ORIGINAL RESEARCH
Ferric carboxymaltose with or without erythropoietin in anemic
patients with hip fracture: a randomized clinical trial
 ximo Bernabeu-Wittel,1 Manuel Romero,2 Manuel Ollero-Baturone,1 Reyes Aparicio,3
Ma
Jose Murcia-Zaragoza,4 Manuel Rincon-Gomez,1 Rafael Monte-Secades,5 Marıa Melero-Bascones,6
Clara M. Rosso,1 and Alberto Ruiz-Cantero,7 on behalf of the PAHFRAC-01 Investigators
BACKGROUND: The increasing incidence of
osteoporotic hip fracture (HF) has raised the
requirements of red blood cell (RBC) transfusions,
whereas this scarce resource may cause morbidity and
mortality.
STUDY DESIGN AND METHODS: This study was a
multicenter, randomized, double-blind, clinical trial that
aimed to assess efficacy of ferric carboxymaltose (FCM)
with or without erythropoietin (EPO) in reducing RBC
transfusion in the perioperative period of HF. Participants
(patients > 65 years admitted with HF and hemoglobin
[Hb] levels of 90-120 g/L) were randomly assigned to
receive a preoperative single dose of 1 g of FCM (short
intravenous [IV] infusion over 15 min), plus 40,000 IU of
subcutaneous EPO (EPOFE arm); versus 1 g of IV FCM
plus subcutaneous placebo (FE arm); and versus IV and
subcutaneous placebo (placebo arm). Primary endpoint
was the percentage of patients who received RBC
transfusion, and secondary endpoints were the number of
RBC transfusions per patient, survival, hemoglobinemia,
and health-related quality of life (HRQoL; by means of
Short Form 36 Version 2 questionnaire).
RESULTS: A total of 306 patients (85% women, mean
age 83 6 6.5 years) were included. A total of 52, 51.5, and
54% of patients required RBC transfusion in the EPOFE,
FE, and placebo arms, respectively, with no significant
differences in the number of RBC transfusions per patient,
survival, HRQoL, and adverse events among treatment
groups. A significant increase in Hb levels was achieved at
discharge (102 g/L vs. 97 g/L) and 60 days after discharge
(125 g/L vs. 119 g/L) in the EPOFE arm with respect to
placebo arm; in addition, a higher rate of patients
recovered from anemia in the EPOFE arm with respect to
the placebo arm (52% vs. 39%), 60 days after discharge.
CONCLUSION: Preoperative treatment with FCM alone
or in combination with EPO improved recovery from
postoperative anemia, but did not reduce the needs of
RBC transfusion in patients with HF.
ABBREVIATIONS: AE(s) 5 adverse event(s); COPD 5
chronic obstructive pulmonary disease; EPOFE arm 5 1 g
of ferric carboxymaltose (short intravenous infusion over 15
min) plus 40,000 IU of subcutaneous erythropoietin; FCM 5
ferric carboxymaltose; FE arm 5 1 g of intravenous ferric
carboxymaltose plus subcutaneous placebo; HF 5 hip
fracture; HRQoL 5 health-related quality of life; placebo
arm 5 intravenous and subcutaneous placebo; SF-36v2 5
Short Form 36 Version 2.
From the 1Hospital Universitario Virgen del Rocıo, Sevilla,
Spain; the 2Hospital Infanta Elena, Huelva, Spain; the 3Hospital
San Juan de Dios del Aljarafe, Sevilla, Spain; the 4Hospital de la
Vega Baja, Alicante, Spain; the 5Hospital Lucus Augusti, Lugo,
Spain; the 6Hospital General Universitario de Albacete,
Albacete, Spain; and the 7Hospital de la Serranıa, Ma
laga,
Spain.
ximo Bernabeu-Wittel,
Address reprint requests to: Ma
Department of Internal Medicine, Hospitales Universitarios Vir-
gen del Rocıo, Avenida Manuel Siurot, s/n. 41013 Sevilla, Spain;
e-mail: wittel@cica.es.
All authors have contributed substantially to this work,
and fully agree with the manuscript. They have completed the
uniform disclosure form and declare: no support from any
organisation for the submitted work; no financial relationships
with any organisations that might have an interest in the sub-
mitted work in the previous three years.
This independent clinical trial has been financially sup-
ported by the Ministry of Health, Consumption, Social Policy,
and Equity of the Spanish Government (Experiment Number
TRA-2009). All authors declare their absolute independence
from funders. The Internal Medicine Department received in
2010 a grant for clinical investigation from ViforFarma SL.
Trial registration Eudra-CT 2009-015865-30; ClinicalTrials.
gov identifier NCT01154491.
Received for publication January 18, 2016; revision
received March 8, 2016; and accepted March 17, 2016.
doi:10.1111/trf.13624
C 2016 AABB
V
TRANSFUSION 2016;00;00–00
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BERNABEU-WITTEL ET AL.

