intravenous iron for the treatment of anaemia in critical ... · anaemia in intensive care...
Post on 25-Sep-2020
4 Views
Preview:
TRANSCRIPT
Intravenous Iron for the Treatment of Anaemia in Critical Illness
Edward Litton MBChB MSc FCICM
This thesis is presented for the degree of Doctor of Philosophy of the University of Western Australia
School of Medicine
January 2018
ii
Thesis declaration
I, Edward Litton certify that:
This thesis has been substantially accomplished during enrolment in the degree.
This thesis does not contain material which has been accepted for the award of any other degree
or diploma in my name, in any university or other tertiary institution. No part of this work will, in
the future, be used in a submission in my name, for any other degree or diploma in any university
or other tertiary institution without the prior approval of The University of Western Australia and
where applicable, any partner institution responsible for the joint-award of this degree. This thesis
does not contain any material previously published or written by another person, except where
due reference has been made in the text. The work(s) are not in any way a violation or
infringement of any copyright, trademark, patent, or other rights whatsoever of any person. The
research involving human data reported in this thesis was assessed and approved by The
University of Western Australia Human Research Ethics Committee. Approval #: RA/4/1/6200
Written patient consent has been received and archived for the research involving patient data
reported in this thesis. The following approvals were obtained prior to commencing the relevant
work described in this thesis: EMHS HREC REG 13-042, SCGH HREC RN 2013/065, JHC
HREC 1307, SMHS HREC ref 12/347. The work described in this thesis was partially funded
by SHRAC Research Translation Project Grant 2016 (Round 6) Ref: F-AA-12440 $200,000
Intravenous iron or placebo for anaemia in intensive care: a randomised controlled study. This
thesis contains published work and/or work prepared for publication, some of which has been
co-authored.
Signature:
Date: 04/07/2017
iii
Abstract
Both anaemia and allogeneic red blood cell transfusion are common and potentially harmful in
patients admitted to the intensive care unit (ICU). This project was designed to test the
hypothesis that intravenous iron therapy is effective in reducing allogeneic red blood cell (RBC)
transfusion requirement in critically ill patients with anaemia who are admitted to the ICU.
A systematic review and meta-analysis of 75 studies of intravenous iron administration in acute
care settings found that intravenous iron compared with oral or no iron was effective in
decreasing RBC transfusion (risk ratio [RR] 0.7, 95% CI 0.6-0.9), but was associated with an
increased risk of infection (RR 1.3, 95% CI 1.1-1.6). No high quality randomised controlled trials
(RCT) of intravenous iron therapy in critically ill patients admitted to the ICU were identified.
Having established a plausible effect size for intravenous iron therapy in reducing the risk of RBC
transfusion, a prospective observational study was conducted to inform the design of a phase II
RCT of intravenous iron therapy in critically ill patients admitted to the ICU. In this study, simple
clinical characteristics available early after ICU admission were identified that could predict the
subsequent risk RBC transfusion. In addition, standard measures of iron metabolism were found
to be of limited value in predicting subsequent RBC transfusion.
A multicentre, randomised, placebo-controlled trial of 140 participants was designed on the basis
of these data, including pre-publication of the study protocol. The Intravenous Iron or Placebo for
Anaemia in Intensive Care (IRONMAN) RCT was conducted in four centres in Western Australia
over a period of two years. The iron group received 97 red blood cell units versus 136 red blood
cell unit in the placebo group. The incidence rate ratio for RBC transfusion was 0.71 [95%
confidence interval (0.43-1.18) P=0.19]. The median haemoglobin at hospital discharge was
significantly higher in the IV iron group compared with the placebo group (107 g/L (IQR 97-115)
vs. 100 g/L (IQR 89-111), P=0.02). No immediate severe adverse reactions were reported in
participants receiving intravenous iron and no between-group difference was found in incident
infection.
iv
In a follow up study using a nested cohort design, baseline hepcidin concentration of patients
enrolled in the IRONMAN study was found to be an independent predictor of subsequent RBC
transfusion requirement. The association between intravenous iron therapy and RBC transfusion
was also modified by baseline hepcidin concentration, suggesting that baseline hepcidin
concentration may have prognostic value in identifying patients in whom intravenous iron therapy
is effective in decreasing RBC transfusion quantity.
On the basis of these results, future studies of intravenous iron therapy in critically ill patients
admitted to the ICU may benefit from targeting a cohort of patients at higher risk of subsequent
RBC transfusion and, potentially, greater response to intravenous iron therapy. Based on a mean
RBC transfusion of 1.9 units (standard deviation 3), and a mean difference of 0.5 units, found in
the IRONMAN study, a future trial of 567 participants per group would have 80% power to detect
a change in RBC units transfused of 0.5 units (alpha=0.05).
v
Table of Contents
Thesis declaration……………………………………………................................... ii
Abstract…………………………………………………………………………………. iii
Table of contents………………………………………………………………………. v
Acknowledgements…………………………………………………………………… viii
Authorship declaration: Co-authored publications……………………….………… ix
Abbreviations…………………………………………………………………………… xiv
Chapter 1. Introduction……………………………………………………………… 1
Chapter 2. The Safety and Efficacy of Intravenous Iron Therapy in Reducing
Allogeneic Blood Transfusion: A Systematic Review and Meta-analysis of
Randomised Clinical Trials…………………………………………………………....
8
2.1 Introduction…………………………………………………………………….. 9
2.2 Methods………………………………………………………………………… 10
2.3 Results………………………………………………………………………….. 12
2.4 Discussion……………………………………………………………………… 15
2.5 Conclusion……………………………………………………………………… 17
2.6 Figures………………………………………………………………………….. 18
2.7 Tables…………………………………………………………………………… 24
Chapter 3. Iron-Restricted Erythropoiesis and Risk of Red Blood Cell
Transfusion in the Intensive Care Unit: A Prospective Observational Study……
42
3.1 Introduction…………………………………………………………………….. 43
3.2 Methods………………………………………………………………………… 44
3.3 Results………………………………………………………………………….. 46
3.4 Discussion……………………………………………………………………… 48
3.5 Conclusion……………………………………………………………………… 50
3.6 Figures……………………...………………………………………………….. 51
3.7 Tables…………………………………………………………………………… 52
vi
Chapter 4. The IRONMAN trial: A Protocol For a Multicentre Randomised
Blinded Trial of Intravenous Iron in Intensive Care Unit Patients With
Anaemia…………………………………………………………………………………
56
4.1 Introduction…………………………………………………………………….. 57
4.2 Study design…………………………………………………………………… 59
4.3 Data management…………………………………………………………….. 63
4.4 Conclusion……………………………………………………………………… 64
4.5 Figures……………………...………………………………………………….. 65
4.6 Tables…………………………………………………………………………… 66
Chapter 5. Intravenous Iron or Placebo for Anaemia in Intensive Care: The
IRONMAN Multicentre Randomized Blinded Trial…………………………...…….
69
5.1 Introduction…………………………………………………………………….. 70
5.2 Methods………………………………………………………………………… 71
5.3 Results………………………………………………………………………….. 75
5.4 Discussion……………………………………………………………………… 77
5.5 Conclusion……………………………………………………………………… 81
5.6 Figures……………………...………………………………………………….. 82
5.7 Tables…………………………………………………………………………… 83
5.8 Supplementary data…………………………………………………………… 86
Chapter 6. Utility of Hepcidin in Predicting risk of Red Blood Cell Transfusion
and Response to IV Ion Therapy in Patients Admitted to the Intensive Care
Unit: A Nested Cohort Study…...……………………………………………………..
89
6.1 Introduction…………………………………………………………………….. 87
6.2 Methods………………………………………………………………………… 88
6.3 Results………………………………………………………………………….. 90
6.4 Discussion……………………………………………………………………… 92
6.5 Conclusion……………………………………………………………………… 94
vii
6.6 Figures……………………...………………………………………………….. 95
6.7 Tables…………………………………………………………………………… 97
Chapter 7. Conclusion……………………………………………………………….... 104
7.1 Thesis overview………………………………………………………………... 105
7.2 Limitations……………………………………………………………………… 106
7.3 Significance and future directions…………………………………………… 108
References…………………………………………………………………..………… 110
Appendix 1 – Human Research Ethics Committee Approvals……………………. 120
Appendix 2 - Publications, Presentations and Prizes Arising From this Thesis… 126
viii
Acknowledgements I would like to thank my supervisors Prof S Webb, A/Prof K M Ho, Prof W Erber and Dr J Allan for
the time and support provided to me in completing this work. I would also like to thank my co-
investigators and colleagues in the ICU who contributed to this research.
The IRONMAN study (Chapters 4,5 & 6) was funded by a grant from the West Australian State
Health Research Advisory Council. Study drug was supplied by Vifor Pharma according to a
Letter of Understanding reviewed and agreed upon by Royal Perth Hospital and adhering to the
principles of scientific independence in the conduct and reporting of the trial. The IRONMAN
study was endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials
Group (ANZICS CTG) and is part of the Blood-Centre of Research Excellence.
The IRONMAN study was registered prospectively with the Australian New Zealand Clinical Trials
Registry (ACTRN12612001249842).
This research was not supported by an Australian Government Research Training Program
(RTP) Scholarship.
ix
Authorship Declaration: Co-authored Publications
This thesis contains work that has been published and is being prepared for publication:
Details of the work: The Safety and Efficacy of Intravenous Iron Therapy in Reducing
Allogeneic Blood Transfusion: A Systematic Review & Meta-analysis of RCTs
Litton et al BMJ 2013;347;f4822
Location in thesis: Chapter 2
Student contribution to work: Edward Litton conceived the initial idea for the systematic review,
devised the research protocol, the case report form and the database, and was one of two
authors (along with Dr Xiao) who conducted the online search and extracted data into the case
report form. Edward Litton conducted all analyses of the data (except for the meta-regression
conducted by A/Prof Ho), wrote the first draft of the manuscript and was responsible for editing
all subsequent drafts including submitted and accepted versions to the BMJ.
Co-author signatures and dates:
x
Details of the work: Iron-restricted erythropoiesis and risk of red blood cell transfusion in the
Intensive Care Unit: A prospective observational study
Litton et al. Anaesthesia and Intensive Care 2015; 43(5) 612-6
Location in thesis: Chapter 3
Student contribution to work: Edward Litton conceived the initial idea for the observational study,
devised the research protocol, the case report form and the database, and was one of two
authors (along with Dr Xiao) who collected the data and transcribed it into the database. Edward
Litton conducted all analyses of the data, wrote the first draft of the manuscript and was
responsible for editing all subsequent drafts including submitted and accepted versions to
Anaesthesia & Intensive Care.
Co-author signatures and dates:
xi
Details of the work: The IRONMAN trial: A protocol for a multicentre randomised placebo-
controlled trial of intravenous iron in intensive care unit patients with anaemia
Litton et al. Critical Care & Resuscitation 2015 17(2) 144-5
Location in thesis: Chapter 4
Student contribution to work: Dr Edward Litton conceived the initial idea for the randomised
controlled trial along with Prof Steve Webb (supervisor and co-author) and Prof Toby Richards
(co-author). Dr Edward Litton wrote the first and subsequent drafts of the protocol, the case
report form, data dictionary and managed the study databases. Dr Edward Litton, along with
other site investigators, the project manager and research coordinators, contributed to data
collection and gaining participant consent. Dr Edward Litton conducted start up meetings at all
contributing sites and chaired all meetings of the study management committee.
Dr Edward Litton wrote the first draft of the protocol manuscript and was responsible for editing all
subsequent drafts including submitted and accepted versions to Critical Care & Resuscitation. I
certify the above statement of contribution to be correct and agree to inclusion of the above work
in the PhD thesis of Dr Edward Litton
Coordinating Supervisor signature:
xii
Details of the work: Intravenous Iron or Placebo for Anaemia in Intensive Care: The IRONMAN
multicentre randomized blinded trial
Litton et al. Intensive Care Medicine 2016 42(11) 1715-1722
Location in thesis: Chapter 5
Student contribution to work: Dr Edward Litton conceived the initial idea for the randomised
controlled trial along with Prof Steve Webb (supervisor and co-author) and Prof Toby Richards
(co-author). Dr Edward Litton wrote the first and subsequent drafts of the protocol, the case
report form, data dictionary and managed the study databases. Dr Edward Litton, along with
other site investigators, the project manager and research coordinators, contributed to data
collection and gaining participant consent. Dr Edward Litton conducted start up meetings at all
contributing sites and chaired all meetings of the study management committee. Dr Edward
Litton was responsible for collating and cleaning the database and conducted all analyses of
the data. Dr Edward Litton wrote the first draft of the primary results manuscript and was
responsible for editing all subsequent drafts including submitted and accepted versions to
Intensive Care Medicine. I certify the above statement of contribution to be correct and agree
to inclusion of the above work in the PhD thesis of Dr Edward Litton
Coordinating Supervisor signature:
xiii
Details of the work: Utility of hepcidin in predicting risk of red blood cell transfusion and
response to IV iron therapy in patients admitted to the Intensive Care Unit: A nested cohort
study
(Submitted for publication)
Location in thesis: Chapter 6
Student contribution to work: Dr Edward Litton conceived the initial idea for the hepcidin
substudy. Dr Edward Litton wrote the first and subsequent drafts of the substudy protocol, the
case report form, data dictionary and managed the study databases. Dr Edward Litton, along
with other site investigators, the project manager and research coordinators, contributed to
data collection and gaining participant consent. Dr Edward Litton was responsible for collating
and cleaning the database and conducted all analyses of the data.
Dr Edward Litton wrote the first draft of the hepcidin sub study manuscript and was responsible
for editing all subsequent drafts including submitted and accepted versions to the target journal. I
certify the above statement of contribution to be correct and agree to inclusion of the above work
in the PhD thesis of Dr Edward Litton
Coordinating Supervisor signature:
xiv
Abbreviations
AE ……………… Adverse Event
AKI ……………… Acute Kidney Injury
ANZICS ……………… Australian and New Zealand Intensive Care Society
APACHE ……………… Acute Physiology and Chronic Health Evaluation
CI ……………… Confidence Interval
COAD ……………… Chronic Obstructive Airways Disease
CRF ……………… Case Report Form
CTG ……………… Clinical Trials Group
ESA ……………… Erythropoiesis-Stimulating Agent
Fe ……………... Iron
DOH ……………… Department of Health
DVT ……………… Deep Vein Thrombosis
Hb ……………… Haemoglobin
HREC ……………… Human Research Ethics Committee
ICU ……………… Intensive Care Unit
IQR …………… Interquartile Range
IRE ……………. Iron-Restricted Erythropoiesis
IV ……………… Intravenous
LOS ……………… Length Of Stay
MCV ……………… Mean Corpuscular Volume
MV ……………… Mechanical Ventilation
NaCl ……………… Sodium Chloride
NHMRC ……………… National Health & Medical Research Council
PE ……………… Pulmonary Embolism
RBC ……………… Red Blood Cell
RCT ……………… Randomised Controlled Trial
xv
RRT ……………… Renal Replacement Therapy
SAE ……………… Serious Adverse Event
SD ……………… Standard Deviation
SOFA ……………… Sequential Organ Failure Assessment Score
SIRS ……………… Systemic Inflammatory Response Syndrome
WA ……………… Western Australia
1
Chapter 1
Introduction
2
Epidemiology of RBC transfusion and anaemia in critically ill patients admitted to ICU
RBC transfusion is common in critically ill patients in Australia and worldwide, with 17-45% of all
patients admitted to ICU, and more than 70% of those staying greater than 7, days receiving one
or more RBC units 1-3. Critically ill patients who are transfused receive a mean of 4 RBC units in
ICU accounting for nearly 20% of all RBC units transfused in Australia 4. Although RBC
transfusion for major haemorrhage may be life saving, more than 75% of all RBC units transfused
in ICU are given for anaemia 1 2. IV iron is a plausible candidate intervention to improve outcomes
in critically ill patients because it may reduce RBC transfusion and anaemia.
