 1 2 3 4 5 6 7
ing 2016 patients undergoing surgery for hip
Days since Randomization
fracture and found no evidence that maintaining
the hemoglobin level above 10 g per deciliter was Figure 1. Lowest Daily Hemoglobin Levels.
superior to transfusion for symptoms or main- Shown are the lowest daily hemoglobin levels among patients in the liberal-
taining a hemoglobin level of less than 8 g per strategy group versus those in the restrictive-strategy group. Data for the
deciliter with respect to the primary outcome (a two groups are pooled on the day of randomization and are presented for
days 1, 2, 4, and 7, when hemoglobin levels were required to be measured
composite of death or an inability to walk across
while patients remained in the hospital. The center line within each box
the room without human assistance) and to sev- represents the median, and the extremes the interquartile range.
eral clinically relevant secondary outcomes, in-
cluding cardiovascular event rates and other func-
tional measures. We enrolled a high-risk group of suggesting a higher rate of death or an inability to
patients with a mean age of more than 81 years walk without human assistance at 60-day follow-up
for whom untreated anemia would probably be in men but not in women. This difference was not
more harmful than in a healthier or younger pop- anticipated and could have been due to chance.
ulation undergoing most surgical procedures. We obtained primary-outcome information
An ability to walk across the room at 60 days (including data regarding deaths) for more than
was selected as a main component of the pri- 99% of patients and validated vital status. How-
mary outcome because such a measure is recog- ever, we did not perform follow-up examinations,
nized to be an important functional outcome after and our telephone ascertainment of functional
hip fracture and is likely to be affected by factors outcomes was subject to possible miscommuni-
that transfusion might influence (e.g., aerobic ca- cation, poorly informed proxy respondents, and
pacity and muscle strength). We hypothesized, in recording errors. Although we did not validate
particular, that a higher hemoglobin level might patients’ ability to walk, in cases in which both
facilitate more active participation in rehabilitation, patients and their proxies answered the question
leading to more successful recovery of ambulation. about walking ability, we found strong agree-
We achieved a clinically important difference ment between the two reports. Scores for physi-
in the use of packed red cells and a good separa- cal activities of daily living, instrumental activities
tion in hemoglobin levels in the two transfusion of daily living, and fatigue were not validated
groups (Fig. 1). Patients in the restrictive-strategy and were not useful for analysis for 45 to 60% of
group received 65% fewer units of blood than patients. We revised eligibility criteria in the course
those in the liberal-strategy group; more than of the trial to include lower-risk patients who
half the patients in the restrictive-strategy group had cardiovascular risk factors but no history of
did not receive any blood transfusion. Widespread cardiovascular disease, and there was no impor-
implementation of this restrictive approach to tant treatment interaction with cardiovascular-
transfusion in similar patients would greatly re- disease status.
duce blood use. Our study had excellent statistical power for
We found an interaction between the transfu- determining the primary outcome of death or
sion strategy and sex in the liberal-strategy group, inability to walk. On the basis of the 95% confi-

n engl j med 365;26 nejm.org december 29, 2011 2459

The New England Journal of Medicine
Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 2460
Table 3. Outcomes at 30 Days and 60 Days.*

Variable 30-Day Period 60-Day Period

Absolute Risk Absolute Risk
Liberal Strategy Restrictive Strategy Odds Ratio Difference Liberal Strategy Restrictive Strategy Odds Ratio Difference
(N = 1007) (N = 1009) (99% CI) (99% CI) (N = 1007) (N = 1009) (95% CI) (95% CI)
percentage percentage
no./total no.(%) points no./total no. (%) points
Death or inability to walk indepen- 459/995 (46.1) 481/1000 (48.1) 0.92 −2.0 351/998 (35.2) 347/1001 (34.7) 1.01 0.5
dently (0.73 to 1.16) (−7.7 to 3.8) (0.84 to 1.22) (−3.7 to 4.7)
Inability to walk independently 407/995 (40.9) 438/1000 (43.8) 275/998 (27.6) 281/1001 (28.1)
Death 52/995 (5.2) 43/1000 (4.3) 1.23 0.9 76/998 (7.6) 66/1001 (6.6) 1.17 1.0
(0.71 to 2.12) (−1.5 to 3.4) (0.75 to 1.83)† (−1.9 to 4.0)†