H
ip fracture (HF) is highly prevalent throughout
the world, mainly affecting the elderly. It is
estimated that 0.7% of women 65 years or
older will suffer a HF during their lifetime,
and the demand for care will double in the next 40
years.1-3 A total of 4% to 8% will die during hospitaliza-
tion, and fewer than 25% will regain mobility.4,5 The soci-
oeconomic burden associated with HF is enormous.6
Anemia is one of the most frequent complications in
the perioperative period of HF; approximately one- to
two-thirds of patients will require red blood cell (RBC)
transfusion(s) during their hospitalization.7,8 The increas-
ing incidence of HF in this population has also raised the
need for this valuable and scarce resource. Additionally,
RBC transfusions are not without complications,9-13 mak-
ing it necessary to develop blood-saving strategies.7,9,14,15
The most important factor in the development of ane-
mia in HF is blood loss; however, some other mechanisms
(renal failure, inflammation, iatrogenic hemodilution) are
also implicated, prompting the choice of different thera-
peutic approaches.14-21 Although evidence that supporting
marrow RBC production saves RBC transfusion is weak, an
increasing number of studies have demonstrated notable
reductions in RBC transfusion, nosocomial infections, hos-
pital stay, and even survival.20-24
Most of these previous studies were performed using
intravenous (IV) iron sucrose administered in a period
ranging from 2 to 6 days. Ferric carboxymaltose (FCM)
has considerable advantages because it allows doses of 1 g
in a single session (and may be administered in a short IV
infusion over 15 min), equivalent to 1000 mg of iron
sucrose. Moreover, FCM also provides excellent tolerabil-
ity and safety.25-29
Additionally, the benefits of perioperative use of
erythropoietin (EPO) with or without IV iron in major
orthopedic procedures are well established.30-41 This evi-
dence could be promising for patients with HF. We
hypothesized if the sum up of EPO with the concomitant
use of FCM could serve to save blood transfusions in
patients with HF. Therefore, we have developed a multi-
center Phase III clinical trial to assess the efficacy of com-
bined treatment with FCM and EPO (EPOFE arm) versus
FCM (FE arm) versus placebo (placebo arm), to assess a
reduction in the percentage of patients who receive blood
transfusions in the perioperative period of HF.
MATERIALS AND METHODS
This was a multicenter, randomized, controlled, double-
blind clinical trial of parallel groups, performed on adult
patients admitted to hospital due to a HF. The detailed
method has been already published.42 Inclusion period
extended from June 24, 2010, to May 15, 2013.
Inclusion and randomization
The inclusion criteria were as follows: age at least 65 years,
osteoporotic HF requiring surgical repair, hemoglobin
(Hb) levels between 90 and 120 g/L, and signed informed
consent form. The exclusion criteria were as follows: mar-
row diseases that could interfere in the erythropoietic pro-
cess, blood coagulation diseases or current treatment with
anticoagulants, documented allergy or intolerance and/or
contraindication to EPO use and/or IV iron, rheumatoid
arthritis and/or another demonstrated origin of inflamma-
tory anemia and/or uncontrolled arterial hypertension,
current or previous treatment with EPO or IV iron for at
least 3 months, and chronic renal failure receiving hemo-
dialysis or peritoneal dialysis.
All patients were included after they or their medical
surrogate(s) signed informed consent forms. The random-
ization assignment list was stratified by centers and per-
formed by unequal blocks technique.
Treatment arms
Treatment was administered in the three arms as detailed
in Table 1.
Common standards of medical care
All patients received the best standards of clinical care, by
a multidisciplinary team that included integral geriatric
care, thromboprophylaxis with low-weight heparin, pro-
phylaxis of upper gastrointestinal bleeding with proton
pump inhibitors, perioperative analgesia avoiding poten-
tial nephrotoxic and neurotoxic drugs, prophylaxis and

TABLE 1. The three treatment arms of the PAHFRAC-01 clinical trial*

Treatment arm Treatment description
EPOFE  Subcutaneous single dose of 40,000 IU of EPO in a prefilled 1-mL syringe.
 1000 mg of IV FCM (two 500-mg vials diluted in a bottle of 250 mL of saline, with opaque plastic bag and
infusion system), in a 20-min infusion.
FE  Subcutaneous single-dose placebo (saline) in a prefilled 1-mL syringe.
 1000 mg of IV FCM (two 500 mg vials diluted in a bottle of 250 mL of saline, with opaque plastic bag and infusion
system), in a 20-min infusion.
Placebo  Subcutaneous single-dose placebo (saline) in a prefilled 1-mL syringe.
 IV placebo (250 mL of saline, with opaque plastic bag and infusion system), in a 20-min infusion.
* Treatment was administered to all patients after randomization and always previously to surgery.