Risks and benefits associated with RBC transfusion
In a recent systematic review, RBC transfusion in critically ill patients was an independent
predictor of death [pooled odds ratio 1.7, 95% confidence interval (CI) 1.4-1.9], nosocomial
infection, multi-organ dysfunction syndrome and acute respiratory distress syndrome 5. Although
there have been substantial changes to practice in the ensuing period, including widespread
implementation of leukoreduction, the 1999 RCT by Hebert et al. remains the highest quality
evidence to guide threshold for RBC in ICU. In this study, a liberal compared with a restrictive
transfusion policy was associated with a 4.6% absolute increase in mortality (p=0.11) 6. The
mortality difference was significant for those with an Acute Physiology and Chronic Health
Evaluation (APACHE) II score of <20 and those under 55 years of age. Proposed mechanisms by
which RBC transfusion could influence mortality and morbidity include the inherent effects of
associated with exposure to an allogeneic material and the potentially modifiable effects of RBC
storage and immunomodulation. Biochemical changes occurring during storage of RBC units
prior to transfusion include depletion of nitric oxide, adenosine triphosphate, and 2,3-
diphosphoglycerate (2,3-DPG). Together with the reduced deformability of stored RBCs, these
changes may mediate adverse effects including impaired oxygen delivery, reduced
microcirculatory flow and activation of the vascular endothelium with intravascular thrombosis,
vasoconstriction and leucocyte adhesion 7.
3
Irrespective of any causal relationship with adverse outcomes, there are additional societal risks
associated with RBC transfusion. Changing population demographics are increasing the scarcity
of this resource. As the population ages the proportion of potential donors (younger people)
decreases and the proportion of potential recipients (older people) increases. The cost of
producing and delivering RBC units for transfusion is difficult to quantify but is also increasing 8.
Although there are risks associated with RBC transfusion, these must be balanced against
potential benefits. RBC transfusion is life-saving for patients with life-threatening bleeding. In the
ICU setting, the most common indication for RBC transfusion is anaemia. For patients with
anaemia, the potential benefit of RBC transfusion relates predominantly to increasing the total
oxygen carrying capacity (DO2) of the blood. Mechanisms to compensate for the decrease in DO2
associated with progressive anaemia include increase in stroke volume, heart rate and oxygen
extraction (VO2). The threshold of anaemia below which DO2 decompensates and is insufficient
to maintain cellular oxygenation varies, depending on the severity of illness and physiological
reserve of the patient. Consequently, there is a threshold below which the benefits of RBC
transfusion will outweigh the risks but this requires individual assessment based on the potential
indication for RBC transfusion, severity of critical illness and physiological reserve.
Risks and benefits associated with anaemia
Anaemia in patients admitted to the ICU is associated with increased risk of adverse outcomes
including prolonged invasive ventilation, myocardial infarction and mortality 9. Although large
studies are lacking, Bateman et al found that a substantial proportion of patients who survive ICU
admission at a single institution were still anaemic at six months, and that this was associated
with evidence of ongoing inflammation 10. However, high quality evidence is lacking to understand
whether the association between anaemic and adverse outcomes is causal.
The needs for additional evidence is heightened by the fact that there may be benefits associated
with anaemia occurring at the onset of critical illness. Anaemia is part of a highly evolutionarily
conserved component of the acute inflammatory response. Mechanisms including the inhibition of
erythropoietin, direct inhibition of erythroid precursors by circulating cytokines and iron
sequestration decrease RBC production. At the same time, RBC destruction is increased and
4
there may be a dilutional effect related to expansion in plasma volume. Potential benefits of the
resultant anaemia include maintenance of blood fluidity in the setting of high concentrations of
circulating cytokines as well the contribution of RBC rheology to microvascular vasoregulation 9.
Physiological iron metabolism
The majority of the 3-4g of iron occurring in a healthy adult human occurs as part of haemoglobin
molecules in red blood cells. Intracellular ferritin stores the majority of the remaining iron, so that
only a very small proportion, less than one percent, is freely available in the circulation.
Regulation of iron body stores occurs entirely by modulation of uptake. Loss occurring through
shedding of mucosal linings and bleeding is not regulated.
The predominant regulator of iron metabolism is hepcidin an endogenous peptide primarily
produced by liver hepatocytes11. Hepcidin inhibits iron absorption and availability by binding to
and degrading ferroportin, the principle cellular iron efflux channel. Hepcidin release is stimulated
by iron loading and inflammation and inhibited by erythropoiesis, iron deficiency and hypoxia.
High hepcidin concentrations result in iron sequestration and may therefore have a role in
predicting whether exogenous iron, delivered as IV iron therapy is likely to made available to
developing RBCs and thus increase erythropoiesis. As such, hepcidin may be useful both as a
diagnostic guide and to monitor response to treatment with IV iron. However its role in critical
illness has not been evaluated to date12.
Iron metabolism in critical illness
Critical illness results in an acute inflammatory response that has substantial effects on iron
metabolism. Both ferritin and hepcidin release occur as part of the acute phase response. The
increased ferritin results in increased iron sequestration due to the higher affinity of circulating
iron for ferritin than transferrin and the down-regulation of macrophage ferroportin by hepcidin.
Increased hepcidin levels also decrease iron absorption. The net effect is decreased circulating
iron levels and reduced iron availability.
Rationale for IV iron therapy in critically ill patients admitted to ICU
In a recent large multicentre observational study of transfusion practice in 47 ICUs in Australia,
only 2% of RBC transfusions were administered outside of current National Health and Medical
5
Research Council (NHMRC) guidelines1. Given that transfusion in the ICU is common despite
extremely high concordance to current restrictive transfusion guidelines, and that current
transfusion thresholds exacerbate the incidence and severity of anaemia in critically ill patients,
there is an unmet need for novel interventions that both reduce the incidence of RBC transfusion
and incidence and/or severity of anaemia.
Epoetin alpha has been investigated as one such agent. Endogenous erythropoietin levels
decrease rapidly in the setting of acute inflammation associated with the onset of critical illness 13.
However, previous RCTs found that ESAs were not effective in reducing RBC transfusion in
critically ill patients and may be associated with an increased risk of thrombotic complications 14.
Iron is essential for endogenous RBC production. In critically ill patients iron-restricted
erythropoiesis may occur through multiple pathways including absolute iron deficiency, iron
sequestration or functional iron deficiency. Risk factors for both iron deficiency and critical illness
include advancing age and chronic illness. However, enteral administration of iron is ineffective
in patients who are critically ill due to gastrointestinal intolerance, decreased iron absorption from
routine use of gastric acid suppression, physiological limits to maximal enteral iron absorption
and inhibition of absorption due to high hepcidin levels that occur in critical illness. Parenteral iron
overcomes these disadvantages and has been shown to be superior to enteral iron for the
correction of iron-restricted erythropoiesis in a number of patient populations 15 16. IV iron is an
established therapy in guidelines for the management of the anaemia of chronic kidney disease17.
In a recent systematic review of 13 studies comparing IV to oral or no iron in a range of patient
populations, and including observational ICU data, IV non-dextran iron was associated with a
significant increase in short-term haemoglobin concentration 18. IV iron is also effective in
improving the anaemia of inflammation associated with iron-restricted erythropoiesis in iron-
replete patients19.
IV Iron Safety
Newer, non-dextran IV iron preparations have a favorable safety profile with a low risk of serious
side effects including anaphylaxis. Of perhaps greater concern for critically ill patients is the
possible association of IV iron with oxidative stress and infection. In an experimental canine
6
model of bacterial pneumonia and anaemia, IV iron compared to fresh RBC transfusion was
associated with an increase in non-transferrin-bound iron, shock and mortality 20. Clinical data
related to oxidative stress associated with IV iron in critically ill patients is lacking. However free
iron, either as a result of endogenous over-saturation or excessive exogenous iron, can result in
cellular injury by catalysing the production of reactive oxygen species causing lipid peroxidation
and oxidation of amino acids 21.
Iron can also potentiate bacterial growth in vitro 22. The growth of certain bacterial species that
are common in patients admitted to the ICU, including Escherichia coli, Klebsiella species and
Pseudomonas species are enhanced by unbound iron, whilst organisms including
Staphylococcus aureus are able to acquire bound iron through membrane transferrin receptors 23.
There is also clinical evidence of a potential causal relationship between IV iron therapy and
infection. Iron therapy was associated with increased malaria, non-malarial infection and mortality
in several studies of oral iron supplementation conducted in malarial regions 24. In contrast, no
increase in infection has been observed with IV iron therapy in large cohort studies of patients
undergoing long-term dialysis, or following surgery in the developed world setting 25 26.
Furthermore, a mouse model of critical illness and anaemia also found no association between IV
iron and risk of infection 27.
The available evidence suggests that the strength of the relationship between iron therapy and
infection risk is likely to be context-dependent. Relevant factors are likely to include the specific
indication, iron preparation, route and dose used, the severity of the acute illness, immune status
and co-morbidities of the cohort under investigation, and the iron scavenging capacity of the
specific pathogenic organisms to which the host is likely to be exposed. Thus, the variation in
findings relevant to critically ill patients have several potential explanations. The majority of
studies in which no association between iron and infection have been found are either
observational, for which the relationship may be obscured by residual confounding, or are smaller
RCTs that may be underpowered to detect a clinically important difference. It is also plausible
that the low free iron levels associated with newer IV iron preparations has attenuated the risk of
infection. In addition, there is evidence that allogeneic RBC transfusion increases the risk of
7
bacterial infection 28. Given that RBC transfusion may be an alternative treatment to IV iron, an
important question remains as to the risk of infection related to IV iron relative to RBC
transfusion. For critically ill patients, a group that are at increased risk of nosocomial infection, the
relationship between IV iron and infection requires consideration in the design of clinical trials in
patients admitted to the ICU 29.
Summary
IV iron therapy is an established treatment for anaemia in a wide variety of clinical settings. RBC
transfusion in critically ill patients admitted to the ICU is a major public health issue. Critically ill
patients account for a substantial proportion of the total quantity of this scarce and costly
resource. RBC transfusion is also associated with adverse outcomes. This project was designed
to test the hypothesis that intravenous iron therapy is effective in reducing allogeneic RBC
transfusion requirement in critically ill patients with anaemia who are admitted to the ICU. The
aims will be addressed in Chapters 2-6. The aim of Chapter 2 was to conduct a systematic review
and meta-analysis of the safety and efficacy of IV iron focusing primarily on RBC transfusion
infection risk. The aim of Chapter 3 was to conduct an observational study describing the
characteristics of patients with iron-restricted erythropoiesis (IRE) on admission to ICU and the
determinants of subsequent RBC transfusion risk. The aims of Chapters 4 and 5 were to describe
the study protocol and the results of a multicentre RCT of IV iron administration in critically ill
patients admitted to the ICU. Chapter 6 describes a nested sub-study, with the aim of assessing
baseline hepcidin concentration as a predictor of RBC transfusion and response to IV iron. In
Chapter 7, the results of the preceding chapters are integrated to answer the hypothesis of the
thesis. Figures and tables occur at the end of each subsequent chapter after the chapter
conclusion and are referenced throughout.
8
Chapter 2
The Safety and Efficacy of Intravenous Iron Therapy in Reducing
Allogeneic Blood Transfusion: A Systematic Review and Meta-
analysis of Randomised Clinical Trials
9
2.1 Introduction
Iron is essential for the production of red blood cells (RBCs) and is the most common nutritional
deficiency worldwide, both in developed and developing countries 30. Allogeneic RBC transfusion
may be lifesaving for the management of acute severe blood loss, however there are increasing
concerns about its associated serious adverse events, costs and scarcity 31. Safe and effective
strategies to reduce RBC transfusion are urgently needed.
Correction of iron deficiency anaemia using oral iron is limited by gastrointestinal absorption and
is particularly ineffective in the setting of co-existing acute or chronic medical conditions32. IV iron
therapy has an established role in the treatment of iron deficiency anaemia, supported by
laboratory results, where oral iron preparations are ineffective or cannot be used 17. Recent
advances in the understanding of iron metabolism and the association between allogeneic RBC
transfusion and adverse outcomes has increased the interest in the use of IV iron to reduce RBC
transfusion in a variety of acute clinical settings 33 34. Although older IV iron preparations were
associated with a risk of anaphylaxis, newer preparations have largely alleviated this problem 35.
Nevertheless, whether IV iron is associated with other important adverse events, in particular the
theoretical risk of infection, remains uncertain18 22 25.
This systematic review and meta-analysis, undertaken according to PRISMA guidelines36, aimed
to evaluate the safety and efficacy of IV iron focusing primarily on its effects on transfusion
requirement and risk of infection.
10
2.2 Methods
Eligibility Criteria
Published RCTs were searched to identify those in which IV iron was compared with either oral
iron or no iron supplementation. Studies were excluded if they were randomised but with a
crossover design, observational, did not report an outcome of interest, provided insufficient data
for outcomes to be reported or did not contain a group or sub-group in which the independent
effect of IV iron could be assessed. The primary outcomes of interest were: change in
haemoglobin (Hb) and risk of transfusion (efficacy), and risk of infection (safety). Secondary
outcomes of interest included adverse events, and serious adverse events as defined by the
primary studies, anaphylaxis, mortality, length of hospital stay (LOS), cost and cost-effectiveness.
Search Strategy
The primary search was conducted using MEDLINE, EMBASE and the Cochrane Central
Register of Controlled Trials for randomised trials using the terms ‘iron’ and ‘ferric compounds’
and ‘intravenous’. The search included the time period between 1966 and June 2013 and was
conducted without language restrictions. Reference lists of all included studies were searched as
well as relevant review articles and conference proceedings. The manufacturers of IV iron
formulations were also contacted to request access to unpublished trial data.
