Comment
Iron therapy for preoperative anaemia
In The Lancet Haematology, Talboom and colleagues1
report the FIT multicentre, open-label, randomised,
controlled trial (RCT) in 202 patients with colorectal
cancer and iron deficiency anaemia randomly assigned
to either oral or intravenous iron 2–3 weeks before
surgery. The primary endpoint was correction of
anaemia at the time of surgery. Additional endpoints
included perioperative blood transfusion, patient
Thierry Dosogne
complications, and length of hospital stay. The main trial
analysis showed no difference between the two groups
Published Online in any predefined endpoints. This trial helps resolve
February 27, 2023
https://doi.org/10.1016/
the fractured debate between opinions and guidelines
S2352-3026(23)00012-1 proposing the use of intravenous iron therapy for
See Articles page e250 preoperative anaemia2 and results of RCTs3 that have not
shown patient benefit in the perioperative period.
To address why preoperative intravenous iron was
not superior in the FIT trial,1 we need to understand
the two key limitations of previous data. First, the link
between anaemia and adverse outcomes was derived
from large database studies.4 Although statistical
modelling attempts to control for confounding
variables, the outcomes from these analyses can only
propose association and not causation. Second, case
series and cohort studies have shown that intravenous
iron can increase haemoglobin levels and reduce
transfusion rates,5 but are prone to bias without a
comparator. Patients with worse anaemia are more
likely to be selected for treatment, and this group might
show a greater response; doctors might be less likely
to transfuse knowing someone has had a treatment,
and readers’ interpretation might be biased because
only those series with good results are reported and
published. These biases can only be mitigated in RCTs.
The FIT trial team are to be congratulated for
delivering this RCT as proposed. Patient characteristics
were well balanced between the two study groups
and fidelity of the trial protocol was reflected by only
three patients crossing over on the intention-to-
treat analysis. Full dose iron therapy (both oral and
intravenous iron) was delivered preoperatively in line
with normal surgical pathways. Readers can be assured
that the outcomes represent high-quality evidence.
The FIT trial validates the findings in the PREVENTT
RCT,6 which compared intravenous iron with placebo
in patients with anaemia undergoing major abdominal
e236 www.thelancet.com/haematology Vol 10 April 2023
surgery, and adds precision by including only patients
with iron deficiency anaemia. It would be incorrect to
interpret from these trials that iron therapy does not
work. Intravenous iron is an effective treatment for
iron deficiency anaemia and produced a significant
increase in preoperative haemoglobin (8·5 g/L) in
FIT, higher than PREVENTT (4·7 g/L) but lower than
the previous smaller IVICA trial7 in colorectal cancer
surgery (15·5 g/L). In the IVICA trial, patients received
interventions 3 weeks preoperatively as opposed to
2 weeks in FIT1 and PREVENTT;6 a longer time might be
required to increase haemoglobin levels, and guidelines8
now propose at least 4 weeks of treatment. Although
these RCTs showed that preoperative intravenous
iron increased haemoglobin, they did not show that
this treatment effect translated into patient benefit
during the surgical stay. It will be important to ensure
patient involvement in developing any preoperative
protocols about acceptability of delaying cancer surgery
for 4 weeks or more to allow iron therapy to increase
haemoglobin levels.
An outstanding problem is that there is no consensus
on definitions of absolute, functional, or inflammatory
iron deficiency or anaemia of chronic disease in
surgical patients. In FIT, iron deficiency anaemia was
defined as transferrin saturation of less than 20%,
and reanalysis of PREVENTT9 showed the greatest
preoperative haemoglobin response (8·9 g/L) in
patients with ferritin less than 30 μg/L. The cause of iron
deficiency anaemia might well be more relevant than
previously thought, because the greatest increase in
haemoglobin in response to intravenous iron was seen
in the postoperative period in FIT,1 results that were
mirrored in PREVENTT.9 One mechanism could be that
preoperative inflammatory mediated (hepcidin) iron
sequestration impairs erythropoiesis, so no matter how
much iron is given, the response is minimal, whereas
surgical blood loss causes an anaemic (erythroferrone)
stimulus that can override this blockade, leading to
a great response after surgery. The clinical relevance
of this mechanism is that postoperative anaemia
was common and treatment with intravenous iron
associated with reduced reintervention and unplanned
readmissions on subgroup and secondary analyses from
FIT and PREVENTT. Although subgroup analyses should

be interpreted with caution, the findings are supported
by a large observational trial on the incidence and effect
of postoperative anaemia.10
The message to haematologists is that intravenous
iron is an effective treatment for iron deficiency
anaemia. However, it showed no benefit in the pre­
operative setting. We need to better understand how
to diagnose and manage iron deficiency in this group
of hospitalised patients to guide when intravenous iron
should be given. Further studies are needed to address
if the use of intravenous iron can improve patients’
recovery after discharge.
TR reports university research grants for work in the field of iron deficiency from
Vifor Pharma, Pharmacosmos, Pfizer Australia, and BioAge Labs, and consulting
fees from BioAge Labs. KH declares no competing interests.