2 TRANSFUSION Volume 00, Month 2016


Renal-liver function
Fig. 1. The visits structure of the PAHFRAC-01 clinical trial. A 5 hospital admission; I 5 inclusion; S 5 surgery; 24h postS 5 24
hours after surgery; 72h postS 5 72 hours after surgery; D 5 hospital discharge; 60d postD 5 60 days after hospital discharge.
management of delirium and constipation, and prophy-
laxis of surgical site infection with cefazolin. All patients
in the study received the same rehabilitation treatment,
which consisted in early sedestation (if clinically stable,
and normal radiologic control, 24 to 48 hr after surgery);
early ambulation (at discharge in subcapital fractures with
partial or total arthroplasty and 25 to 30 days after dis-
charge in perthrocanteric fractures with osteosynthesis);
and home-based rehabilitation.
Follow-up and study visits
This trial was composed of five visits, detailed in Fig. 1.
Transfusion protocol
A common restrictive transfusion protocol was estab-
lished. All patients with any Hb level of less than 70 g/L
received three RBC transfusions independently of symp-
toms. In addition all patients with any Hb level ranging
from 71 to 89 g/L in the presence of severe symptoms
(heart failure with New York Heart Association dysp-
nea  III, acute coronary syndrome, hemodynamic insta-
bility [hypotension, orthostathism], and/or acute or
exacerbated chronic respiratory failure), received two RBC
transfusions. Any other quantitative or qualitative RBC
transfusion indication was considered a protocol devia-
tion or violation, respectively.
Outcome measures and sample size calculation
The primary endpoint was the percentage of patients who
received RBC transfusion during hospitalization and after
60 days of hospital discharge. Secondary endpoints were
the following: number of RBC transfusions per patient; Hb
levels 24 and 72 hours after surgery, at discharge, and after
60 days; all-cause mortality; all adverse events (AEs); and
FCM AND EPO IN HF
finally health-related quality of life (HRQoL; assessed by
the Short Form 36 Version 2 for acute patients [SF-36v2],
which was administered basally and 60 days after dis-
charge).20 We calculated the sample size to obtain single-
sided significance in the comparison between the EPOFE
arm and placebo arm, with a confidence level of 95% and
80% power, and to obtain an absolute reduction in the pri-
mary endpoint of 20%. According to this, we expected the
percentage of patients who would need to be transfused
in the placebo arm to be 60% and in the EPOFE arm 40%.
We applied an additional 10% increase factor according to
both the multiple comparisons (due to the three-arm
nature of the trial [by means of Bonferroni inequalitiy test,
a 1.06 correction factor]) and the projected interim analy-
sis (following O’Brien-Fleming rule, a 1.04 correction
factor).
Hence, a total of 87 patients per arm were needed
with the foregoing conditions. Taking into account a per-
centage of dropouts of 15% per arm, the total number of
patients per arm was set at 102 (306 patients).
Interim analysis and stopping rules
Three interim analyses were performed when 80, 160, and
240 of patients were recruited, to detect possible imbalan-
ces among the three arms of the trial with respect to
safety, to list of independent variables, and to assess
whether the primary efficacy endpoint was obtained at
this point.
Statistical analysis
Both intention-to-treat and per-protocol analyses were
performed. The intention-to-treat analysis included all
patients who agreed to participate in the study, who
signed the informed consent, and who had been
Volume 00, Month 2016 TRANSFUSION 3
BERNABEU-WITTEL ET AL.
randomized. Per-protocol analysis included the patients
who were randomized, received the dose of the trial medi-
cation, and were operated on, excluding those who dis-
continued the trial or with any protocol violation. An
additional per-protocol analysis was performed excluding
also those patients with protocol deviations.
A chi-square test (with Yates correction and Fisher
exact test when necessary) was performed to compare the
endpoints among the study arms, for qualitative endpoints.
Analysis of variance (with post hoc test of Tukey and T3-
Dunett) and/or Kruskal-Wallis test were performed for
quantitative dependent variables. All comparisons were
globally performed and, if statistical significance was ob-
tained, by pairs (EPOFE arm vs. FE arm, EPOFE arm vs. pla-
cebo arm, and FE arm vs. placebo arm); for this purpose a
Bonferroni adjustment of p value for multiple comparisons
was established. Differences between groups were quanti-
fied using 95% confidence intervals.
All calculations were performed using computer soft-
ware (SPSS 18.0, SPSS, Inc.). The threshold of significance
was set at a p value of less than 0.044.
Adverse clinical events, side effects,
and safety issues
An AE was defined as any untoward medical occurrence
that did not necessarily have a causal relationship with the
study medication. A serious adverse event was considered
if the AE resulted in death, any life-threatening event, any
event requiring hospitalization or prolongation of hospitali-
zation, any event resulting in persistent or significant dis-
ability or incapacity, or other important medical event.
Ethical, deontologic, quality control,
and regulatory considerations
This study was conducted in accordance with the princi-
ples of the Declaration of Helsinki and ICH Guidelines for
Good Clinical Practice and in full conformity with relevant
regulations. The protocol, informed consent form, partici-
pant information sheet, and any applicable documents
were approved by the Andalusian, as well as by all local
ethics committees of participant centers, and the Spanish
Regulatory Authorities.
Documents constituting the master file of the study
included all the documents established in the good clinical
practice (CPMP/ICH/135/95). The investigators warranted
the confidentiality of any information on the subjects of the
trial, as well as the protection of their personal data.
RESULTS
Patients features
A total of 306 patients from 13 centers signed informed
consent. Three were excluded because of not meeting
inclusion criteria. A total of 303 patients were randomized
4 TRANSFUSION Volume 00, Month 2016
(85% women) with a mean age of 83.5 6 6.5 years, as
represented in Fig. 2. The mean global recruitment rate
was 11 patients per month. A complete description of
all patients’ baseline and surgical features is detailed in
Table 2.
Interim analysis
No significant differences were detected in the independ-
ent, safety parameters, and primary efficacy endpoint.
Intention-to-treat endpoints
A total of 159 (52.5%) patients required RBC transfusion.
The transfusion criteria were an Hb level of less than
70 g/L in 60 (19.8%) patients and severe symptoms plus
Hb level between 71 and 89 g/L in 99 (32.7%) patients. A
total of 147 patients required RBC transfusion once, 11
required it two times, and one patient required it three
times. No significant differences were observed among
the three arms with respect to these variables. The
median (range) time to first RBC transfusion was 3 (1-4.5)
days; the cumulative transfusion rates were as follows: a
total of 43 (14.2%), 99 (32.7%), and 131 (43.2%) patients
received the RBC transfusion in the first 24 hours, 72
hours, and 5 days after surgery, respectively. The remain-
ing 28 patients (9.3%) received the RBC transfusion after
the sixth day of postoperative period. No significant dif-
ferences were observed among the three arms with
respect to these variables. Additionally, no differences
were detected among study arms, when stratifying by
baseline Hb level and HF type (perthocantheric or subca-
pital). The differential transfusion-free cumulative sur-
vival is detailed in Fig. 3. Global survival was 95.7% at
discharge and 88.8% in the 60 days period after discharge.
The most frequent causes of death were heart failure
(nine patients), chronic obstructive pulmonary disease
(COPD) exacerbation (four patients), and sepsis (three
patients). We observed no differences among the study
groups with respect to death and death causes.
In the follow-up period we observed significantly
higher Hb levels in EPOFE arm with respect to placebo
arm at discharge as well as 60 days after discharge; in
addition, a higher rate of patients recovered from anemia
(Hb level > 120 g/L) in the EPOFE arm with respect to the
placebo arm 60 days after discharge. With respect to
HRQoL there were no significant differences among the
three treatment arms in both physical component and
mental component scores, respectively. In all groups a sig-
nificant decrease in both components was detected with
respect to their baseline values; no significant differences
in this decrease were detected among the three treatment
arms. All these endpoints’ data are structured in Table 4.
The main medical complications developed during
the study were renal function deterioration in 82 patients
(27%), delirium in 81 (26.7%), heart failure in 37 (12%),