The primary search was conducted independently by two investigators. Where uncertainty
existed on study eligibility or additional data on end points were needed, the corresponding
author was contacted to request further information.
Study Selection
Potentially relevant titles were retrieved for full text review and data from eligible studies was
transcribed into a prespecified proforma. Studies that were published only in abstract form were
excluded. Disagreement on study inclusion or endpoints was resolved by a third investigator.
11
Data Analysis
The primary outcomes of interest of this review were efficacy (change in Hb and proportion of
patients requiring allogeneic RBC transfusion) and safety (all-cause infection). Where studies
included both oral iron and no iron comparison groups, IV iron was compared preferentially with
oral iron. For categorical data, the risk of an outcome was defined as the number of patients with
an event compared with the number of patients with and without an event. For continuous data,
mean, standard deviation and participant number were used. Data from studies fulfilling the
eligibility were pooled for meta-analysis using a random- effects model. Studies with zero events
in one of the study groups were included as this has been shown to provide a more valid estimate
of true treatment effect 37. Standardised mean difference and risk ratio (RR) with 95% confidence
interval for continuous and categorical outcomes were calculated respectively, and a P value of
<0.05 was taken as significant. Heterogeneity was assessed using the I2 statistic and an I2>40%
was considered as significant heterogeneity. Meta-regression was undertaken to examine the
effect of IV iron dose, baseline iron study results and ESA therapy on the associations between
IV iron and the primary outcomes.
A sensitivity analysis was conducted on the efficacy (transfusion) and safety (infection) outcomes
by excluding studies with a high risk of bias for one or more key domains using the Cochrane
Collaboration’s Tool for Assessing Risk of Bias 38. Publication bias was assessed by a funnel plot,
plotting the odds ratio for proportion transfused against the standard error of the log odds ratio.
The statistical analysis was conducted using STATA (Intercooled Version 11.2, StataCorp,
College Station, Texas, USA) and Comprehensive Meta-analysis (version 2.2.034, Biostat, USA,
2006).
12
2.3 Results
The initial electronic search returned 1815 citations. After examination of the titles and abstracts,
126 were retrieved for more detailed examination. A total of 75 studies including 10879
participants fulfilled the inclusion criteria and were included in the systematic review 11 15 16 39-108.
Of the included studies, 72 studies including 10605 participants provided sufficient quantitative
outcome data to be included in the primary meta-analyses. The flow chart of study inclusion is
presented in Figure 1.
Study Characteristics and Validity Assessment
The sample size of the included studies varied between 25 and 507 participants and involved a
wide range of clinical specialties (renal n=19, obstetric n=19, surgical n=11,
oncology/haematology n=11, cardiology n=4, gastroenterology n=4, other n=7 ). The baseline Hb
(range in mean Hb 6.0-14.5 g/dl) and iron studies (range in mean ferritin 7-761 mcg/dl) of the
included patients also varied between studies. The most common IV iron preparation used in the
included studies was iron sucrose (n=42), followed by iron gluconate (n=10) and ferric
carboxymaltose (n=10). Dextran iron was used in seven studies a further six studies used other
iron preparations. Efficacy outcomes including change in Hb and transfusion were variably
reported, as were safety outcomes including infection, mortality, serious adverse events, and
anaphylaxis. The characteristics of the included studies are shown in table 1.
Overall, the risk of bias was low for 18 studies and high for 57 studies The overall high risk of
bias was accounted for by the majority of studies not being blinded to participants or study
personnel (n=56). Additional data included in the systematic review was provided from the
authors of nine studies. The results of the validity assessment are shown in Table 2.
Quantitative Data Synthesis
Change in Hb and proportion of patients requiring allogeneic RBC transfusion
A total of 59 studies comprising 7610 participants reported the change in Hb before and after
treatment. When pooled, IV iron was associated with a significant increase in standardised mean
Hb (0.7 g/dl, 95% CI 0.5-0.8) compared with oral iron or no iron supplementation (see Figure 2).
There was significant heterogeneity between the studies (I2 87.7% p<0.01).
13
A total of 22 studies comprising 3321 participants reported on the risk of requiring allogeneic RBC
transfusion. IV iron therapy was associated with a significant reduction in the risk of requiring
allogeneic RBC transfusion, (RR 0.7, 95% CI 0.6-0.9) without significant heterogeneity (I2 9%,
p=0.3) (see Figure 3).
There was a potential interaction between use of ESA and the effect of IV iron therapy, with a
greater effect of IV iron on reducing risk of requiring transfusion when concurrent ESA was used
(slope of the regression line 0.32, 95% CI 0.02-0.63, p=0.04) (see Figure 4). Similarly, a lower
baseline ferritin level was associated with greater therapeutic effect in reducing the risk of
requiring RBC transfusion after IV iron therapy (slope of the regression line 0.002, 95% CI 0.002-
0.004, p=0.04). There was however, no interaction between baseline transferrin saturation and
risk of requiring RBC transfusion after IV iron therapy.
Effect of IV iron on all-cause infection
After excluding three studies with zero events in both intervention and comparison groups67 89 94,
a total of 24 studies (n=4400) reported data on risk of infection after receiving IV iron compared
with either oral iron on no iron supplementation. IV iron was associated with a significant increase
in risk of infection of 1.3 (95% CI 1.1-1.6) (see Figure 5) without significant heterogeneity (I2
22.7% p=0.2).
Increased risk of infection was observed both in studies comparing IV iron to oral iron and no
iron. There was no interaction between baseline ferritin, transferrin saturation, iron per dose or
ESA and risk of infection.
Effect of IV iron therapy on other safety end-points
There was no significant difference in mortality (RR 1.1, 95% CI 0.8-1.5), or serious adverse
events (RR 1.1 95%CI 0.9-1.2) with IV iron therapy in 20 and 19 trials respectively. Adverse
events were also not significantly different between IV iron therapy and oral iron or no
supplemental iron (RR 0.9, 95% CI 0.8-1.1). Of the 32 studies reporting anaphylaxis, eight cases
of anaphylaxis were reported in participants receiving IV iron (n=2186).
14
Sensitivity analysis and publication bias
Excluding studies with high risk of bias using the Cochrane Collaboration’s Tool for Assessing
Risk of Bias38, limited the meta-analysis of risk of transfusion to only five studies57 65 77 92 98
(n=901) and this did not change the direction of the association between IV iron and risk of
requiring allogeneic RBC transfusion, but this association was no longer statistically significant
(RR 0.8, 95% CI 0.6-1.1, p=0.66). The sensitivity analysis for risk of infection limited the meta-
analysis to eight studies44 45 58 62 71 81 92 98, and did not substantially change the direction and
magnitude of the association between IV iron therapy and risk of infection (RR 1.4, 95% CI 1.0-
1.8, p=0.03). There was no evidence of publication bias in reporting allogeneic RBC transfusion
requirement in the pooled studies (see Figure 6).
15
2.4 Discussion
IV iron is increasingly advocated to treat anaemia with the aim of reducing allogeneic RBC
transfusion; however, the risks and benefits of IV iron remain uncertain. This is the largest
systematic review and meta-analysis of IV iron to date specifically assessing both the safety and
efficacy of IV iron in patients from a wide spectrum of specialties. In this meta-analysis IV iron
was effective in increasing Hb and reducing the risk of requiring allogeneic RBC transfusion but
was associated with an increased risk of all-cause infection.
Allogeneic RBC transfusion is associated with increased risk of serious adverse events including
increased mortality 5. In this meta-analysis, IV iron was found to be effective in reducing the risk
of RBC transfusion. This benefit appeared consistent across different disease categories and IV
iron formulations and was present whether IV iron was compared with oral iron or no iron. These
findings are in keeping with recent advances in the understanding of iron metabolism; IV iron is
more effective than oral iron, particularly in the setting of acute or chronic inflammation by
bypassing the effects hepcidin - an inhibitor of gastrointestinal iron absorption 109. As such, IV iron
may have an important role in a patient blood management strategy designed to reduce
allogeneic RBC transfusion for many hospitalised patients.
Additionally, these data showed that the effect of IV iron on the risk of requiring allogeneic RBC
transfusion can be further enhanced by concomitant use of ESA. None of the studies included in
the transfusion meta-analysis were conducted in patients with chronic renal failure where ESA
use is a standard of care. The use of ESAs alone may induce a state of functional iron deficiency
and has been postulated as a potential mechanism for the negative results of previous studies of
ESA use in critical care 110 111. Whether the addition of IV iron to ESA in this setting is beneficial
requires further investigation.
The reduction in allogeneic RBC transfusion must be considered alongside our finding of an
increased risk of all-cause infections after IV iron therapy. Free iron has been shown to potentiate
bacterial growth in vitro22. Clinical evidence however, on the association between IV iron therapy
and infection, has been inconclusive, with no increase in infection observed with IV iron therapy
in dialysis, or postoperative surgical patients, or a mouse model of critical care anaemia 27 26 25.
16
This discrepancy may be explained by the low free iron levels associated with newer IV iron
preparations 112 29. Our finding may also be a false positive result. Infection was not a pre-defined
end-point in many pooled studies and it is possible that missing data could have created
unmeasured bias in our analysis. Furthermore, no significant association between iron dose and
risk of infection was found, and overall, serious adverse events and mortality were not
significantly increased in those receiving IV iron compared with oral or no iron. Until RCTs of IV
iron adequately powered for patient-centered outcomes are available, including standardised
definitions for infection, it may be preferable to use IV iron preparations associated with relatively
low free iron concentrations.
Although this was a large a comprehensive systematic review, several limitations bear
consideration. First, data on all outcomes were not available from each study and the doses and
preparations of IV iron used in the pooled studies varied. Nevertheless, heterogeneity in the risk
of requiring transfusion and infection were low, and the number of studies available was sufficient
to conduct a number of meta-regression analyses to assess the interaction between different
predictors and efficacy of IV iron therapy in increasing Hb concentration. Previous smaller
systematic reviews of IV iron therapy were unable to provide sufficient data to estimate important
outcomes such as infection risk or assess the effect of different predictors on efficacy 113 114.
Second, the quality of the included studies was variable and the overall risk of bias of the
included studies was high despite excluding studies that had not been published in their full form.
Finally, meta-regression of trial characteristics using participant level characteristics, such as
baseline ferritin, may lead to aggregation bias and may be underpowered to detect true
differences, such as the effect of IV iron type and dose.115 A large number of studies were
included and meta-regression was only conducted where heterogeneity was low on forest plot
based on an a priori-defined criterion of insignificant heterogeneity (I I2<40%), which reduces but
cannot completely exclude the risk of bias.
17
2.5 Conclusion
IV iron therapy is associated with a significantly reduced risk of requiring allogeneic RBC
transfusion. These findings suggest that IV iron may potentially have broad applicability to many
hospitalised patients in whom anaemia is common. This benefit is counterbalanced by a potential
increased risk of infection. Further RCTs of IV iron are required to define whether it should be
used as a first line agent in reducing allogeneic RBC transfusion in hospitalised patients. Such
trials should include well-defined infection end-points and be adequately powered for important
patient-centered endpoints including mortality and major morbidity.
18
2.6 Figures
Figure 1. Flow Diagram of Study Selection
19
Figure 2. Forrest Plot of Standardised Mean Difference in Haemoglobin with IV Iron Compared
with Oral Iron and No Iron
NOTE: Weights are from random effects analysis
.
.