P Value P Value
The

Residence 0.17 0.34

Home or retirement home 457/994 (46.0) 425/999 (42.5) 617/996 (61.9) 603/1001 (60.2)
Nursing home 135/994 (13.6) 161/999 (16.1) 137/996 (13.8) 161/1001 (16.1)
Other 402/994 (40.4) 413/999 (41.3) 242/996 (24.3) 237/1001 (23.7)

score score

n engl j med 365;26

Function and symptom scales
Lower-extremity physical ADL‡ 7.3±4.0 7.4±3.9 0.72 5.1±4.2 5.1±4.3 0.85
Instrumental ADL§ 3.9±0.5 3.9±0.4 0.10 3.7±0.8 3.7±0.9 0.94

nejm.org
FACIT-Fatigue scale¶ 38.7±7.7 38.6±7.6 0.84 41.8±7.3 42.3±7.4 0.26
n e w e ng l a n d j o u r na l

The New England Journal of Medicine

of

* Plus–minus values are means ±SD. Odds ratios and risk differences are for the comparison between the liberal-strategy group and the restrictive-strategy group.
† Values are 99% confidence intervals.
‡ Scores on the lower-extremity physical activities of daily living (ADL) scale range from 0 to 11, with higher scores indicating greater dependency. Scores were calculated by totaling the
number of dependencies with respect to 11 basic activities. Patients who reported that they had any human assistance in an activity or that they did not perform the activity for a health

december 29, 2011

reason were considered to be dependent with respect to that activity. Patients who had missing data or who did not perform the activity for reasons other than those related to health

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

were excluded from the analysis. Scores were not used in this analysis on 30-day follow-up for 535 patients in the liberal-strategy group and 502 in the restrictive-strategy group and on
m e dic i n e

60-day follow-up for 484 in the liberal-strategy group and 456 in the restrictive-strategy group.
§ Scores on the instrumental ADL scale range from 0 to 4, with higher scores indicating greater dependency. Scores were calculated by totaling the number of dependencies with respect
to four advanced activities. Patients who reported that they needed assistance or were unable to perform a task for health reasons were considered to be dependent with respect to that
activity. Patients who had missing data or did not perform the activity for reasons other than those related to health were excluded from the analysis. Scores were not used in this analysis
on 30-day follow-up for 570 patients in the liberal-strategy group and 559 in the restrictive-strategy group and on 60-day follow-up for 618 in the liberal-strategy group and 598 in the
­restrictive-strategy group.
¶ The Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) scale includes 13 items with scores ranging from 0 to 4 (0, not at all; 1, a little bit; 2, somewhat; 3, quite
a bit; and 4, very much), with higher scores indicating a greater energy level. Missing items were imputed as the mean of item scores within the same scale. No proxy responses were
possible. Scores were missing on 30-day follow-up for 551 patients in the liberal-strategy group and 550 in the restrictive-strategy group and on 60-day follow-up for 463 in the liberal-
strategy group and 484 in the restrictive-strategy group.

Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
 Liber al or Restrictive Tr ansfusion in High-Risk Patients

Table 4. Hospital Outcomes.*

Absolute Risk
Liberal Strategy Restrictive Strategy Odds Ratio Difference
Variable (N = 1007) (N = 1009) (99% CI) (99% CI)
number/total number (percent) percentage points
Myocardial infarction, unstable angina, or in-hospital
death† 43/1005 (4.3) 52/1008 (5.2) 0.82 (0.48 to 1.42) −0.9 (−3.3 to 1.6)
Myocardial infarction† 23/1005 (2.3) 38/1008 (3.8) 0.60 (0.30 to 1.19) −1.5 (−3.5 to 0.5)
Unstable angina† 2/1005 (0.2) 3/1008 (0.3) 0.67 (0.06 to 7.03) −0.1 (−0.7 to 0.5)
In-hospital death 20/1005 (2.0) 14/1008 (1.4) 1.44 (0.58 to 3.56) 0.6 (−0.9 to 2.1)
Isolated troponin elevation‡ 62/1005 (6.2) 59/1008 (5.9) 1.06 (0.65 to 1.71) 0.3 (−2.4 to 3.1)
Physician diagnosis of congestive heart failure 27/1005 (2.7) 35/1007 (3.5) 0.77 (0.39 to 1.50) −0.8 (−2.8 to 1.2)
Stroke or transient ischemic attack
On CT or MRI 5/1005 (0.5) 1/1007 (0.1) 5.03 (0.30 to 84.73) 0.4 (−0.2 to 1.0)
On physician diagnosis or CT or MRI 8/1005 (0.8) 3/1007 (0.3) 2.69 (0.47 to 15.42) 0.5 (−0.3 to 1.3)
Chest radiograph with new or progressive infiltrate 60/1005 (6.0) 48/1007 (4.8) 1.27 (0.76 to 2.12) 1.2 (−1.4 to 3.8)
New-onset purulent sputum 9/1005 (0.9) 3/1007 (0.3) 3.02 (0.54 to 16.91) 0.6 (−0.3 to 1.5)
Wound infection 14/1005 (1.4) 8/1007 (0.8) 1.76 (0.56 to 5.56) 0.6 (−0.6 to 1.8)
Deep-vein thrombosis or pulmonary embolism 12/1005 (1.2) 8/1007 (0.8) 1.51 (0.46 to 4.92) 0.4 (−0.7 to 1.5)
Death, myocardial infarction, pneumonia 89/1005 (8.9) 90/1007 (8.9) 0.99 (0.66, 1.48) −0.1 (−3.4 to 3.2)
Death, myocardial infarction, pneumonia, thrombo-
embolism, or stroke 103/1005 (10.2) 94/1007 (9.3) 1.11 (0.75 to 1.63) 0.9 (−2.5 to 4.3)
Returned to operating room 15/1005 (1.5) 18/1007 (1.8) 0.83 (0.34 to 2.06) −0.3 (−1.8 to 1.2)
Transfer to intensive care unit 30/1005 (3.0) 29/1007 (2.9) 1.04 (0.53 to 2.05) 0.1 (−1.8 to 2.0)

days P Value
Time from randomization to discharge§
United States 3.67±3.38 3.97±3.89 0.15
Canada 12.03±9.31 12.70±9.48 0.32

* Plus–minus values are means ±SD. Odds ratios and risk differences are for the comparison between the liberal-strategy group and the re-
strictive-strategy group. CT denotes computed tomography, and MRI magnetic resonance imaging.
† Electrocardiographic results after randomization were incomplete for 135 patients in the liberal-strategy group and 130 in the restrictive-
strategy group.
‡ Blood samples obtained for troponin testing on day 4 after randomization or at the time of hospital discharge were not available for 180 pa-
tients in the liberal-strategy group and 175 in the restrictive-strategy group.
§ Of the 2011 patients who were evaluated (1220 in the United States and 791 in Canada), 944 patients (93.9%) in the liberal-strategy group
and 934 (92.8%) in the restrictive-strategy group were discharged alive.