Fig. 2. Executive summary of patients included in PAHFRAC-01 study. All patients’ data were primarily analyzed using intention-
to-treat approach. Besides, a per-protocol analysis was also performed.
infections in 29 (9.6%; urinary tract infections in 15, pneu-
monia in two, and surgical site infections in five patients
[two deep and three superficial]), skin pressure ulcers in
25 (8.25%), COPD exacerbations in 20 (6.6%; mild-
moderate in 16 and severe in four [1.3%]), thromboem-
bolic disease in 15 (4.9%), acute coronary syndromes in
four (1.3%), and stroke in three patients (0.9%). No statis-
tical differences were observed among the three arms of
the study.
Safety and AE
The main AEs observed after the administration of the
trial medication were nausea and/or vomiting in 10
patients (3.3%), constipation in eight (2.6%), hypotension
in four (1.3%), and diarrhea in four (1.3%). No significant
differences were observed among the three study arms.
Follow-up after discharge
A total of 32 patients (10.5%) required new hospitaliza-
tion(s) (24 one readmission and 8 two readmissions) after
Visit 3. The most frequent causes of these readmissions
FCM AND EPO IN HF
were urinary tract infections (five patients), surgical
instrumentation complications (four patients), and skin
pressure ulcer (four patients). No significant differences
were observed in these readmission causes.
Protocol violations and deviations
Eight patients (2.64%) did not have surgery, and in 18
additional patients (5.9%), protocol violations were
observed (eight patients were administered additional IV
ferric sacharate, in five patients violations of inclusion or
randomization were detected, and five patients did not
receive the trial treatment). No violations regarding the
qualitative RBC transfusion protocol were detected. We
detected 26 patients (8.6%) with protocol deviations (22
received one RBC transfusion less than protocolized and
four received one RBC transfusion more than protocol-
ized). The distribution of all these incidences was similar
in the three study arms.
Per-protocol analysis
After patients with protocol violations and/or devia-
tions were excluded, there were no significant
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BERNABEU-WITTEL ET AL.

TABLE 2. Baseline features of patients included in the PAHFRAC-01 clinical trial*

Arm
EPOFE
Clinical feature (n 5 100) FE (n 5 103) Placebo (n 5 100)
Female sex 87 (87) 84 (81.5) 87 (87)
Age (years) 83.4 (6.4) 84.6 (6.2) 82.3 (6.9)
Fracture type
Perthrocanteric 61 65 (63) 57
Subcapital 37 36 (35) 42
Others 2 2 (2) 1
Polypathology 30 (30) 24 (23) 20 (20)
Number of comorbidities/patient 6.3 (2.9) 5.8 (2.7) 5.8 (3.2)
Main chronic conditions
Hypertension 73 (73) 71 (69) 63 (63)
Hyperlipidemia 26 (26) 36 (35) 31 (31)
Diabetes 35 (35) 35 (34) 39 (39)
Cognitive impairment 21 (21) 22 (21.4) 17 (17)
Heart failure 13 (13) 9 (8.7) 11 (11)
Chronic renal disease 13 (13) 13 (12.6) 13 (13)
Cerebrovascular disease 15 (15) 14 (13.6) 8 (8)
COPD 10 (10) 6 (5.8) 8 (8)
Osteoarthritis 9 (9) 13 (12.6) 11 (11)
Depression 15/15) 11 (10.7) 16 (16)
Atrial fibrillation 10 (10) 9 () 7 (7)
Thromboembolic disease 1 (1) 1 (0.9) 1 (1)
GERD 0 3 (2.8) 6 (6)
Peptic ulcer 2 (2) 1 (0.9) 2 (2)
Nephrolythiasis 1 (1) 4 (3.8) 0
Biliary lythiasis 2 (2) 4 (3.8) 1 (1)
Charlson index 1.5 (1.5) 1.3 (1.3) 1.5 (1.5)
ASA 3 (2-3) 3 (2-3) 3 (2-3)
HRQoL by SF-36v2
Physical component score 38.56 (10) 36.91 (11) 39 (11.9)
Mental component score 45.5 (13) 45 (15) 45.7 (15)
Number of drugs per patient 6.1(3.2) 6 (3.2) 6.1 (3.3)
Treatment in previous 3 months
Oral iron 10 (10) 11 (10.7) 10 (10)
Folate 2 (2) 3 (2.8) 3 (3)
B12 vitamin 5 (5) 5 (4.9) 4 (4)
Aspirin 39 (39) 41 (39.8) 39 (39)
Clopidogrel 4 (4) 10 (9.7) 5 (5)
Other antiagregants 2 (2) 1 (0.97) 1 (1)
Hb (g/L) 109.5 (7.4) 109.8 (7.8) 110.2 (7)
9-9.9 g/dL 12 (12) 13 (12.6) 9 (9)
10-10.9 g/dL 28 (28) 28 (27) 29 (29)
11-12 g/dL 60 (60) 62 (60) 62 (62)
RBCs (31012/L) 3.79 (0.5) 3.86 (0.7) 3.83 (0.4)
MCV (fL) 89.7 (6.6) 89.7 (7.4) 89.1 (7.7)
MCHC (g/L) 317 (52) 315 (58) 317 (52)
Ferritin (mg/L) 0.137 (0.15) 0.155 (0.17) 0.141 (0.13)
Creatininemia (mg/dL) 1.07 (0.4) 1.07 (0.5) 0.99 (0.4)
INR 1.02 (0.1) 1.04 (0.3) 1 (0.08)
APTT 26.7 (7.1) 26.3 (7.7) 26.3 (6.7)
* Results are expressed in n (%) or mean 6 standard deviation (SD).
APTT 5activated partial thromboplastin time; ASA 5 American Society of Anesthesiologist risk scale; GERD 5 gastroesophagic reflux
disease; INR 5 international normalized ratio; MCHC 5 mean corpuscular Hb concentration; MCV 5 mean corpuscular volume.