Overall (I−squared = 87.7%, p = 0.000)
Hulin, S
Bencaiova, G
Li, H
Qunibi, WY
Edwards, TJ
Al−Momen, AK
Hedenus, M
Krayenbuehl, PA
Subtotal (I−squared = 89.2%, p = 0.000)
Li, H
Dangsuwan, P
Okonko, DO
Kim, YH
Pollack, A
Toblli, JE
Aggarwal, HK
Garrido−Martin, P
Madi−Jebara, SN
Provenzano, P
Auerbach, M
Sloand, JA
Warady, BA
Khalafallah, A
Singh, K
Steensma, DP
Van Iperen, CE
Agarwal, R
Anker, SD
Froessler, B
Charytan, C
Verma, S
Karkouti, K
name
McMahon, LP
Li, H
Adhikary, L
Al, RA
Spinowitz, BS
Singh, H
Grote, L
Onken, JE
IV Iron Compared With No Iron
Schroder, MD
Kulnigg, S
Kochhar, PK
Seid, MH
Kasper, SM
Henry, DH
Stoves, J
Neeru, S
Subtotal (I−squared = 78.6%, p = 0.000)
Maccio, A
Breymann, C
Schindler, E
Macdougall, IC
Bayoumeu, F
Westad, S
Beck−Da−Silva, L
Bhandal, N
Coyne, DW
Auerbach, M
Shafi, D
Olijhoek, G
IV Iron Compared With Oral Iron
2005
2009
2008
2011
2009
1996
2007
2011
2008
2010
2008
2009
2001
2007
2003
2012
2004
2009
2004
2004
2004
2010
1998
2011
2000
2006
2009
2013
2005
2011
2006
year
2010
2009
2011
2005
2008
2006
2009
2013
2005
2008
2012
2008
1998
2007
2001
2012
2010
2008
1994
1996
2002
2008
2013
2006
2007
2010
2012
2001
0.65 (0.51, 0.79)
0.11 (−0.30, 0.52)
−0.02 (−0.26, 0.22)
1.71 (1.31, 2.10)
0.44 (0.19, 0.70)
0.62 (0.10, 1.14)
1.70 (1.27, 2.14)
0.24 (−0.24, 0.72)
1.54 (1.07, 2.01)
0.66 (0.49, 0.82)
1.13 (0.50, 1.76)
0.59 (−0.02, 1.19)
0.09 (−0.62, 0.80)
1.57 (0.97, 2.17)
1.60 (0.72, 2.48)
2.91 (2.01, 3.82)
1.59 (0.88, 2.31)
0.00 (−0.38, 0.38)
0.56 (0.12, 1.00)
0.43 (0.17, 0.70)
1.41 (1.06, 1.76)
1.20 (0.34, 2.06)
0.02 (−0.64, 0.68)
0.70 (0.41, 1.00)
1.01 (0.60, 1.43)
0.13 (−0.06, 0.32)
0.28 (−0.53, 1.08)
0.23 (−0.22, 0.69)
0.29 (0.08, 0.51)
0.10 (−0.18, 0.38)
0.42 (0.02, 0.83)
1.39 (1.03, 1.75)
0.28 (−0.47, 1.04)
SMD (95% CI)
0.86 (0.42, 1.31)
0.65 (0.37, 0.94)
0.76 (0.33, 1.19)
0.65 (0.23, 1.08)
0.56 (0.30, 0.83)
0.70 (0.26, 1.14)
0.35 (−0.16, 0.86)
0.77 (0.59, 0.95)
0.33 (−0.25, 0.92)
0.60 (0.29, 0.91)
2.17 (1.67, 2.67)
0.67 (0.43, 0.90)
0.00 (−0.39, 0.39)
0.96 (0.57, 1.35)
0.07 (−0.52, 0.65)
1.13 (0.68, 1.58)
0.62 (0.34, 0.90)
−0.18 (−0.50, 0.14)
0.05 (−0.17, 0.28)
1.53 (0.96, 2.11)
1.77 (0.97, 2.58)
0.01 (−0.56, 0.58)
−0.77 (−1.13, −0.41)
−1.16 (−2.21, −0.11)
0.40 (−0.20, 1.00)
0.37 (0.03, 0.71)
0.60 (0.34, 0.86)
1.00 (0.71, 1.29)
0.43 (−0.12, 0.98)
100.00
1.79
1.97
1.81
1.96
1.63
1.75
1.69
1.70
77.92
1.49
1.52
1.37
1.52
1.17
1.14
1.37
1.82
1.75
1.95
1.86
1.18
1.44
1.92
1.78
2.02
1.25
1.73
2.00
1.94
1.79
1.85
1.31
Weight
1.74
1.93
1.76
1.77
1.95
1.74
1.65
2.03
1.55
1.91
1.67
1.98
1.81
1.81
1.55
1.73
22.08
1.89
1.99
1.56
1.25
1.56
1.85
0.98
1.52
1.87
1.96
1.92
1.59
%
0.65 (0.51, 0.79)
0.11 (−0.30, 0.52)
−0.02 (−0.26, 0.22)
1.71 (1.31, 2.10)
0.44 (0.19, 0.70)
0.62 (0.10, 1.14)
1.70 (1.27, 2.14)
0.24 (−0.24, 0.72)
1.54 (1.07, 2.01)
0.66 (0.49, 0.82)
1.13 (0.50, 1.76)
0.59 (−0.02, 1.19)
0.09 (−0.62, 0.80)
1.57 (0.97, 2.17)
1.60 (0.72, 2.48)
2.91 (2.01, 3.82)
1.59 (0.88, 2.31)
0.00 (−0.38, 0.38)
0.56 (0.12, 1.00)
0.43 (0.17, 0.70)
1.41 (1.06, 1.76)
1.20 (0.34, 2.06)
0.02 (−0.64, 0.68)
0.70 (0.41, 1.00)
1.01 (0.60, 1.43)
0.13 (−0.06, 0.32)
0.28 (−0.53, 1.08)
0.23 (−0.22, 0.69)
0.29 (0.08, 0.51)
0.10 (−0.18, 0.38)
0.42 (0.02, 0.83)
1.39 (1.03, 1.75)
0.28 (−0.47, 1.04)
SMD (95% CI)
0.86 (0.42, 1.31)
0.65 (0.37, 0.94)
0.76 (0.33, 1.19)
0.65 (0.23, 1.08)
0.56 (0.30, 0.83)
0.70 (0.26, 1.14)
0.35 (−0.16, 0.86)
0.77 (0.59, 0.95)
0.33 (−0.25, 0.92)
0.60 (0.29, 0.91)
2.17 (1.67, 2.67)
0.67 (0.43, 0.90)
0.00 (−0.39, 0.39)
0.96 (0.57, 1.35)
0.07 (−0.52, 0.65)
1.13 (0.68, 1.58)
0.62 (0.34, 0.90)
−0.18 (−0.50, 0.14)
0.05 (−0.17, 0.28)
1.53 (0.96, 2.11)
1.77 (0.97, 2.58)
0.01 (−0.56, 0.58)
−0.77 (−1.13, −0.41)
−1.16 (−2.21, −0.11)
0.40 (−0.20, 1.00)
0.37 (0.03, 0.71)
0.60 (0.34, 0.86)
1.00 (0.71, 1.29)
0.43 (−0.12, 0.98)
100.00
1.79
1.97
1.81
1.96
1.63
1.75
1.69
1.70
77.92
1.49
1.52
1.37
1.52
1.17
1.14
1.37
1.82
1.75
1.95
1.86
1.18
1.44
1.92
1.78
2.02
1.25
1.73
2.00
1.94
1.79
1.85
1.31
Weight
1.74
1.93
1.76
1.77
1.95
1.74
1.65
2.03
1.55
1.91
1.67
1.98
1.81
1.81
1.55
1.73
22.08
1.89
1.99
1.56
1.25
1.56
1.85
0.98
1.52
1.87
1.96
1.92
1.59
%
0−3.82 0 3.82
20
Figure 3. Forrest Plot of Risk of Red Blood Cell Transfusion with IV Iron Compared With Oral Iron
and No Iron
NOTE: Weights are from random effects analysis
.
.
Overall (I−squared = 9.0%, p = 0.339)
Weisbach, V
name
Subtotal (I−squared = 13.5%, p = 0.325)
Auerbach, M
Na, HS
Subtotal (I−squared = 0.0%, p = 0.448)
Meyer, MP
Steensma, DP
Dangsuwan, P
Breymann, C
Froessler, B
Hedenus, M
Kim, YT
Auerbach, M
Garrido−Martin, P
Henry, DH
Pedrazzoli, P
Al, RA
Karkouti, K
Edwards, TJ
Madi−Jebara, SN
Serrano−Trenas, JA
Westad, S
Kochhar, PK
IV Iron Compared with No Iron
IV Iron Compared with Oral Iron
Bayoumeu, F
1999
year
2004
2011
1996
2011
2010
2008
2013
2007
2007
2010
2012
2007
2008
2005
2006
2009
2004
2011
2008
2012
2002
0.74 (0.62, 0.88)
2.40 (0.80, 7.23)
RR (95% CI)
0.64 (0.49, 0.85)
0.91 (0.39, 2.12)
0.38 (0.21, 0.68)
0.82 (0.67, 1.00)
0.20 (0.01, 3.93)
0.92 (0.56, 1.52)
0.36 (0.16, 0.82)
1.55 (0.06, 37.82)
0.32 (0.03, 3.03)
2.06 (0.20, 21.65)
0.62 (0.38, 1.01)
0.90 (0.65, 1.25)
0.73 (0.47, 1.13)
1.08 (0.55, 2.12)
0.42 (0.08, 2.08)
0.33 (0.01, 7.97)
0.48 (0.15, 1.52)
0.15 (0.01, 3.08)
0.94 (0.46, 1.93)
0.80 (0.56, 1.16)
0.43 (0.14, 1.28)
0.33 (0.01, 7.99)
0.32 (0.01, 7.48)
199/1479
6/30
Treatment
81/425
9/78
11/54
118/1054
0/21
20/164
5/22
1/227
1/101
2/33
12/30
Events,
41/116
20/54
11/63
2/73
0/45
4/21
0/34
17/80
33/100
4/59
0/50
0/24
306/1594
5/60
Control
120/385
10/79
29/54
186/1209
2/21
43/326
14/22
0/117
3/97
1/34
29/45
Events,
48/122
27/53
20/124
5/76
1/45
4/10
2/26
9/40
41/100
11/70
1/50
1/23
100.00
2.25
Weight
41.38
3.73
7.28
58.62
0.32
9.54
3.83
0.28
0.56
0.51
9.77
%
17.56
11.70
5.69
1.08
0.28
2.03
0.32
5.09
15.30
2.30
0.28
0.29
0.74 (0.62, 0.88)
2.40 (0.80, 7.23)
RR (95% CI)
0.64 (0.49, 0.85)
0.91 (0.39, 2.12)
0.38 (0.21, 0.68)
0.82 (0.67, 1.00)
0.20 (0.01, 3.93)
0.92 (0.56, 1.52)
0.36 (0.16, 0.82)
1.55 (0.06, 37.82)
0.32 (0.03, 3.03)
2.06 (0.20, 21.65)
0.62 (0.38, 1.01)
0.90 (0.65, 1.25)
0.73 (0.47, 1.13)
1.08 (0.55, 2.12)
0.42 (0.08, 2.08)
0.33 (0.01, 7.97)
0.48 (0.15, 1.52)
0.15 (0.01, 3.08)
0.94 (0.46, 1.93)
0.80 (0.56, 1.16)
0.43 (0.14, 1.28)
0.33 (0.01, 7.99)
0.32 (0.01, 7.48)
199/1479
6/30
Treatment
81/425
9/78
11/54
118/1054
0/21
20/164
5/22
1/227
1/101
2/33
12/30
Events,
41/116
20/54
11/63
2/73
0/45
4/21
0/34
17/80
33/100
4/59
0/50
0/24
1.00772 1 129
21
Figure 4. Regression of Erythroid Stimulating Agent on Log Risk Ratio of Red Blood Cell
Transfusion. Slope of regression line = 0.60 (95% confidence interval [CI] 0.09-1.11, p=0.02)
22
Figure 5. Forrest Plot of Risk of Infection with IV Iron
NOTE: Weights are from random effects analysis
.
.
Overall (I−squared = 22.7%, p = 0.156)
Steensma, DP
Henry, DH
Bastit, L
Kulnigg, S
Grote, L
Serrano−Trenas, JA
Hedenus, M
Schroder, MD
Friel, JKEvstatiev, R
Van Wyck, DB
Pollack, A
IV Iron Compared With No Iron
Coyne, DW
Khalafallah, A
Breymann, C
Allen, RP
Subtotal (I−squared = 10.2%, p = 0.345)
Singh, K
Okonko, DO
Singh, H
Van Wyck, DB
name
Meyer, MP
Anker, SD
Qunibi, WY
IV Iron Compared With Oral Iron
Lindgren, S
Bencaiova, G
Krayenbuehl, PA
Subtotal (I−squared = 25.3%, p = 0.196)
Schindler, E
2011
2007
2008
2008
2009
2011
2007
2005
19952013
2007
2001
2007
2010
2008
2011
1998
2008
2006
2005
year
1996
2009
2011
2009
2009
2011
1994
1.34 (1.10, 1.64)
2.53 (1.30, 4.91)
0.77 (0.38, 1.56)
1.10 (0.75, 1.64)
1.38 (0.58, 3.31)
3.20 (0.14, 75.55)
1.23 (0.63, 2.42)
3.09 (1.40, 6.81)
5.43 (0.28, 107.33)
1.10 (0.59, 2.04)1.41 (0.60, 3.31)
1.12 (0.65, 1.91)
0.95 (0.21, 4.32)
0.78 (0.33, 1.85)
(Excluded)
2.45 (0.85, 7.03)
1.31 (0.24, 7.12)
1.17 (0.94, 1.47)
(Excluded)
0.16 (0.01, 3.64)
0.61 (0.26, 1.43)
5.19 (0.25, 106.38)
RR (95% CI)
1.00 (0.16, 6.45)
1.06 (0.68, 1.66)
1.75 (0.80, 3.82)
3.07 (1.07, 8.80)
9.00 (1.16, 70.03)
1.82 (0.72, 4.59)
1.63 (1.16, 2.29)
(Excluded)
326/2413
28/164
9/63
43/203
18/137
1/29
16/100
18/33
2/22
9/1412/105
24/174
2/10
8/68
0/92
19/227
3/24
179/1022
0/50
0/24
9/75
2/79
Treatment
2/21
50/304
20/147
12/45
9/130
10/43
Events,
147/1391
0/30
208/2056
11/163
23/124
37/193
6/63
0/31
13/100
6/34
0/24
7/128/99
22/178
4/19
10/66
0/91
4/117
2/21
123/815
0/50
1/11
9/46
0/82
Control
2/21
24/155
8/103
4/46
1/130
6/47
Events,
85/1241
0/30
100.00
6.41
5.83
11.60
4.24
0.40
6.22
4.96
0.45
7.054.42
8.35
1.64
4.31
0.00
3.11
1.34
59.32
0.00
0.41
4.45
0.44
Weight
1.11
10.28
5.06
3.12
0.93
3.88
%
40.68
0.00
1.34 (1.10, 1.64)
2.53 (1.30, 4.91)
0.77 (0.38, 1.56)
1.10 (0.75, 1.64)
1.38 (0.58, 3.31)
3.20 (0.14, 75.55)
1.23 (0.63, 2.42)
3.09 (1.40, 6.81)
5.43 (0.28, 107.33)
1.10 (0.59, 2.04)1.41 (0.60, 3.31)
1.12 (0.65, 1.91)
0.95 (0.21, 4.32)
0.78 (0.33, 1.85)
(Excluded)
2.45 (0.85, 7.03)
1.31 (0.24, 7.12)
1.17 (0.94, 1.47)
(Excluded)
0.16 (0.01, 3.64)
0.61 (0.26, 1.43)
5.19 (0.25, 106.38)
RR (95% CI)
1.00 (0.16, 6.45)
1.06 (0.68, 1.66)
1.75 (0.80, 3.82)
3.07 (1.07, 8.80)
9.00 (1.16, 70.03)
1.82 (0.72, 4.59)
1.63 (1.16, 2.29)
(Excluded)
326/2413
28/164
9/63
43/203
18/137
1/29
16/100
18/33
2/22
9/1412/105
24/174
2/10
8/68
0/92
19/227
3/24
179/1022
0/50
0/24
9/75
2/79
Treatment
2/21
50/304
20/147
12/45
9/130
10/43
Events,
147/1391
0/30
1.00702 1 142
23
Figure 6. Funnel Plot for the Odds Ratio of Transfusion Against the Standard Error of the Log
Odds Ratio
0.5
11.