Katie Hands, *Toby Richards
toby.richards@uwa.edu.au
Scottish National Blood Transfusion Service, Ninewells Hospital, Dundee, UK
(KH); University of Western Australia, Perth 6012, WA, Australia (TR); Institute of
Clinic Trials and Methodology, University College London, London, UK (TR);
Department of Anaesthesia & Perioperative Medicine Monash, Monash
University, Melbourne, VIC, Australia (TR)
1 Talboom K, Borstlap WAA, Roodbeen SX, et al. Ferric carboxymaltose
infusion versus oral iron supplementation for preoperative iron deficiency
anaemia in patients with colorectal cancer (FIT): a multicentre, open-label,
randomised, controlled trial. Lancet Haematol 2023; published online
Feb 27. https://doi.org/10.1016/S2352-3026(22)00402-1.
Hydroxyurea and stroke prevention in sickle cell anaemia:
the challenge of application in sub-Saharan Africa
Stroke is a catastrophic complication in children with
sickle cell anaemia; it is a major cause of death and
disability and occurs in up to 11% of patients by age
20 years.1 Stroke results from stenosis of large cerebral
arteries, limiting the flow of red cells that have reduced
deformability because of the sickling. Cerebral artery
stenosis is preceded by an increase in transcranial
Doppler velocities. The combination of screening
for cerebral blood flow abnormalities by transcranial
Doppler and replacement of sickle red cells with
deformable red cells by regular transfusion has been
shown to reduce the risk of primary stroke by 92%.2
However, transcranial Doppler facilities are very scarce in
Africa, and regular transfusion regimens are not widely
available because of shortage of blood supplies and the
risks of infectious and immunological complications.3
Hydroxyurea is a cytostatic drug that induces
fetal haemoglobin production, thereby reducing
www.thelancet.com/haematology Vol 10 April 2023 e237
Comment
2 National Institute for Health and Care Excellence. Blood transfusion:
NICE guideline [NG24]: alternatives to blood transfusion for patients
having surgery: intravenous and oral iron. Nov 18, 2015. www.nice.org.uk/
guidance/ng24/chapter/Recommendations#intravenous-and-oral-iron-2
(accessed Jan 10, 2023).
3 Ng O, Keeler BD, Mishra A, et al. Iron therapy for preoperative anaemia.
Cochrane Database Syst Rev 2019; 12: CD011588.
4 Musallam KM, Tamim HM, Richards T, et al. Preoperative anaemia and
postoperative outcomes in non-cardiac surgery: a retrospective cohort
study. Lancet 2011; 378: 1396–407.
5 Muñoz M, Gómez-Ramírez S, Cuenca J, et al. Very-short-term perioperative
intravenous iron administration and postoperative outcome in major
orthopedic surgery: a pooled analysis of observational data from
2547 patients. Transfusion 2014; 54: 289–99.
6 Richards T, Baikady RR, Clevenger B, et al. Preoperative intravenous iron to
treat anaemia before major abdominal surgery (PREVENTT): a randomised,
double-blind, controlled trial. Lancet 2020; 396: 1353–61.
7 Keeler BD, Simpson JA, Ng O, et al. Randomized clinical trial of preoperative
oral versus intravenous iron in anaemic patients with colorectal cancer.
Br J Surg 2017; 104: 214–21
8 Care for Perioperative Care. Guideline for the management of anaemia in
the perioperative pathway, September 2022. London: Care for Perioperative
Care, 2022.
9 Richards T, Miles LF, Clevenger B, et al. The association between iron
deficiency and outcomes: a secondary analysis of the intravenous iron
therapy to treat iron deficiency anaemia in patients undergoing major
abdominal surgery (PREVENTT) trial. Anaesthesia 2022; published online
Dec 8. https://doi.org/10.1111/anae.15926.
10 POSTVenTT Study Collaborative. The management of peri-operative
anaemia in patients undergoing major abdominal surgery in Australia and
New Zealand: a prospective cohort study. Med J Aust 2022; 217: 487–93.
polymerisation. Hydroxyurea has been shown to
reduce transcranial Doppler flow velocities in children
with sickle cell anaemia.4–6 In The Lancet Haematology,
Emmanuela Ambrose and colleagues7 report the
findings of their prospective, open-label, phase 2 trial
(SPHERE) in children with sickle cell anaemia in Tanzania.
Children aged 2–16 years (mean 6·8 years [3·5]) at
Per-Anders Pettersson
enrolment had transcranial Doppler screening by a local
examiner. At baseline, 47 (24%) of 196 children had
elevated transcranial Doppler velocities, 43 (22%) in
the conditional category (170–199 cm/s) and four (2%) Published Online
March 1, 2023
in the abnormal category (≥200 cm/s). 45 children https://doi.org/10.1016/
with elevated Doppler velocities were treated with S2352-3026(23)00003-0
hydroxyurea escalated per protocol to the maximum See Articles page e261
tolerated dosage, with a mean dose of 27·4 mg/kg per
day (SD 4·8) at 12 months. This dose was maintained
with minor adjustments for an additional 12 months.
Treatment response was analysed after 12 months