differences in RBC transfusion rate, transfusion indica-
tion, transfusion timing, survival, and HRQoL among
the three treatment arms. We detected higher levels of
Hb at discharge and 60 days after discharge and a
higher rate of patients recovered from anemia (Hb >
120 g/L) 60 days after discharge in the EPOFE arm
compared with the placebo arm. Data are fully struc-
tured in Table 5.
DISCUSSION
In this trial the preoperative administration of FCM with
or without EPO did not reduce the blood transfusion
needs in the perioperative period of patients admitted
with HF. The mean RBC transfusion required per patient
was slightly higher in the placebo arm (1.28) with respect
to the EPOFE (1.18) and FE arms (1.26); this difference
was not significant, but could be clinically important for

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 FCM AND EPO IN HF

TABLE 3. Surgical and perioperative features of patients included in the PAHFRAC-01 clinical trial*
Arm
Surgical feature EPOFE (n 5 97†) FE (n 5 101‡) Placebo (n 5 97§)
Hospital hours before surgery 53 (36-101) 48 (26-91) 52 (25-89)
Anaesthesia type
Spinal 94 (97) 93 (92.2) 89 (92)
General 3 (3) 8 (7.8) 8 (8)
Orotracheal intubation 3 (3) 9 (8.7) 9 (9)
Hip surgery
Osteosyntesis 66 (68) 70 (69) 60 (62)
Partial arthroplasty 27 (28) 28 (28) 33 (34)
Total arthroplasty 4 (4) 3 (3) 4 (4)
Surgery duration (min) 90 (60-110) 75 (55-105) 90 (55-110)
Postsurgical reanimation duration (hr) 2.5 (1.75-3.15) 2.3 (1.75-4) 2.5 (1.6-3)
Early perioperative complications
Hypotension 8 (8.2) 11 (10.8) 14 (14.4)
Major bleeding (>800 mL) 3 (3) 5 (5) 7 (7.2)
Other anesthetic complications 6 (6.2) 6 (5.9) 10 (10.3)
Other surgical complications 5 (5.1) 8 (7.9) 9 (9.3)
* Results are expressed as number (%), mean 6 SD, or median (first quartile-third quartile).
† Three patients were not operated.
‡ Two patients were not operated.
§ Three patients were not operated.

Fig. 3. Transfusion-free cumulative survival in patients with HF receiving FCM plus EPO (EPOFE), FCM plus placebo (FE), or
placebo (placebo).

blood saving strategies and must be reassessed in future
studies focusing sample size calculations to this specific
endpoint.
Our data contrast with previous studies, which
pointed toward a significant reduction of transfusion rates
in this population with the use of IV iron with or without
EPO.20-24,30 Nevertheless previous reports were based on
observational data or pooled analysis; in addition, mean
waiting time from the fracture to surgery in this study was
approximately 48 hours but in most of the previous stud-
ies was approximately 4 days, and this may explain some
differences in the results. In a previous clinical trial per-
formed with iron sucrose in patients with HF, the authors
only detected benefits in RBC transfusion reductions in
intracapsular fractures and in those patients with basal
Hb levels of at least 120 g/L.24 The most important differ-
ences between this and our trial are that this study was
unblinded; the authors did not establish any cutoff point
of Hb level as inclusion criteria, so the mean basal Hb
level was approximately 120 g/L. Nevertheless, and in

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BERNABEU-WITTEL ET AL.

TABLE 4. Intention-to-treat main outcome measures of patients included in the PAHFRAC-01 clinical trial*
Arm
Endpoint EPOFE (n 5 100) FE (n 5 103) Placebo (n 5 100)
Patients transfused 52 (52) 53 (51.5) 54 (54)
Number of RBC transfusions/patient 1.18 (1.2) 1.26 (1.3) 1.28 (1.4)
Survival
Hospital discharge 95 (95) 99 (96) 96 (96)
60 days after discharge 88 (88) 91 (88) 90 (90)
Hb level (g/L)
24 hr postoperative 93.91 (13) 92.78 (13.2) 93.53 (12.2)
72 hr postoperative 93.63 (13) 92.17 (11) 91.13 (11.5)
Discharge 102.6 (11)† 100 (10.7) 97.2 (12)
60 days after discharge 124.8 (13)‡ 123.6 (15) 119 (11.3)
Patients with Hb  120 g/L in V3 6 (6) 3 (2.9) 2 (2)
Patients with Hb  120 g/L in V4 52 (52)§ 47 (46) 39 (39)
Ferritin (mg/L)
Discharge 1047 (150)k 1067 (170)k 249 (250)
60 days after discharge 425 (260)k 472 (310)k 137 (120)
HRQoL by SF-36v2
Physical summary 33.4 (9.7) 31.9 (9.2) 35(9.7)
Mental summary 45.1 (13) 46.1(16) 46.8 (12)
Physical summary decrease 7.4 (11) 4.4 (14) 4.5 (15)
Mental summary decrease 1.2 (13) 2.7 (20) 22 (20)
Medical complications
Acute coronary disease 1 (1) 1 (0.97) 2 (2)
Stroke 1 (1) 1 (0.97) 1 (1)
Heart failure 16 (16) 9 (8.7) 12 (12)
VTE 7 (7) 5 (4.9) 3 (3)
COPD exacerbation
Mild-moderate 6 (6) 5 (4.9) 5 (5)
Severe 1 (1) 1 (0.97) 2 (2)
Renal function deterioration 27 (27) 30 (29.1) 25 (25)
Infections 14 (14) 6 (5.8) 9 (9)
Pneumonia 1 (1) 0 1 (1)
Urinary tract 7 (7) 3 (2.9) 5 (5)
Surgical site (superficial) 2 (2) 0 0
Surgical site (deep) 1 (1) 2 (1.9) 0
Delirium 30 (30) 25 (24.6) 26 (26)
Skin pressure ulcer 12 (12) 5 (4.9) 8 (8)
Adverse clinical events
Nausea and/or vomiting 4 (4) 3 (2.9) 3 (3)
Constipation 2 (2) 3 (2.9) 3 (3)
Hypotension 1 (2) 2 (1.9) 1 (1)
Diarrhea 2 (2) 1 (0.9) 1 (1)
Low grade fever 1 (1) 2 (1.9) 0
Cholestasis 1 (1) 1 (0.9) 1 (1)
Epigastralgia 0 1 (0.9) 1 (0.9)
Peripheral phlebitis 1 (1) 0 0
Hospital stay (days) 8 [6-11] 7 [5-10] 8 [6-10]
Patients with readmissions after V3 13 (13) 10 (9.7) 9 (9)
Number of readmissions/patient 0.19 (0.47) 0.13 (0.4) 0.14 (0.43)
* Results are expressed as number (%), mean 6 SD, or median (first quartile-third quartile).
† p 5 0.009 compared to placebo arm.
‡ p 5 0.05 compared to placebo arm.
§ p 5 0.015 (OR, 2.3; 95% CI, 1.2-4.8) compared to placebo arm.
k p < 0.0001 compared to placebo arm.
COPD 5 chronic obstructive pulmonary disease; V3 5 Visit 3 (at discharge); V4 5 Visit 4 (60 days after discharge); VTE 5 venous
thromboembolism.