52
Stan
dard
Erro
r Log
Odd
s Ra
tio
−4 −2 0 2 4Log Odds Ratio
Funnel plot with pseudo 95% confidence limits
24
2.7 Tables
Table 1. Description of Included Studies
Name Year N Category Iron Type
Dose Schedule
Control ESA Outcomes Measures Follow Up (weeks)
Hb RBC Transfusion
Infection
Mortality
Other
1 Adhikary, L
2011
90 Renal Sucrose 200mg alternate days for 5 doses
Oral ferrous fumarate 125mg three times daily
Yes, both groups
Y Anaphylaxis
4
2 Agarwal, R
2006
75 Renal Gluconate
250mg weekly, total dose 10mg/kg
Oral iron No Y AE SAE Anaphylaxis Mortality
10
3 Aggarwal, HK
2003
40 Renal Dextran 100mg every 2 weeks
Oral iron Yes, both groups
Y SAE Anaphylaxis
12
4 Al, RA 2005
90 Obstetrics Sucrose Ganzoni formula. Max 400mg/day over 5 days. Total dose 11mg/kg
Oral iron polymaltose
No Y Y SAE Anaphylaxis Iron studies Fetal birth weight
10
5 Al-Momen, AK
1996
111
Obstetrics Sucrose Calculated from body weight
Oral ferrous sulphate
No Y AE Anaphylaxis
15
6 Allen, RP
2011
46 Restless leg syndrome
Carboxymaltose
500mg twice, 2 days apart
Placebo No Y IRLS restless leg score
4
7 Anker, SD
2009
459
Heart failure
Carboxymaltose
Ganzoni Formula 200mg weekly till replete
Placebo No Y Y Y Self-reported patient global assessment SAE Anaphylaxis
26
8 Auerbach, M
2004
157
Oncology Dextran Total dose infusion or 100mg repeated
Oral iron group and no iron group
Yes, both
Y Y Y AE Anaphylaxis
6
9 Auerbach, M
2010
243
Oncology Dextran 50mg per dose, three weekly for 12 weeks
Oral iron or no iron
Yes, both groups
Y Y Y Functional assessment AE SAE Anaphylaxis
15
10 Bastit, L*
2008
396
Oncology Sucrose 200mg every 3 weeks
Standard care, no iron
Yes, Both
Y Y Y Y QOL SAE Anaphylaxis
16
25
11 Bayoumeu, F
2002
50 Obstetrics Sucrose Lorentz Formula
Oral iron sulphate
No Y Y SAE Anaphylaxis
4
12 Beck-Da-Silva, L
2013
23 Cardiac failure
Sucrose 200mg weekly for 5 weeks
Oral ferrous sulphate 200mg three times per day
No Y VO2 max
13
13 Benacaiova, G
2009
260
Obstetrics Sucrose 200mg twice or three times
Oral ferrous sulphate
No Y Y Y Iron studies SAE
20-25
14 Bhandal, N
2006
44 Obstetrics Sucrose 200mg two days apart
Oral ferrous sulphate
No Y Y SAE Anaphylaxis
5
15 Birgregard, G
2010
120
Healthy blood donors
Sucrose 200mg after each donation
Oral ferrous sulphate
No Iron studies AE SAE Anaphylaxis RLS
8-52
16 Breymann, C
2008
349
Obstetrics Carboxymaltose
15mg/kg to max of 1000mg weekly up to 3 doses mean total dose 1347mg
Oral ferrous sulphate
No Y Y Y AE SAE Anaphylaxis
12
17 Charytan , C
2005
96 Renal Sucrose 200mg weekly for 5 doses
Oral ferrous sulphate
No Y Y SAE Anaphylaxis Iron studies
5
18 Coyne, DW
2007
134
Renal Gluconate
125mg 3 times a week for 8 doses
No iron Yes, Both
Y Y Y SAE Iron studies
6
19 Dangsuwan, P
2010
44 Oncology Sucrose 200mg Oral ferrous sulphate
No Y Y SAE Anaphylaxis
2
20 Edwards, TJ
2009
62 Colorectal surgery
Sucrose 300mg twice (BMI)
Placebo No Y Y LOS hospital
2
21 Evstatiev, R
2013
256
Gastrointestinal
Ferric carboxymaltose
500mg per dose, median dose 1000mg
Placebo No Y Y Y SAE 34
22 Friel, JK
1995
26 Neonatal TPN
Dextran 200mcg/kg/ day
No iron No Y Y 8
23 Froessler, B
2013
271
Obstetric Sucrose 200mg twice, minimum 24 hours apart
Oral ferrous sulphate 500mg daily
No Y Y AE 7
24 Garrido-Martin, P
2012
210
Cardiothoracic Surgery
Sucrose Three doses of 100mg each
Oral ferrous fumarate 105mg or placebo
No Y Y SAE 4
25 Grote, L*
2009
60 Restless Leg Syndrome
Sucrose 200mg, 5 doses over 3 weeks
Placebo No Y Y RLS score AE Anaphylaxis
11
26
26 Hedenus, M*
2007
67 Haematological Malignancy
Sucrose 100mg weekly for 6 weeks then fortnightly for 8 weeks
No iron Yes, Both
Y Y Y Y AE Epoetin dose
16
27 Henry, DH
2007
187
Oncology Gluconate
125mg weekly for 8 weeks
Oral iron or no iron
All Y Y Y Y AE SAE
12
28 Hulin, S
2005
93 Surgery - Cardiac
Sucrose 5mg/kg No iron No Y 0.7
29 Karkouti, K
2006
38 Surgery – Cardiac and orthopaedic
Sucrose 200mg daily for 3 days
Placebo Yes but ESA group excluded from analysis
Y Y 6
30 Kasper, SM
1998
128
Surgery – autologous blood
Gluconate
102.5mg Oral iron or placebo
No Y AE 3
31 Khalafallah, A*
2010
200
Obstetrics Polymaltose
Formula Oral ferrous sulphate
No Y Y SAE 24
32 Kim, YH
2009
76 Gynecology
Sucrose 200mg alternate days until replete by formula
Oral iron No Y SAE 3
33 Kim, YT
2007
75 Oncology Sucrose 200mg per dose
No iron No Y SAE Anaphylaxis
6
34 Kochhar, PK
2012
100
Obstetrics Sucrose 200mg per dose
No iron No Y SAE Anaphylaxis
6
35 Krayenbuehl, PA*
2011
90 Fatigue Sucrose 800mg over 2 weeks. Total dose 13mg/kg
Placebo No Y Y SAE AE Anaphylaxis
12
36 Kulnigg, S*
2008
200
Gastroenterology
Carboxymaltose
Ganzoni formula max per dose 1000mg or 15mg/kg
Oral ferrous sulphate
No Y Y Y AE SAE Anaphylaxis QOL
12
37 Li, H (1)
2008
46 Renal Sucrose 200mg weekly for 4 weeks then fortnightly
Oral ferrous succinate
Yes, Both
Y Y AE Anaphylaxis
8
38 Li, H (2)
2008
136
Renal Sucrose 100mg twice weekly for 8 weeks
Oral ferrous succinate
Yes, Both
Y AE SAE
12
39 Li, H (3)
2009
194
Renal Sucrose 200mg weekly for 4 weeks then either 100 or 200mg weekly for 8 weeks
Oral ferrous succinate
Yes, Both
Y Iron studies ESA requirement AE Cost-effectiveness
12
40 Lindgren, S*
2009
91 Gastroenterology
Sucrose Ganzoni formula, 200mg weekly till replete. Mean dose 1708 mg
Oral ferrous sulphate
No Y Iron studies AE
20
41 Maccio, A
2010
148
Oncology Gluconate
125mg weekly
Oral iron lactoferrin
Yes, Both
Y SAE 12
42 Macdoug
1996
37 Renal Dextran 250mg every 2
Oral iron or no iron
All Y Anaphylaxis
16
27
all, IC weeks Cost 43 Madi-Jebara, SN
2004
120
Cardiac Surgery
Sucrose Target formula 200mg/day
Placebo Yes but ESA group excluded from analysis
Y Y SAE Anaphylaxis
4
44 McMahon, LP
2010
100
Renal Sucrose 100-200mg every 2 months
Oral ferrous sulphate
No Y Y Y 52
45 Meyer, MP
1996
42 Neonates Sucrose 6mg/kg/week
Oral ferrous lactate
Yes, Both
Y Y Epoetin dose
4
46 Na, HS 2011
113
Orthopaedics
Sucrose 200mg, one to three doses total.
No iron or epoetin
Yes, Iron group only
Y Y 6
47 Neeru, S
2012
100
Obstetrics
Sucrose Formula based on target Hb 110g/l
Oral ferrous fumarate 300mg
No Y 4
48 Okonko, DO
2008
35 Cardiac Failure
Sucrose Formula No iron No Y Y Y VO2 peak SAE
18
49 Onken, JE
2013
507
Haematology
Ferric carboxymaltose
Two doses of 15mg/kg 1 week apart
Oral iron, ferrous sulphate 325mg three times daily
No Y Y SAE
6
50 Olijhoek, G
2001
110
Surgery - preoperative
Saccharate
200mg Oral iron Yes, but excluded from metaanalysis
Y SAE anaphylaxis
2
51 Pedrazzoli, P
2008
149
Oncology Gluconate
125mg weekly for 6 doses
No iron Both Y Y Y SAE Anaphylaxis
16
52 Pollack, A
2001
29 Neonates Sucrose 2mg/kg Oral, oral iron + epoetin, or IV iron + epoetin
Yes Y Y Y Y AE 3
53 Provenzano, R
2009
230
Renal Ferumoxytol
510mg twice within 1 week
Oral iron Both Y Y SAE 5
54 Qunibi, WY
2011
255
Renal Carboxymaltose
Maximum total 2000mg over 3 doses
Oral iron Both Y Y AE 8
55 Schaller, G
2005
38 Renal Sucrose 300mg Placebo Both Anaphylaxis
0.1
56 Schindler, E
1994
60 Orthopaedic
Gluconate
0.75mg/kg, 3 doses two weeks apart
Oral iron No Y Y SAE Anaphylaxis
6
57 Schroder, MD
2005
46 Gastrointestinal
Sucrose 7mg/kg initially, then 200mg 1-2 times weekly
Oral iron sulphate
No Y SAE Anaphylaxis
6
28
58 Seid, MH
2008
291
Obstetrics Carboxymaltose
Formula – modified Ganzoni, weekly iron
No Y SAE Anaphylaxis
6
59 Serrano-Trenas, JA*
2011
200
Orthopaedics
Sucrose 200mg, 3 doses 2 days apart
No iron No Y Y Y 4
60 Shafi, D
2012
200
Obstetrics
Sucrose Formula based on weight and target Hb
Oral ferrous ascorbate 100mg per day
No Y SAE Anaphylaxis
6
61 Singh, H
2006
121
Renal Sucrose 1000mg total in divided doses
No iron Yes, both groups
Y Y Anaphylaxis
10
62 Singh, K
1998
100
Obstetrics Polymaltose
Formula, total dose
Oral iron fumarate
No Y Y Anaphylaxis
12
63 Sloand, JA
2004
25 Renal and Restless legs syndrome
Dextran 1000mg No iron No Y 4
64 Spinowitz, BS
2008
304
Renal Ferrumoxytol
510mg, two doses
Oral iron Both Y SAE 5
65 Steensma, DP*
2011
502
Oncology Gluconate
187.5mg every 3 weeks
Oral ferrous sulphate
Yes, both
Y Y Y Y SAE 16
66 Stoves, J
2001
45 Renal Sucrose 300mg monthly
Oral ferrous sulphate
Yes, both
Y Y 20
67 Toblli, JE
2007
40 Cardiac (CCF)
Sucrose 200mg weekly
Placebo No Y 26
68 Van Iperen, CE
2000
36 Intensive Care
Iron Sacharate
20mg per dose
No iron, IV iron, or IV iron + epoetin
Yes but ESA excluded from analysis
Y Mortality
3
69 Van Wyck, DB (1)
2007
361
Obstetrics Carboxymaltose
Formula, mean cumulative dose 1403mg
Oral ferrous sulphate
No Y Y Y SAE 6
70 Van Wyck, DB (2)
2009
477
Gynecology
Carboxymaltose
Formula, mean dose 1568mg
Oral ferrous sulphate
No Y Y SAE QoL
6
71 Van Wyck, DB (3)
2005
188
Renal Sucrose 1000mg total, divided doses over 14 days
Oral ferrous sulphate
Yes, Both groups
Y Y Y AE 8
72 Verma, S
2011
150
Obstetrics Sucrose 600mg Oral ferrous sulphate
No Y Anaphylaxis AE
4
73 Warady, BA
2004
35 Renal Dextran Oral iron Yes Y SAE 16
74 Weisbach, V
1999
123
Surgery – preoperative Orthopaedics & Cardiothoracic
Sucrose 200mg Oral iron fumarate
No Y Y 5
75 Westad, S
2008
129
Obstetrics Sucrose 600mg total in 3 divided doses
Oral ferrous sulphate
No Y Y QoL 12
29
Table 2 Risk of Bias of Included Studies Name Randomisatio
n Sequence Generation
Allocation Concealment
Blinding of Participants or Personnel
Blinding of Outcome Assessment
Incomplete Outcome Data
Selective Reporting
Other Bias
1 Adhikary, L
Unclear Reported only as assigned to two groups
Unclear No method of allocation concealment
High Open-label study
Unclear No reporting of blinding of outcome assessment
Unclear 90 participants included in outcome analysis but number randomised not reported
Unclear Primary and secondary end-points not reported in methodology
Unclear Analysis not reported as intention-to-treat, differences in baseline Hb between groups
2 Agarwal, R Low Computer-generated randomisation schedule
Low Central randomisation
High Open-label study
Unclear No reporting of blinding of outcome assessment
Unclear 89 participants randomised, 75 included in intention-to-treat analysis
Low Data provided on all prespecified outcomes
Low Intention to treat analysis, good baseline balance, administration of ESA prohibited
3 Aggarwal, HK
High Patients only described as divided into two groups
High Patients only described as divided into two groups
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Follow up was complete
Low Data provided on all prespecified outcomes
Unclear All patients given stable dose of ESA, good baseline balance but whether analysis was intention to treat not reported
4 Al, RA Low Use of a computer-generated randomisation table
Low Use of consecutively numbered opaque envelopes
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Follow up was complete
Low Data was provided on all prespecified outcomes
Low Intention to treat analysis, potential effect of prior use of oral iron explored
5 Al-Momen, AK
High Sequential selection
High Sequential selection
High Open-label study
Unclear No reporting of blinding of outcome assessment
Unclear Participant numbers differed by 7 in the two groups despite sequential selection
Unclear List of prespecified outcomes not reported
Unclear Co-interventions and whether analysis was intention to treat not described.
6 Allen, RP Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
Low Study staff and participants blinded
Unclear Described as independently evaluated
Low Outcome data not available on only 3 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis was intention to treat but co-interventions not described.