dence interval, the restrictive transfusion policy Our results are consistent with most of the
plausibly resulted in at most a 3.7% increase in findings of the Transfusion Requirements in Criti-
the risk of death or inability to walk without hu- cal Care (TRICC) trial, in which outcomes did not
man assistance, a composite outcome that oc- differ significantly between a transfusion thresh-
curred in about 35% of patients. We had less old of 7 g per deciliter and a threshold of 10 g per
statistical power for in-hospital outcomes; our deciliter among patients in intensive care units.5,13
data are compatible with an absolute change in However, in contrast to that report, we did not
the composite outcome of in-hospital acute myo- find increased rates of myocardial infarction or
cardial infarction, unstable angina, or death, rang- congestive heart failure in the liberal-strategy
ing from an increase of 3.3 percentage points to a group. Furthermore, we did not confirm findings
decrease of 1.6 percentage points for the restrictive from observational studies of markedly higher
transfusion strategy. mortality in patients who received transfusion

n engl j med 365;26 nejm.org december 29, 2011 2461

The New England Journal of Medicine
Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 Liber al or Restrictive Tr ansfusion in High-Risk Patients

than in patients who did not.14 A randomized Dr. Carson reports receiving grant support to his institution
from Amgen; Dr. Lewis, receiving a salary from the Orthopaedic
clinical trial allows us to evaluate transfusion Associates of Hartford, receiving a stipend for serving as presi-
while avoiding selection bias.15 dent of the Hartford County Medical Association, and providing
In summary, we found that a liberal transfu- expert testimony representing the American Academy of Ortho-
paedic Surgery on the Medicare Evidence Development and
sion strategy, as compared with a restrictive strat- Coverage Advisory Committee; Dr. Apple, serving as a scientific
egy, did not result in reduced rates of death or an advisory board member for Abbott Laboratories, Alere, Beck-
inability to walk on 60-day follow-up or in sig- man Coulter, Ortho Clinical Diagnostics, and Instrumentation
Laboratories, receiving consulting fees from Abbott Diagnos-
nificant reductions in rates of in-hospital compli- tics, Ortho Clinical Diagnostics, and Instrumentation Labora­
cations in this population at increased cardiovas- tories, receiving grant support to his institution from Abbott
cular risk. Our findings suggest that it is reasonable Diagnostics, Siemens, Ortho Clinical Diagnostics, Roche Diag-
nostics, BioRad, Response Biomedical, Radiometer, and
to withhold transfusion in patients who have un- BRAHMS, and receiving lecture fees and travel expenses from
dergone surgery in the absence of symptoms of Abbott Diagnostics and Alere; Dr. Magazine, serving as a board
anemia or a decline in the hemoglobin level be- member for Amgen, Novartis, and GlaxoSmithKline and receiv-
ing consulting fees from Eli Lily, Sanofi-Aventis, and Amgen,
low 8 g per deciliter, even in elderly patients with grant support to his institution from Novartis, Merck, and Eli
underlying cardiovascular disease or risk factors. Lilly, and lecture fees from Novartis. No other potential conflict
of interest relevant to this article was reported.
Supported in part by grants from the National Heart, Lung, Disclosure forms provided by the authors are available with
and Blood Institute (U01 HL073958 and U01 HL074815). the full text of this article at NEJM.org.

Appendix
The authors’ affiliations are as follows: the Division of General Internal Medicine, Department of Medicine, University of Medicine and
Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick (J.L.C., H.N., K.D.); the Department of Epidemiology
and Public Health, University of Maryland School of Medicine (M.L.T., J.M.); and Johns Hopkins Bayview Medical Center (K.J.Z.) —
both in Baltimore; the Division of Orthopaedic Surgery, University of Western Ontario, London (D.W.S.); the Department of Physical
Therapy and Surgery and the Division of Orthopaedic Surgery (L.B.), University of Alberta, Edmonton; the Division of Orthopedic Sur-
gery (K.H.) and Department of Medicine (D.R.C.), University of Calgary, Calgary, AB; and the Department of Orthopedic Surgery, QEII
Health Sciences Centre, Halifax, NS (G.D.) — all in Canada; the Department of Medicine, Saint Louis University School of Medicine,
St. Louis (B.R.C.); the Department of Epidemiology, University of Medicine and Dentistry of New Jersey–School of Public Health, Pis-
cataway (G.G.R.); the Transfusion Medicine and Cellular Therapeutics Branch, Division of Blood Diseases and Resources, National
Heart, Lung, and Blood Institute, Bethesda (G.N.); and the Cooperative Studies Program Coordinating Center, Veterans Affairs Medical
Center, Perry Point (R.A.H.) — both in Maryland; the Department of Orthopedic Surgery, New York–Presbyterian Hospital at Columbia
University, New York (W.M.); Hartford Hospital, Hartford, CT (C.L.); and Minneapolis Medical Research Foundation of Hennepin
County Medical Center and University of Minnesota School of Medicine, Minneapolis (F.S.A.).