spite of the differences between both studies, in ours, we
did not detect any supplementary benefit in RBC transfu-
sion reduction, in the subgroups of intracapsular HF, or in
those patients with highest Hb levels (in our case those
with inclusion Hb level  115 g/L). Data from our study
also contrast with the established benefit of preoperative
EPO and IV iron in patients undergoing elective major
orthopedic procedures.31-40 Nevertheless, results obtained
in the previous trials are difficult to extrapolate to patients
with HF. The HF population is elderly, with higher comor-
bidity and higher preoperative anemia. All HF patients
bleed before surgery and produce an important

8 TRANSFUSION Volume 00, Month 2016


inflammation that blocks erythropoiesis before the proce-
dure. Finally, the chronology of surgery is considered as
an urgent or at least semiurgent procedure in patients
with HF, in contrast with elective orthopedic procedures.
These features make it more difficult to obtain a timely
erythropoietic response, and a clinically significant
increase in total RBC mass in terms of this response is
needed.
IV iron can help to enhance fivefold the erythro-
poietic response to blood loss anemia in healthy per-
sons.41 Nevertheless, a greater rate of Hb production is
probably not possible unless red marrow expands into yel-
low marrow space. Another limitation to exclusive IV iron
therapy may be that much of the administered iron is
transported into the reticuloendothelial system as storage
iron, where it is less readily available for erythropoiesis.
Indeed, classically for iron-deficient patients, only 50% of
dextran iron is incorporated into Hb within 3 to 4 weeks,
whereas for patients with concomitant chronic diseases or
renal failure, dextran iron is even less rapidly mobilized
from the reticuloendothelial system. FCM has notably
improved these kinetics, being rapidly cleared from the
circulation and distributed primarily to the marrow and
also to the liver and spleen. Subsequently, it is quickly
used in iron-deficient patients.28,41,43 In spite of this phar-
macokinetic profile, the response to FCM is probably not
enough for patients with HF to assure some efficacy in
preventing RBC transfusion.
In different studies the measured response to EPO
has documented linear and dose-dependent increases in
28% to 79% of RBC mass (378-1764 mL, or two to nine
RBC transfusions) after a mean of 3 weeks of treatment.41
In this sense the response to EPO has a limiting factor in
the basal RBC precursor mass. Half-maximal Hb synthesis
can be achieved by as few as 50 molecules of EPO per tar-
get cell. This means that the high levels of serum EPO
present initially after parenteral injection are not entirely
used for erythropoiesis. The biologic response is, there-
fore, maximal at lower levels than the EPO concentration
required to saturate all EPO-binding sites. It has been
observed that the reticulocyte mobilization and peak is
higher after a high single dose of EPO (1000-1800 IU/kg),
while storage iron is mobilized more effectively after
multiple-dose regimens. As a matter of fact, a 72-hour
interval between EPO administrations is superior to a 24-
hour interval. EPO therapy stimulates the gradual expan-
sion of erythroblast mass, so that acute demands for
erythropoiesis are met by an influx from preerythroid col-
ony forming unit pools, and chronic demands are met by
an amplified pool of later erythroid precursors. Expansion
and maturation of erythroid precursor cells are, therefore,
limiting factors in the erythropoietic response to acute
blood loss anemia and in treatment strategies using larger
EPO dosages.41 This mechanism could explain the notable
efficacy differences among patients undergoing scheduled
FCM AND EPO IN HF
orthopedic surgery in whom the administration of EPO
was established during the 3 to 4 weeks before surgery,
and the results obtained in this study in patients with HF,
in whom a single high dose of EPO was administered in
the 24 to 72 hours previous to surgery. The hematopoietic
response may be notably enhanced by the coadministra-
tion of IV iron with EPO.30,37,38,44-47 In spite of this, the
time needed for an effective hematopoietic response
probably does not match the needs of an early surgery in
patients with HF, in whom evidence has established that
the optimal time to enter the operating theater is in the
first 12 to 48 hours after admission.48,49
We detected significantly higher Hb levels at dis-
charge and 60 days after discharge in the EPOFE arm with
respect to the placebo arm and also more patients in the
EPOFE arm recovered from anemia with respect to the
placebo arm. This makes sense with the lapse to hemato-
poietic response and its enhancement by EPO and FCM.
Nevertheless, this hematopoietic effect was not correlated
to an objective and on-time clinical benefit as demon-
strated by primary and secondary endpoints. These results
have been observed by other authors when analyzing
patients with HF.50 However, the effects of these analytical
differences, in additional more subtle clinical and func-
tional variables, have not been determined in this study
and remain to be evaluated in ongoing or future trials.51
We detected no differences in the HRQoL among the
three study arms. The inclusion of this subjective variable
aimed at assessing any possible differences in patients’
wellness, which could be related to the drugs tested in the
trial, even if any of them or both were unable to save
blood transfusions. Our results are in accordance with a
recent trial, in which authors did not find HRQoL differen-
ces between a liberal versus a restrictive transfusion strat-
egy in patients with HF.52 It is true that the functional
properties of young native RBCs are different from those
of stored RBCs, mainly in their half-life, but this advantage
could probably be counteracted by the immediate effect
of the RBC transfusions.
Early postoperative complications occurred with no
statistical differences in incidence and severity in all
patients. We detected no significant differences in the
medical complications or in the adverse reactions. As a
matter of fact, medical complications were similar to or
lower than those reported in other studies. Medical com-
plications have been reported to occur globally in around
20% of patients. As examples, delirium occurs in 13.5% to
33% of patients; cardiovascular events (acute coronary
syndromes and/or heart failure) in 35% to 42%; deep
venous thrombosis and pulmonary embolism in 27% and
1.4% to 7.5%, respectively; urinary retention or urinary
tract infections in 12.5% to 61%; nosocomial pneumonia
in 7%; pressure ulcers in 7% to 9%; constipation or
abdominal distension in 5%; and exacerbation of chronic
lung disease in 4%.53 Arterial and venous thromboembolic
Volume 00, Month 2016 TRANSFUSION 9
BERNABEU-WITTEL ET AL.