7 Anker, SD Low Computer-generated permuted block randomisation
Low Central randomisation
Low Study staff and participants blinded
Low Outcome assessment blinded
Low withdrawal of 37 participants from a total of 459
Low Data was provided on all prespecified outcomes
Low Analysis was intention to treat and co-interventions described
30
randomised
8 Auerbach, M
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available on 155 of 157 participants randomised
Low Data was provided on all prespecified outcomes
High Enrolment ceased before target enrolment reached due to slow recruitment
9 Auerbach, M
Low Randomisation list created and maintained by an independent group
Low Allocation by central telephone system
High Open-label study
Unclear Study blinded for ESA whilst ongoing but unblinded after all participants completed the study
Low Outcome data available for 238 out of 243 participants randomised
Low Prespecified outcome measures reported
Unclear Use of oral iron acceptable but not protocolised in non-IV iron group, no interaction detected between ESA and iron but power low
10 Bastit, L Low Randomisation sequence stratified by site
Low Allocation concealed using an interactive voice response system
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Safety data analysed on all patients randomised
Low Data was provided on all prespecified outcomes
Low All participants received fixed dose ESA, intention to treat analysis provided
11 Bayoumeu, F
Low Randomisation table used
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available on 47 of 50 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention to treat, co-interventions described
12 Beck-Da-Silva, L
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
Low Participants and study personnel blinded to allocation
Unclear No reporting of blinding of outcome assessment
High Primary outcome available for 18 out of 23 participants randomised
Low Data was provided on all prespecified outcomes
High Study terminated early with <30% of planned sample size recruited
13 Benacaiova, G
Low Computer-generated randomisation sequence
Low Consecutively numbered opaque envelopes
High Open-label study
Unclear No reporting of blinding of outcome assessment
High Outcome data not available for 31 of 260 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention to treat, co-interventions described
14 Bhandal, N
Low Computer-generated randomisation sequence
Low Consecutively numbered opaque envelopes
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available in 43 out of 44 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis was intention-to-treat but co-interventions were not described
15 Birgregard, G
Low Minimisation
Low Centralised
High Open-label
Unclear No reporting of
Low Outcome
Low Data was
Low Analysis was
31
method used
randomisation via web-based system
study blinding of outcome assessment
data available in 112 out of 120 participants randomised
provided on all prespecified outcomes
intention-to-treat
16 Breymann, C
Unclear Randomised in 2:1 ratio, stratified by country and severity of anaemia by method of sequence generation not reported
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available in 344 out of 349 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis was intention-to-treat, co-interventions not reported
17 Charytan , C
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
High 83 participants out of a total of 102 randomised completed the study
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat, participants stratified according to previous ESA use
18 Coyne, DW
Low Computer-generated randomisation scheme
Low Central randomisation
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available in 129 out of 134 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat, ESA dose changes accounted for in study design
19 Dangsuwan, P
Low Random table used
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available on all 44 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat, all patients received RBC transfusion according to standardised protocol
20 Edwards, TJ
Low Computer-generated randomisation sequence used
Low Sealed, sequentially numbered opaque envelopes
Low Participants blinded, chief investigator and perioperative clinicians blinded, investigator administering infusion not blinded
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 60 out of 62 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat, potential confounders collected, RBC transfusion in accordance with a strict protocol
21 Evstatiev, R
Low Randomised 1:1 according to predefined computer-generated list
Low Sequentially numbered envelopes used
Low Participants blinded
Unclear No reporting of blinding of outcome assessment
High Outcome data not available for 52 out of 256 participants randomised
Low Data provided on all prespecified outcome measures
Unclear Unclear whether full analysis participant set was intention-to-treat
32
22 Friel, JK Unclear
Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Unclear Outcome data available for 26 participants, total number randomised not reported
Unclear Specific primary and secondary a priori-defined end-points not reported
Unclear Unclear whether analysis was intention to treat and co-interventions such as ESA use not reported
23 Froessler, B
Low 1:1 randomisation via telephone service
Low Telephone service used
High Open-label study
Low Data were analysed by a statistician blinded to the treatment group
High No outcome data for 77 out of 271 participants randomised
Low Data provided on all prespecified outcome measures
Low Intention-to-treat analysis performed, transfused patients excluded from further Hb analysis
24 Garrido-Martin, P
Low Random number list used
Low Assigned to intervention in pharmacy department
Low Blinding by placebo
Unclear No reporting of blinding of outcome assessment
High No outcome data for 51 out of 210 participants randomised
Unclear Discussion states no increase in infection but data not provided
Low Analysis was intention-to-treat
25 Grote, L Low Minimisation method used
Unclear Allocation concealment not described
Low Participants and study staff blinded
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for all 60 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Intention-to-treat analysis provided, co-interventions not described
26 Hedenus, M
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 60 of 67 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis included per-protocol and intention-to-treat, ESA dosing accounted for
27 Henry, DH
Low Central randomisation
Low Central randomisation
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Safety population evaluated with 187 out of 189 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis included per-protocol and intention-to-treat, oral iron, ESA dosing and RBC transfusion accounted for in methodology
28 Hulin, S Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available on 47 of 50 participants randomised
Unclear Specific primary and secondary a priori-defined end-points not reported
Unclear Analysis not reported as intention-to-treat, co-interventions not described
29 Karkouti, Low Low Low Unclear Low Low Unclear
33
K Computer-generated randomisation sequence used
Sequentially numbered sealed, opaque envelopes
Participants and study staff blinded
No reporting of blinding of outcome assessment
Outcome data missing for 7 of 38 participants randomised
Data was provided on all prespecified outcomes
Analysis was intention-to-treat, transfusion guidelines provided but co-interventions not described
30 Kasper, SM
Unclear Randomisation sequence described as blocks of 5
Unclear Allocation concealment not described
Low Participants and study staff blinded
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 108 out of 128 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis not reported as intention-to-treat, co-interventions not described
31 Khalafallah
Low Randomised in blocks of 10
Low Assignment performed by pharmacy department
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 183 out of 200 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis was intention-to-treat but co-interventions not described
32 Kim, YH Low Computer-generated randomisation sequence
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data missing for 20 out of 76 participants enrolled but safety data analysed on all participants
Unclear No secondary outcomes measures reported as pre-specified
Unclear Analysis not reported as intention-to-treat, co-interventions not described
33 Kim, YT Unclear Randomisation sequence generation not described
Low Envelope procedure described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Unclear Number of participants randomised not reported
Unclear A-priori endpoints not reported
Unclear Protocol for RBC transfusion provided, analysis not reported as intention-to-treat
34 Kochhar, PK
Low Randomisation table used
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 98 out of 100 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis not reported as intention-to-treat, co-interventions not described
35 Krayenbuehl, PA
Low Randomisation schedule generated by external provider
Low Randomisation schedule generated by external provider
Low participants and study staff blinded
Low Investigators blinded to study group
Low Outcome data available on all 90 participants randomised
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis conducted
36 Kulnigg, S
Low Randomisatio
Low Central
High Open-label
Unclear No reporting of
Low Outcome
Low Data was
Low Intention-to-
34
n schedule generated by external provider
randomisation system
study blinding of outcome assessment
data available for 196 out of 200 participants randomised
provided on all prespecified outcomes, no post-hoc analyses performed
treat analysis conducted, co-interventions described
37 Li, H (1) Low Computer-generated randomisation sequence
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for all 46 participants randomised
Unclear Clearly defined a-priori endpoints not reported
Uncertain Titration of ESA allowed but not reported as an outcome, analysis not reported as intention-to-treat
38 Li, H (2) Low Computer-generated random number list used
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for all 136 participants randomised
Unclear Clearly defined a-priori secondary end-points not reported
Uncertain Titration of ESA allowed but not reported as an outcome, analysis not reported as intention-to-treat
39 Li, H (3) Low Computer-generated randomisation sequence
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for all 194 participants randomised
Unclear Clearly defined a-priori secondary end-points not reported
Uncertain Titration of ESA allowed but not reported as an outcome, analysis not reported as intention-to-treat
40 Lindgren, S
Low Minimisation method used
Low Internet used for allocation to treatment arm
High Open-label study
Unclear final assessment done from computerized information only
Unclear 13 participants out of total of 91 randomised were withdrawn
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis performed, co-intervention data collected
41 Maccio, A
Unclear Sequence generation not described
Unclear Randomisation 1:1 but allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for all 148 participants randomised
Low Data was provided on all prespecified outcomes
Low Study design controlled for co-interventions
42 Macdougall, IC
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 37 out of 38 participants randomised
Unclear Principle end-points provided but without specifics, e.g. ‘iron status’
Uncertain Analysis not reported as intention-to-treat
43 Madi-Jebara, SN
Unclear Randomisation sequence generation not
Unclear Allocation concealment not described
Low Participants and study staff blinded
Unclear No reporting of blinding of outcome
Low Outcome data available
Low Data was provided on all
Low Participants receiving RBC transfusion
35
described
assessment for all 120 study participants
prespecified outcomes
excluded from further analysis
44 McMahon, LP
Low Block randomisation
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
High Outcome data available for 85 out of 100 participants enrolled
Low Data was provided on all prespecified outcomes
Unclear 6 oral iron group patients received infrequent IV iron, analysis not reported as intention-to-treat
45 Meyer, MP
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 39 out of 42 participants randomised
Uncertain Specific, a priori end-points not reported
Unclear Analysis not described as intention-to-treat
46 Na, HS Unclear Randomisation sequence generation not described
Low Sealed envelopes used
High Open-label study
Unclear No reporting of blinding of outcome assessment
Low Outcome data available for 108 out of 113 participants randomised
Low Data was provided on all prespecified outcomes
Low RBC transfusion guideline used
47 Neeru, S
Unclear Block randomisation but no further description of methods
Unclear No description of allocation concealment
High Open-label study
Unclear No blinding reported of outcome assessment
Low Outcome data available for 89 out of 100 participants randomised
Unclear RBC transfusion reported only for one group, unclear whether primary outcome prespecified
Unclear 6 participants crossed over from oral to IV iron
48 Okonko, DO
Low Computer-generated randomisation in a 2:1 ratio
Low Treatment allocation concealed from the investigators
Low Study investigators blinded
Low outcome assessment by blinded investigators
Unclear Outcome data available for 30 out of 35 participants
Low Data was provided on all prespecified outcomes
Low Missing data imputed but sensitivity analysis conducted without imputation
49 Olijhoek, G
Low randomisation schedule used, 1:1:1:1 ratio
Unclear Allocation concealment not described
Low Administration of ESA blinded
Unclear No outcome assessment blinding reported
Low Outcome data available for 107 out of 110 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat
50 Onken, JE
Low Randomised 1:1 using interactive voice system
Low Use of an interactive voice system
High Open-label
Low Composite safety events adjudicated by a blinded clinical committee
Low Outcome data available in 495 out of 507 participants
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat
36
51 Pedrazzoli, P
Unclear Randomisation sequence generation not described
Low Central randomisation
High Open-label study
Unclear No outcome assessment blinding reported
High 33 participants out of a total of 149 randomised were exclude from per protocol population
Low Data was provided on all prespecified outcomes
Unclear Study stopped early with 149 out of 420 planned participants recruited
52 Pollack, A
Unclear Randomisation sequence generation not described
Low Sequentially numbered sealed envelopes
High Open-label study
Unclear No outcome assessment blinding reported
High No outcome data for 9 out of 38 participants enrolled
Unclear Specific a priori-defined primary and secondary end-points not reported
Unclear Characteristics of participants disqualified did not differ from those who completed study but data not provided
53 Provenzano, P
Low Telephone system
Low Telephone system
Low Open-label study
Unclear No outcome assessment blinding reported
Low Outcome data available for 224 out of 230 participants randomised
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis conducted, safety population included all patients receiving at least one dose of study medication
54 Qunibi, WY
Low Interactive voice-response system used
Low Centralised system
High Open-label study
Unclear No outcome assessment blinding reported
Low Outcome data available for 245 out of 255 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Initial 2:1 randomisation ratio, changed to 1:1 due to slow recruitment
55 Schaller, G
Low Computer-generated randomisation sequence
Unclear Allocation concealment not reported
Low Participants and study staff blinded
Low Laboratory personnel blinded to group assignment
Low Outcome data available for all 38 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Potential differential use of ESA
56 Schindler, E
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available for all 60 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis not described as intention-to-treat
57 Schroder, MD
Low Computer-generated random number table
Unclear Allocation concealment not described
High Open-label study
Unclear No blinding of outcome assessment reported
High Outcome data not available for 11 out of 46 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Differential distribution of inflammatory bowel disease type
58 Seid, MH Low Unclear High Unclear Low Low Low
37
1:1 randomisation, stratified by baseline Hb
Allocation concealment not described
Open-label study
No blinding of outcome assessment reported
All 291 participants randomised included in the intention-to-treat analysis
Data was provided on all prespecified outcomes