References
1. Report of the Department of Health 6. Carson JL, Terrin ML, Magaziner J, et 11. Breslow NE, Day NE. The analysis of
and Human Services: the 2009 national al. Transfusion Trigger Trial for Functional case-control studies. Vol. 1. Lyon, France:
blood collection and utilization survey re- Outcomes in Cardiovascular Patients Un- International Agency for Research on
port. Washington, DC: Department of dergoing Surgical Hip Fracture Repair Cancer, 1980. (IARC scientific publica-
Health and Human Services, Office of the (FOCUS). Transfusion 2006;46:2192-206. tions no. 32.)
Assistant Secretary for Health, 2011. 7. Alpert JS, Thygesen K, Antman E, 12. Hosmer DW, Lemeshow S. Applied lo-
2. Anderson SA, Menis M, O’Connell K, Bassand JP. Myocardial infarction re­ gistic regression. New York: John Wiley,
Burwen DR. Blood use by inpatient elderly defined — a consensus document of The 1989.
population in the United States. Transfu- Joint European Society of Cardiology/ 13. Hébert PC, Yetisir E, Martin C, et al. Is
sion 2007;47:582-92. American College of Cardiology Com- a low transfusion threshold safe in criti-
3. Cobain TJ, Vamvakas EC, Wells A, mittee for the redefinition of myocardial cally ill patients with cardiovascular dis-
Title­stad K. A survey of the demographics infarction. J Am Coll Cardiol 2000;36: eases? Crit Care Med 2001;29:227-34.
of blood use. Transfus Med 2007;17:1-15. 959-69. [Erratum, J Am Coll Cardiol 2001; 14. Marik PE, Corwin HL. Efficacy of red
4. Carless PA, Henry DA, Carson JL, He- 37:973.] blood cell transfusion in the critically ill:
bert PP, McClelland B, Ker K. Transfusion 8. Thygesen K, Alpert JS, White HD. a systematic review of the literature. Crit
thresholds and other strategies for guid- Universal definition of myocardial infarc- Care Med 2008;36:2667-74. [Erratum, Crit
ing allogeneic red blood cell transfusion. tion. J Am Coll Cardiol 2007;50:2173-95. Care Med 2008;36:3134.]
Cochrane Database Syst Rev 2010;10: 9. Fleiss JL. Statistical methods for rates 15. MacMahon S, Collins R. Reliable
CD002042. and proportions. New York: John Wiley, ­assessment of the effects of treatment on
5. Hébert PC, Wells G, Blajchman MA, et 1981. mortality and major morbidity, II: obser-
al. A multicenter, randomized, controlled 10. Mantel N, Haenszel W. Statistical as- vational studies. Lancet 2001;357:455-
clinical trial of transfusion requirements pects of the analysis of data for retrospec- 62.
in critical care. N Engl J Med 1999;340:409- tive studies of disease. J Natl Cancer Inst Copyright © 2011 Massachusetts Medical Society.
17. [Erratum, N Engl J Med 1999;340:1056.] 1959;22:719-48.

2462 n engl j med 365;26 nejm.org december 29, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UNIVERSITATSBIBLIOTHEK on February 26, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.