TABLE 5. Per-protocol main outcome measures of patients included in the PAHFRAC-01 clinical trial*
Arm
EPOFE FE Placebo
Protocol violations and deviations n 5 100 n 5 103 n 5 100
Violations
Not operated 3 (3) 2 (1.9) 3 (3)
Iron sucrose administration 3 (3) 4 (3.9) 1 (1)
Inclusion/randomization incidences 1 (1) 3 (2.9) 1 (1)
Not receiving trial medication 1 (1) 2 (1.9) 2 (1)
Deviations
Received 1 RBC transfusion less 8 (8) 7 (6.8) 7 (7)
Received 1 RBC transfusion more 1 (1) 2 (1.9) 1 (7)
Endpoints without violations n 5 92 n 5 92 n 5 93
Patients transfused 48 (52) 49 (54) 52 (56)
Criterion (Hb < 70/Hb 70-891 symptoms) 15 (16.3)/33 (35.7) 22 (23.9)/27 (30.1) 18 (19.3)/34 (36.7)
Transfusion timing (days since V0) 1 (0-4) 1 (0-3) 1 (0-2.5)
Number of RBC transfusions/patient 1.17 (1.2) 1.32 (1.3) 1.29 (1.4)
Survival
Hospital discharge 88 (95.6) 88 (95.6) 90 (97)
60 days after discharge 82 (89) 83 (90) 85 (91.4)
Hb level (g/L)
24 hr postoperative 93.8 (13) 92.3 (13.4) 93.55 (12.3)
72 hr postoperative 93.7 (13) 92.3 (11) 91.1 (11.6)
Discharge 102.4 (11)† 99.9 (10.9) 96.7 (11.8)
60 days after discharge 124.6 (12.9) 123.4 (15.5) 120 (11.5)
Patients with Hb  120 g/L in V3 5 (5.4) 3 (3.2) 2 (2.2)
Patients with Hb  120 g/L in V4 49 (53) 43(47) 38 (41)
Ferritin (mg/L)
Discharge 1065 (330)‡ 1057 (500)‡ 251 (250)
60 days after discharge 415 (220)‡ 469 (330)‡ 139 (120)
HRQoL by SF-36v2
Physical summary 33.4 (9.9) 31.8 (9.2) 35.3 (9.8)
Mental summary 44.6 (13) 43.9 (16) 47 (12)
Physical summary decrease 7.2 (11) 3.9 (14) 4.5 (15)
Mental summary decrease 1.4 (13) 2.6 (20) 21.9 (20)
Endpoints without violations and deviations n 5 83 n 5 83 n 5 85
Patients transfused 41 (48.8) 41 (48.8) 44 (52.3)
Criterion (Hb < 70/Hb 70-891 symptoms) 10 (12)/31(36.8) 15 (18)/26 (30.8) 12 (14)/32 (38.3)
Transfusion timing (since V0) 0 (0-4) 0 (0-3) 1 (1-3)
Number of RBC transfusions/patient 1.12 (1.25) 1.21 (1.3) 1.25 (1.4)
Survival
Hospital discharge 80 (96.4) 79 (95.2) 82 (96.5)
60 days after discharge 75 (90.7) 74 (88.7) 77 (90.7)
Hb level (g/L)
24 hr postoperative 94.6 (13) 92.8 (13) 93.53 (12.2)
72 hr postoperative 94.8 (12) 92.9 (10) 91.13 (11.5)
Discharge 102.2 (11)§ 99.9 (11) 97.2 (12)
60 days after discharge 124.9 (13)k 123 (16) 119 (11.3)
Patients with Hb  120 g/L in V3 5 (6) 2 (2.4) 2 (2.3)
Patients with Hb  120 g/L in V4 47 (57)¶ 38 (46) 31 (36.5)
Ferritin (mg/L)
Discharge 1.062 (0.33)** 1.021 (0.5)** 0.259 (0.27)
60 days after discharge 0.405 (0.21)** 0.441 (0.28)** 0.136 (0.12)
HRQoL by SF-36v2
Physical summary 33.5 (10) 32.3 (8) 36.4 (9)
Mental summary 45 (13) 44 (15) 48 (10)
Physical summary decrease 6.7 (11) 2.9 (12) 3.9 (15)
Mental summary decrease 0.7 (13) 1.8 (19) 23.3 (19)
* Results are expressed as number (%), mean 6 SD, and median (first quartile-third quartile).
† p 5 0.006 compared to placebo arm.
‡ p < 0.0001 compared to placebo arm.
§ p 5 0.01 compared to placebo arm.
k p 5 0.05 compared to placebo arm.
¶ p 5 0.003 (OR, 3; 95% CI, 1.5-6.3) compared to placebo arm.
** p < 0.0001 compared to placebo arm; V3 5 Visit 3 (at discharge); V4 5 Visit 4 (60 days after discharge).