Analysis was intention-to-treat
59 Serrano-Trenas, JA
Low Randomisation list used with 1:1 ratio
Low Sealed, opaque envelopes
Low outcome data assessor blinded
Unclear No blinding of outcome assessment reported
Unclear Outcome data available for 179 out of 200 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat, protocol provided for RBC transfusion
60 Shafi, D
Low Computer generated randomisation sequence
Low Sequentially numbered sealed opaque envelopes
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available on all enrolled participants
Low Data provided on all prespecified outcome measures
Unclear All participants analyses in group to which randomised but RBC transfusion not described
61 Singh, H Unclear Randomisation 2:1 but sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available for 121 out of 126 participants randomised
Low Data was provided on all prespecified outcomes
Low Analysis was intention-to-treat
62 Singh, K Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No blinding of outcome assessment reported
Unclear 100 participants randomised but number with outcome data not reported
Unclear Primary outcome specified but not specifics of secondary outcome measures
Unclear 12 participants in oral iron group switched to IV iron
63 Sloand, JA
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
Low participants and study staff blinded
Unclear No blinding of outcome assessment reported
Low Outcome data available for 23 out of 25 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Plan to recruit 30 participants but study stopped after 25 recruited
64 Spinowitz, BS
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available for all 304 participants randomised
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis performed
65 Steensma, DP
Low 1:1:1 stratified randomisation
Low Central allocation concealment
Low Patients and investigators blinded to oral or no iron
Unclear No blinding of outcome assessment reported
Low Outcome data available for 490 out of 502
Low Data was provided on all prespecified outcomes
Unclear Stopped early due to excess serious adverse events in IV
38
participants randomised
iron arm
66 Stoves, J Low Computer-generated randomisation schedule
Low Computer-based allocation
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available for all 45 participants randomised
Low Data was provided on all prespecified outcomes
Unclear Analysis not reported as intention-to-treat
67 Toblli, JE Low Random number table used
Unclear Allocation concealment not described
Low Participants and study staff blinded
Low Physicians performing echocardiography blinded
Low Outcome data available for all 40 participants randomised
Low Data was provided on all prespecified outcomes
Low Baseline balance and co-interventions described
68 Van Iperen, CE
Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available for all 36 participants enrolled
Low Data was provided on all prespecified outcomes
Low Co-interventions described, intention-to-treat analysis performed
69 Van Wyck, DB (1)
Low Computerised random number generation
Low Interactive voice-response system
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data for safety evaluation available for 352 out of 361 participants randomised
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis performed
70 Van Wyck, DB (2)
Low Computerised random number generation
Low Interactive voice-response system
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data for safety evaluation available for 456 out of 477 participants randomised
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis performed
71 Van Wyck, DB (3)
Low Computerised random number generation
Low Interactive voice-response system
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available for 182 out of 188 participants randomised
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis performed
72 Verma, S Unclear Randomisation sequence generation not described
Unclear Allocation concealment not described
High Open-label study
Unclear No blinding of outcome assessment reported
Unclear 150 participants included in outcome analysis but number randomised not reported
Unclear No prespecified outcome parameters other than Hb
Unclear Analysis not reported as intention-to-treat, co-interventions not described
73 Warady, BA
Low Random
Unclear Allocation
High Open-label
Unclear No blinding of
Low Outcome
Low Data was
Unclear 1 patient in
39
number table used
concealment not described
study outcome assessment reported
data available for all 35 participants randomised
provided on all prespecified outcomes
oral iron group received IV iron, analysis not reported as intention-to-treat
74 Weisbach, V
Unclear Randomisation list used
High Chronological enrollment with sequential order of trial medication
High Open-label study
Unclear No blinding of outcome assessment reported
High Outcome data not available for 33 out of 123 participants randomised
Unclear Secondary end-points not specifically reported
Unclear Analysis not reported as intention-to-treat
75 Westad, S
Low Minimisation used
Low Central randomisation
High Open-label study
Unclear No blinding of outcome assessment reported
Low Outcome data available for 117 out of 129 participants randomised
Low Data was provided on all prespecified outcomes
Low Intention-to-treat analysis performed
Table 3. Results Name Baseline
Hb (g/L) Baseline Ferritin (mcg/L)
Baseline TSAT (%)
Hb change mean (g/l) IV iron versus comparator
Hb change (% achieved target)
Transfusion (n) IV iron versus comparator
Infection (n) Mortality (n)
1 Adhikary, L 92
98 16 10.6 vs 3.2 24.4 vs 20.0
2 Agarwal, R 106 69 18 2 vs 4
3 Aggarwal, HK
60 186 61 43 vs 27
4 Al, RA 98 45 12 vs 6 95.6 vs 62.2
5 Al-Momen, AK
76 12 52 vs 35
6 Allen, RP 32 -8.9 vs -4.0
3/24 vs 2/21
7 Anker, SD 119 54 17 11 vs 6 50 vs 28 50/304 vs 24/155
8 Auerbach, M
96 258 18 24 vs 12 68 vs 25 1/78 vs 1/791
9 Auerbach, M
93 312 19 vs 13 41/116 vs 48/122
8/117 vs 13/121
10 Bastit, L 99 279 29 86 vs 73 18/200 vs 39/196
21/200 vs 15/196
11 Bayoumeu, F
96 7 10 11.1 vs 11.0 12.5 vs 17.4
0/24 vs 1/23
12 Beck-Da-Silva, L
112 132 17 10.4 vs 16.9 20 vs 43 2/10 vs 0/7
13 Benacaiova, G
108 12.2 vs 12.4 80 vs 75 1/110 vs 1/119 9/130 vs 1/130
14 Bhandal, N
74 12 11.5 vs 11.2 0/22 vs 1/21
15 Birgregard, G
136 35
16 Breymann, C
96 39 12 33.7 vs 32.9 1/227 vs 0/117 19/227 vs 4/117
17 Charytan 98 114 16 10 vs 7 54.2 vs
40
, C 31.3 18 Coyne, DW
103 761 19 16 vs 11 46.9 vs 29.2
8/68 vs 10/66 1/68 vs 1/66
19 Dangsuwan, P
90 9 vs 4 5/22 vs 14/22
20 Edwards, TJ
135 -1.9 vs -5 2/34 vs 5/26
21 Evstatiev, R
136 75 23 27.2 vs 40.4
12/105 vs 8/99 0/105 vs 0/99
22 Friel, JK 9/14 vs 7/12
23 Froessler, B
102 9 25 vs 24 1/101 3/97 0/100 vs 0/94
24 Garrido-Martin, P
139 252 -13 vs -13 20/54 vs 27/53
25 Grote, L 130 20 5.5 vs 1.5 1/29 vs 0/31
26 Hedenus, M
103 128 22 28 vs 16 93 vs 53 2/33 vs 1/34 18/33 vs 6/34 0/33 vs 4/34
27 Henry, DH
103 351 32 24 vs 16 18 vs 16 11/63 vs 20/124 9/41 vs 23/88
28 Hulin, S 107 67
29 Karkouti, K
84 220 9.5 vs 7.0 16.5 vs 12.0
2/11 vs 4/10
30 Kasper, SM
145 162 25 11.8 vs 11.8
31 Khalafallah
108 18 14 19.2 vs 12.5 84 vs 71 0/92 vs 0/92
32 Kim, YH 76 76.7 vs 11.5
33 Kim, YT 113
12/30 vs 29/45
34 Kochhar, PK
76 17 57 vs 36 0/50 vs 1/50
35 Krayenbuehl, PA
133 22 23 1 vs 0 10/43 vs 6/47
36 Kulnigg, S
88 6 56 37 vs 28 76.5 vs 68.3
18/137 vs 6/63
37 Li, H (1) 88 111 19 34.1 vs 22.1 0/26 vs 0/20
38 Li, H (2) 81 193 22 39.2 vs 18.6 88.6 vs 44.0
39 Li, H (3) 88 151 10 24.7 vs 17.8
40 Lindgren, S
104 13 7 66 vs 47 12/45 vs 3/46
41 Maccio, A 98 493 26 16 vs 18 50 vs 56
42 Macdougall, IC
73 25 45 vs 27
43 Madi-Jebara, SN
142 17/80 vs 9/40
44 McMahon, LP
119 106 21 2 vs 1 5/52 vs 1/48
45 Meyer, MP
0/21 vs 2/21 2/21 vs 2/21
46 Na, HS 121 76 21 11/54 vs 29/54
47 Neeru, S
95 20 vs 12 66.7 vs 61.4
48 Okonko, DO
123 70 21 5 vs 4 0/24 vs 1/11 1/24 vs 0/11
49 Onken, JE
106 33 22 15.7 vs 8.0 57.0 vs 29.1
0/244 vs 2/251
50 Olijhoek, G
123 2 vs -1 no ESA 15 vs 16 ESA
41
51 Pedrazzoli, P
99 341 29 76.7 vs 61.8
2/73 vs 5/76 4/73 vs 3/76
52 Pollack, A -8 v -24
2/10 vs 4/19
53 Provenzano, P
106 350 16 10 vs 5 49 vs 25 1/110 vs 3/114
54 Qunibi, WY
100 108 15 10.5 vs 7.0 60.4 vs 34.7
20/147 vs 8/103
55 Schaller, G
122 171 28
56 Schindler, E
135 105
57 Schroder, MD
97 100 6 25 vs 21 2/22 vs 0/24
58 Seid, MH 89 24 40 vs 34 91.4 vs 66.7
33/100 vs 41/100
16/100 vs 13/100
11/100 vs 10/100
59 Serrano-Trenas, JA
120
60 Shafi, D
79 8 29 vs 20
61 Singh, H 106 175 18 13 vs 6
9/75 vs 9/46
62 Singh, K 84 8 29 vs 13
0/50 vs 0/50
63 Sloand, JA
111 21 2 vs -4
64 Spinowitz, BS
100 145 11 8.2 vs 1.6
65 Steensma, DP
99 465 22 26 vs 24 70 vs 66 20/164 vs 43/326
26/164 vs 10/163
8/164 vs 9/326
66 Stoves, J 98 70 vs 59 0/22 vs 1/23 67 Toblli, JE 102 72 20 15 vs -4
68 Van Iperen, CE
100 13 vs 10 5/12 vs 12/12 2/12 vs 4/12
69 Van Wyck, DB (1)
90 25 10 96.4 vs 94.1
24/174 vs 22/178
1/174 vs 0/178
70 Van Wyck, DB (2)
94 68 6 82.0 vs 61.8
71 Van Wyck, DB (3)
101 98 16 7 vs 4 44.3 vs 28.0
2/79 vs 0/82
72 Verma, S 75 39 vs 27
73 Warady, BA
115 139 38 -1.5 vs -1.7
74 Weisbach, V
144 163 25 5 vs 6 6/30 vs 5/60
75 Westad, S
78 40 vs 46
4/59 vs 11/70
42
Chapter 3
Iron-Restricted Erythropoiesis and Risk of Red Blood Cell
Transfusion in the Intensive Care Unit: A Prospective
Observational Study
43
3.1 Introduction
Anaemia is nearly universal in ICU patients and is the most common indication for RBC
transfusion, despite high concordance with restrictive guidelines 1 2. Both anaemia and RBC
transfusion are associated with increased morbidity and mortality in critical illness 2 3 5.
Intravenous (IV) iron therapy increases haemoglobin and decrease transfusion requirement in
selected patients 116. As such, IV iron therapy may plausibly improve outcomes during critical
illness, however the optimal criteria for selecting patients who may benefit from this therapy in
ICU are uncertain.
IV iron therapy improves haemoglobin by overcoming iron-restricted erythropoiesis (IRE). This is
syndrome includes absolute iron deficiency, functional iron deficiency (the inability of iron stores
to meet elevated erythropoeitic demands) and iron sequestration (a reduction in the availability of
stored iron in the setting of inflammation) 32 110. Recent guidelines have promoted ferritin as an
essential assay in the diagnosis of IRE and decision to initiate IV iron therapy 117 118.
The hypothesis was that that IRE, diagnosed by iron studies on admission to ICU, would identify
a substantial group of patients at high risk for subsequent RBC transfusion, and hence, provide a
simple method to potentially determine likely response to IV iron therapy. The aim of this study
therefore, was to describe the characteristics of patients with IRE on admission to ICU and
determine the optimal variables to identify the group of patients at risk of subsequent RBC
transfusion.
44
3.2 Methods
The study was undertaken in the 23-bed combined medical/surgical ICU at Royal Perth Hospital,
a university-affiliated tertiary referral centre in Perth Western Australia. Data from consecutive
ICU admissions was recorded in a prespecified case report form. Patients were followed from
ICU admission till discharge from hospital, censored at 60 days post admission to ICU. The
diagnosis of IRE using a cutoff of ferritin <300mcg/L and transferrin saturation (TSAT)<20% was
based on previously published consensus statement and guidelines for the laboratory diagnosis
of functional iron deficiency 117-119. The study was approved by the clinical safety quality unit
(110623-1).
Statistical Analysis
The associations between baseline variables and IRE status were assessed using chi-square,
Student t-test and Mann-Whitney U tests for categorical, parametric and non-parametric
continuous variables, respectively. After excluding patients who received IV iron therapy,
univariate logistic analysis was used to assess the association between baseline factors and
odds of any subsequent in-hospital RBC transfusion. Baseline factors with a p value<0.25 in the
univariate logistic regression analyses were then entered in the initial multivariable logistic
regression model and eliminated in backward stepwise fashion with a significance level of
p<0.05. The utility of the final model of risk factors for predicting RBC transfusion was assessed
by receiver operator characteristic curve and the Hosmer-Lemeshow test.
A sensitivity analysis was then conducted investigating the utility of the predictive model for RBC
transfusion in patients eligible for IV iron therapy on the basis of iron study parameters from
previously published RCTs of IV iron. 116. Parameters varied between studies, however none
included patients with a ferritin >1200 mcg/L or TSAT>50%. The sensitivity analysis was
therefore limited to patients with a ferritin <1200mcg/L and TSAT≤50% to exclude patients in
whom iron over-saturation may limit the efficacy of IV iron.
Sample Size Calculation
Compared with a previous estimated prevalence of 35% for functional iron deficiency on
admission to ICU, a prevalence of 45% would require a sample size of 184 (p=0.05 and power
45
80%) 120. Assuming approximately 10% of patients without sufficient baseline results to be
included in the analysis, a sample size of 200 patients was planned for inclusion in the study.
46
3.3 Results
Between 5 March and 14 April 2012 there were 201 consecutive ICU admissions. Admission
blood results were not available in six cases, therefore, a total of 195 patients were included in
the analysis. The median age of the cohort was 53 (interquartile range (IQR) 36-65), 68% (95%
confidence interval (CI) 61-74) were male and 75%, (95%CI 69-81) received mechanical
ventilation. The participant characteristics are presented in table 1.
Characteristics of patients with iron-restricted erythropoiesis
The prevalence of iron-restricted erythropoiesis on admission to ICU, defined according to
ferritin<300mcg/L and TSAT<20%, was 26.2% (95% CI 19.9-32.4). Age, gender, acute
physiology and chronic health evaluation (APACHE) II score, sequential organ failure
assessment (SOFA) score, haemoglobin and C-reactive protein were similar between those with
and without IRE. Compared with patients without IRE, patients with IRE had significantly lower
mean corpuscular volume and mean corpuscular haemoglobin concentration (MCHC), mean
difference 2.5fL (95%CI 0.8-4.3, p<0.001) and 1.3pg (95% CI 0.6-2.0, p<0.001) respectively.
The proportion of patients with IRE subsequently receiving RBC transfusion was significantly
lower than the proportion of patient without IRE receiving RBC transfusion, as was the proportion
of patients with and without IRE discharged from hospital with a haemoglobin<100g/L, absolute
mean difference 18.9% (95%CI 4.7-33.1) and 36.6% (95%CI 20.9-52.2) respectively. Only four
patients received IV iron after admission to ICU, none fulfilled the criteria for IRE on admission to
ICU. The characteristics and outcomes of patients according to admission IRE status are
presented in table 2.
Risk factors for RBC transfusion
After excluding four patients who received IV iron therapy, 16 variables were assessed for
association with subsequent RBC transfusion on univariate analysis (see table 3). Age,
emergency ICU admission, chronic renal impairment, RBC transfusion prior to ICU admission ,
APACHE II score, SOFA score, renal replacement therapy, ICU length of stay, ICU admission
haemoglobin, c reactive protein, mean corpuscular volume, mean corpuscular haemoglobin and
47
IRE (ferritin<300 & TSAT<50%) all had p <0.25 and were therefore included in the subsequent
multivariable logistic regression for stepwise elimination.
In the final multivariable model presented in table 4, five variables were found to be significantly
associated with subsequent risk of RBC transfusion (previous RBC transfusion, SOFA score, ICU
length of stay, admission haemoglobin and c-reactive protein). IRE was not independently
associated with risk of subsequent RBC transfusion.
The receiver operator characteristic (ROC) area under the curve (AUC) for risk of transfusion
using the five variable multiple regression model was 0.93 (95%CI 0.89-0.97). Calibration, as
assessed by Hosmer-Lemeshow was 3.20 (p=0.92), see figure 1.
Predicting RBC transfusion in those who may benefit from IV iron
After excluding patients unlikely to benefit from IV iron (ferritin>1200mcg/L & TSAT>50%), the
ROC AUC for the five-variable model was 0.91 (95%CI 0.84-0.95), see table 4. Predictive
accuracy was also not substantially different when limited to a more clinically useful model
comprising only three simple variables categorized according to maximal ROC AUC (RBC
transfusion prior to ICU admission, Hb<100g/l on admission to ICU and ICU length of stay>3
days), ROC AUC 0.88 (95%CI 0.80-0.95) p=0.20, Hosmer-Lemeshow for three variable model
6.33, p=0.10, , see table 5. In this subgroup, 30 (22.2% (95% CI 15.1-29.3) and 31 (25.5% (95%
(CI17.9-33.8) patients respectively were admitted to ICU and discharged from hospital with a
haemoglobin<100g/L.