10 TRANSFUSION Volume 00, Month 2016


events occurred with similar frequency in the EPOFE arm
with respect to the FE and placebo arms. Additionally
infectious complications did also occur with similar fre-
quency. Some authors have advocated the development of
infections as a danger in patients receiving IV iron, but in
recent meta-analyses this observation was not proved; the
data in the present trial did not detect this effect in the FE
and EPOFE arms in higher percentages compared to the
placebo arm.54,55
The main limitations of this study could be the lack
of an EPO arm, but this is a rare clinical practice in popu-
lations with acute blood loss anemia, in which most clini-
cians use FCM or other IV iron formulations with or
without EPO; as a matter of fact, the main limitation of
erythropoietic response to EPO is the availability of iron;
hence, it must be coadministered, especially in patients
with HF, in whom significant bleeding and inflammation
occurs. The main inclusion criterion Hb interval could be
narrow (90-120 g/L), but we decided this on the basis of
the sex epidemiology of HF (90% of women) and to avoid
treating nonanemic patients in which the need of RBC
transfusions is significantly lower; on the other hand,
those patients with an admission Hb level of less than
90 g/L receive routinely RBC transfusions in the pre- or
intraoperatory period in most centers. Another weakness
could be the sample size for comparing the number of
RBC transfusions needed among the arms; this secondary
endpoint could have relevance from the perspective of
blood saving strategies and remains to be assessed.
Finally, the establishment of a homogeneous restrictive
transfusion protocol could raise the question of being
harmful for patients, but the results have shown similar or
lower mortality and medical complications rates with
respect to previous reports.50
In conclusion, in this trial preoperative treatment
with FCM alone or in combination with EPO did not
reduce the RBC transfusion rate in patients with HF,
despite obtaining significant increases of Hb levels at dis-
charge and after 60 days of follow-up and higher rates of
patients who recovered from anemia after 60 days of fol-
low-up.
ACKNOWLEDGMENTS
The authors give special thanks to all patients and their relatives,
who contributed so much to this work; without their altruism and
generosity these results could not have been reached. This study
was carried with the additional support of the Polypathological
Patient and Advanced Age Study Group of the Spanish Society of
Internal Medicine. MBW was the promoter and designed the
Clinical Trial, coordinated all the different phases, recruited
patients, performed the analysis, and wrote the present manu-
script; MR recruited patients, collaborated with the design, and
revised the manuscript; MOB collaborated on the trial design and
the coordination of the different phases and revised the manu-
FCM AND EPO IN HF
script; RA recruited patients, collaborated with the design, and
revised the manuscript; JMZ recruited patients, collaborated on
the design, and revised the manuscript; MRG recruited patients
and collaborated on the design; RMS recruited patients, collabo-
rated on the design, and revised the manuscript; MMB recruited
patients and collaborated on the design; CMR collaborated on
the design, coordinated all administrative and regulation issues,
coordinated monitoring, coordinated data managing, and revised
the manuscript; ARC recruited patients, collaborated on the
design, and revised the manuscript. The remaining PAHFRAC-01
investigators recruited patients and MBW, MOB, and CMR are
guarantors.
PAHFRAC-01 INVESTIGATORS
Maximo Bernabeu-Wittel, Mercedes Galva n Banqueri, Francisco
Javier Galindo Ocan~ a, Ricardo Parra Alcaraz, Manuel Rinco n
Go 
 mez, Marıa del Val Martın Sanz, Miguel Angel ldez
Gira
nchez, Manuel Anaya Rojas, Manuel Ollero-Baturone, Javier
Sa
Bautista Paloma, Bernardo Santos Ramos, Pedro Cano, Lourdes
Moreno-Gavin ~ o, Sonia Gutie
rrez, Vero
 nica Alfaro-Lara, and Clara
M. Rosso, Hospitales Universitarios Virgen del Rocıo, Sevilla;
 s Romero Jime
Manuel Jesu 
nez, Miguel Angel P
erez Ramos, and
 
Miguel Angel Pascual Dıaz, Hospital Infanta Elena, Huelva; Reyes
Aparicio Santos, Ricardo Espinosa Calleja, Boris Garcıa Benıtez,
Antonio Fernandez-Moyano, and Ana E. Barrero-Almodo  var,
 Murcia Zara-
Hospital San Juan de Dios del Aljarafe, Sevilla; Jose
goza, Hospital de la Vega Baja, Alicante; Rafael Monte Secades,
Hospital Lucus Augusti, Lugo; Marıa Melero Bascones and Teresa
Ros Ample, Hospital General Universitario de Albacete, Albacete;
 Luis Ruiz Arranz, Hospital de la
Alberto Ruiz Cantero and Jose
Serranıa, Ma
laga; Abelardo Montero Sa
ez, Hospital Universitario
de Bellvitge, Barcelona; Fernando Garracho  n, Hospital Virgen
Macarena, Sevilla; Marıa Guil Garcıa, Hospital Comarcal de la
Axarquıa, Malaga; Antonia Mora-Rufete and Oscar Torregosa
Susau, Hospital General Universitario de Elche, Alicante; Laura
Abad Manteca, Hospital Universitario Rıo Hortega, Valladolid;
tima Almagro Mu
and Fa  gica, Hospital de Donosti, Guipuzcoa,
Spain.
CONFLICT OF INTEREST
The authors have disclosed no conflicts of interest.
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