48
3.4 Discussion
In this study a diagnosis of IRE, based on a ferritin<300mcg/L and TSAT<20%, was found to be
moderately prevalent on admission to ICU (26.2% (95% CI 19.9-32.4). However IRE was not
independently associated with risk of subsequent RBC transfusion, despite those with IRE having
a significantly lower mean corpuscular volume and mean corpuscular haemoglobin. Rather than
identifying a group at high risk of RBC transfusion, IRE appeared to be protective on univariate
analysis, possibly due to the competing effect of increased ferritin as a marker of the severity of
acute inflammation and illness severity, itself likely to increase the incidence and severity of
anaemia.
The optimal criteria for determining response to IV iron in critically ill patients with IRE remain
unknown. A previous study in patients with chronic kidney impairment suggested that iron studies
are inadequate in guiding response to IV iron 121. Our findings concur, and suggest that a
diagnosis of IRE on the basis of iron studies alone is likely to have limited clinical utility in
determining response to IV iron in the critical care setting, particularly given the low incidence of
RBC transfusion and severe anaemia on hospital discharge in this group.
In contrast, this study found that a predictive model based on three simple clinical criteria (RBC
transfusion prior to ICU admission, haemoglobin<100g/L and ICU length of stay>3 days)
identified patients at high risk of subsequent in-hospital RBC transfusion and may have greater
clinical utility as a way of identifying patients who may benefit from IV iron therapy. Although
length of ICU stay is not known at baseline, previous RCTs in which trial eligibility requires the
judgment of the treating clinician that the patient is likely to require ICU level care beyond the
next calendar day demonstrate good predictive ability 122. This high-risk group was also at high
risk of discharge from hospital with severe anaemia, a condition that may then persist long after
discharge from hospital and be associated with increased morbidity and mortality 9 10.
Free iron associated with RBC transfusion may increase the risk of oxidative stress and infection
123 124. Whether IV iron therapy is associated with similar free iron release in critical illness is an
important additional consideration. A recent RCT of IV iron in trauma patients excluding patients
with a ferritin > 1000ng/ml or TSAT>50% however found no significant difference in RBC
49
transfusion requirement, infection, or mortality but generalisability may limited by the liberal
haemoglobin inclusion threshold, dose and type of IV iron 125 126.
Several limitations of this study require consideration. First, this was a single centre observational
study and the final predictive model was based on backwards stepwise elimination limited by
consideration only of statistical significance and with a high number of variables to participants.
As such, the generalisability of the model for predicting transfusion is uncertain. However, the
cohort of patients and incidence of RBC transfusion, were generally representative of Australian
tertiary ICU admissions. Second, only four patients received IV iron therapy in ICU. An
association between IV iron therapy and subsequent RBC transfusion in patients who fulfilled the
high risk criteria was therefore unable to be assessed and future RCTs are warranted to evaluate
the safety and efficacy of IV iron in critically ill patients126. Third, bleeding events were not
considered and may have a substantial effect on the outcome of interest for which the
relationship with the exposure of interest is less strong. However, previous studies suggest that
the predominant indication for RBC transfusion in the ICU is anaemia, not bleeding, potentially
mitigating the importance of this omission. Fourth, the competing risk of death was not assessed,
although mortality was low (7.7%) and would not be expected to have a major effect on the
predictive model. Finally, several potential markers of IRE including hepcidin, soluble transferrin
receptors and zinc protophoryn were also not assessed. The addition of these markers may have
helped differentiate absolute iron deficiency from functional iron deficiency although the role of
these markers in critical illness remains uncertain.
50
3.5 Conclusion
Despite moderate prevalence, IRE, diagnosed by iron studies on admission to ICU, is associated
with a low incidence of severe anaemia and subsequent RBC transfusion and not independently
associated with either on multivariable analysis. IRE is unlikely to be useful in determining the
response to IV iron. An alternative approach of early identification of patients at high risk of
subsequent in-hospital RBC transfusion using a simple predictive model and excluding iron over-
saturation may be a preferable strategy for identifying patients that may benefit from IV iron
therapy in ICU.
51
3.6 Figures Figure 1 ROC Probability of RBC Transfusion
N=177, ROC AUC 0.93 (0.89-0.97) Hosmer-Lemeshow 3.20, p=0.92 Figure 2. ROC Probability of RBC Transfusion after Excluding Patients Unlikely to Benefit from IV Iron (ferritin>1200mcg/L and/or TSAT>50%) Comparison of Full Model and Three Risk Factor Model
ROC AUC 0.91 (95%CI 0.84-0.97) versus 0.88 (95%CI 0.80-0.95) p=0.20 Hosmer-Lemeshow for three variable model 6.33, p=0.10, N=121
52
3.7 Tables Table 1 Participant Characteristics
n=195
Age
53 (36-65)
Male Gender, N (%)
132 (68)
Admission Type, N (%) Medical Elective Surgical Emergency Surgical
90 (46) 36 (18) 69 (35)
Apache II Score Admission
14 (9-18)
SOFA Score Admission 5 (3-7)
Mechanical Ventilation, N (%) 146 (75)
Renal Replacement Therapy, N (%)
22 (11)
Median (Interquartile range) unless otherwise stated APACHE Acute Physiology and Chronic Health Evaluation, SOFA Sequential Organ Failure Assessment,.
53
Table 2 Characteristics and Outcomes of Patients With and Without IRE on Admission to ICU
Iron-restricted erythropoiesis N=51
Not iron-restricted erythropoiesis N=144
P Value
Baseline Characteristics Age
44 (23-59) 54 (42-66) <0.01
Male Gender N (%)
31 (61) 101 (70) 0.22
APACHE II
14 (10-17) 14 (9-19) 0.39
SOFA
5 (3-7) 5 (3-7) 0.33
Haemoglobin g/l, mean (95% CI)
118 (112-124) 115 (111-118) 0.40
Mean Corpuscular Volume fL
89 (86-92) 91 (88-93) <0.01
Mean corpuscular haemoglobin pg, mean (95%CI)
29.7 (28.9-30.5) 31.0 (30.6-31.3) <0.001
Fe mcmol/L
5 (3-7) 13 (5-19) <0.01
Transferrin saturation, %
10 (7-14) 26 (13-50) <0.01
Ferritin mcg/L
144 (78-215) 448 (227-1165) 0.03
C Reactive Protein mg/L
65 (9-86) 63 (3-90) 0.88
Outcomes RBC transfusion N (%)
7 (14) 47 (33) 0.01
RBC units in those transfused, mean (95%CI)
3.4 (1.7-5.2) 5.2 (3.4-7.0) 0.46
ICU LOS
1 (1-4) 2 (1-4) 0.21
ICU Mortality N (%)
6 (12) 9 (6) 0.21
Haemoglobin change from ICU admission to hospital Discharge in non-transfused survivors g/l
2 (-3-6)
-7 (-10 - -4) <0.01
Discharged from hospital with Hb<100g/L, n (%)
3 (7) 54 (44) <0.001
Hospital LOS
6 (2-14) 12 (6-21) <0.01
Hospital Mortality
6 (12) 11 (8) 0.37
Median (Interquartile range) unless otherwise stated.
54
Table 3. Univariate Analysis of Association Between Baseline Variable and In-Hospital RBC Transfusion After Admission to ICU (n=191)
Odds ratio (95% CI) P Value
Age
1.03 (1.01-1.05)a 0.004
Gender
1.11 (0.56-2.21) 0.760
Emergency ICU admission
2.02 (0.79-5.20) 0.144
Chronic renal impairment+
3.88 (1.61-9.35) 0.003
Chronic acid suppression use#
1.12 (0.51-2.48) 0.771
RBC units transfused prior to ICU admission
21.32 (8.90-51.08) <0.001
APACHE II
1.07 per point (1.02-1.12)b 0.006
SOFA
1.22 (1.08-1.37)b 0.001
Mechanical ventilation
0.77 (0.38-1.57) 0.470
Renal replacement therapy
6.95 (2.62-18.44) <0.001
ICU LOS
1.27 (1.15-1.41)c <0.001
C reactive protein mg/L
1.01 (1.00-1.01)d 0.001
Hemoglobin g/L
0.93 (0.90-0.95)e <0.001
Mean corpuscular volume (fL)
0.97 (0.91-1.02)f 0.264
Mean corpuscular haemoglobin (pg)
0.92 (0.81-1.05)g 0.236
Iron-restricted erythropoiesis ^
0.34 (0.14-0.80) 0.014
+Chronic renal impairment defined according to creatinine>110 #Chronic acid suppression included all patients receiving proton pump inhibitor or H2 receptor blocker on admission to hospital ^Iron-restricted erythropoiesis defined according to ferritin<300 & transferrin saturation<20% References for odds ratios: a per year, b per point, c per day, d per mg/L, e per g/L, f per fL, g per pg
55
Table 4. Final Multivariable Model After Excluding Four Patients Who Received IV Iron Whilst in ICU, Then Stepwise Elimination of All Variables with p>0.05
Odds ratio (95% CI) Coefficient* P Value
RBC units transfused prior to ICU admission
11.11 (3.74-33.07) 2.408 <0.001
SOFA
1.23(1.03-1.48) 0.210 0.02
ICU LOS
1.25 (1.08-1.45) 0.225 0.003
C reactive protein mg/L
1.01 (1.00-1.01) 0.007 0.007
Hemoglobin g/L
0.95 (0.92-0.98) -0.157 <0.001
, *logistic regression coefficient constant 1.889 Table 5. Model for Predicting RBC Transfusion, Excluding Patients with Iron Over-Saturation and Comprising only Three Simple Variables Categorized According to Maximal ROC AUC (RBC transfusion prior to ICU admission, Hb<100g/l on admission to ICU and ICU length of stay>3 days),
Odds ratio (95% CI) Coefficient* P Value
RBC units transfused prior to ICU admission
7.44 (2.15-25.78) 2.01 0.002
ICU LOS>3 days
3.59 (1.17-11.02) 1.28 0.025
Hemoglobin<100g/L
9.50 (2.92-30.87) 2.25 <0.001
*logistic regression coefficient constant -3.13
56
Chapter 4
The IRONMAN Trial: A Protocol for a Multicentre Randomised
Blinded Trial of Intravenous Iron in Intensive Care Unit Patients
with Anaemia
57
4.1 Introduction
RBC transfusion is common in critically ill patients in Australia and worldwide, with 17-45% of all
patients admitted to an ICU, and more than 70% of those staying greater than 7 days receiving
one or more RBC units 1-3. Transfused critically ill patients receive a mean of 4 RBC units in ICU
and account for nearly 20% of all RBC transfusions in Australia 127.
In a recent systematic review of observational studies, conducted by Marik et al., RBC
transfusion in the critically ill was an independent predictor of death (pooled odds ratio 1.7, 95%
confidence interval 1.4-1.9), nosocomial infection, multi-organ dysfunction syndrome and acute
respiratory distress syndrome 5. Allogeneic RBC transfusion is also an increasingly costly and
scarce resource 128.
Transfusion in the ICU remains common despite extremely high concordance to current
restrictive transfusion guidelines 1. More than 75% of RBC units transfused in ICU are given for
anaemia, rather than major haemorrhage 1 2, and anaemia itself is also associated with adverse
outcomes 129. There is therefore an unmet need for novel interventions that reduce the incidence
of anaemia and therefore transfusion.
Iron-restricted erythropoiesis is extremely common in critically ill patients and may occur through
absolute iron deficiency, functional iron deficiency or iron sequestration 9. Administration of iron
enterally is ineffective in patients who are critically ill due to gastrointestinal intolerance,
decreased iron absorption from routine use of gastric acid suppression, physiological limits to
maximal enteral iron absorption and inhibition of absorption due to high hepcidin levels that occur
in critical illness 119. IV iron overcomes these disadvantages and has been shown to be superior
to enteral iron for the correction of iron-restricted erythropoiesis in a number of patient
populations 19 116. Furthermore, the diagnosis and management of iron deficiency and suboptimal
iron stores in the critically ill has been identified as an important evidence gap by the National
Blood Authority 130.
Iron is essential for bacterial growth, and exogenous iron therefore associated with a theoretical
increased risk of infection, however most RCTs to date have not included infection as a
prespecified endpoint and the risk in critically ill patients remains uncertain 22 116. In an animal
58
model of sepsis, IV iron improved Hb and was not associated with increased risk of death 27. A
RCT by Pieracci et al of low dose iron sucrose in trauma patients found no significant difference
between the groups in infection 125.
The Pieracci trial also found no significant difference in Hb concentration or RBC transfusion
requirement associated with IV iron 116. In comparison, the IRONMAN trial will enroll a broader
population of critically ill patients and has been designed to optimise IV iron efficacy by only
including more severely anaemic patients (included if Hb<100g/L versus Hb<120g/L) and
administering an alternative and higher dose IV iron (500mg ferric carboxymaltose versus 100mg
iron sucrose) associated with greater erythropoeitic response 131.
The hypothesis of this study is that IV iron supplementation in critically ill patients who are
anaemic but do not have severe sepsis is effective in reducing RBC transfusion. A reduction in
mean RBC transfusion requirement may lead to a reduction in mortality and major morbidity, as
well as substantial healthcare costs savings.
59
4.2 Study Design
The IRONMAN trial is a multicentre, phase IIb, randomised, placebo-controlled parallel group trial
comparing IV iron in addition to standard care, to standard care alone, in patients admitted to the
ICU who are anaemic. The primary end-point is the mean number of RBC transfusions from
study enrolment to discharge from hospital. Secondary endpoints included the proportion of
patients transfused, ICU and hospital mortality and infection. A full list of outcome measures is
provided in table 1.
The IRONMAN trial is planned to enroll 140 participants across four centres. Adult patients within
48 hours of admission to ICU (or a high dependency area under the supervision of an Intensivist),
predicted to remain in the ICU beyond the next calendar day, with a haemoglobin (Hb) of <100g/l
in the preceding 24 hours and without exclusion criteria are eligible for enrolment after
prospective consent. A complete list of inclusion and exclusion criteria is provided in table 2.
Participants
Patients admitted to the ICU will be assessed by trained study personnel including the research
coordinators and medical staff, at each study site. Patients will be eligible for enrolment if they
fulfill all of the inclusion criteria and none of the exclusion criteria (table 2). The key inclusion
criteria were based on the findings of the prospective observational study (Chapter 3) that found
that ICU LOS and Hb<100g/L were independent predictors of RBC transfusion. In this study,
ferritin and TSAT were not predictive of future RBC transfusion. Therefore participants were
excluded on the basis of risk of iron overload (ferritin >1200mcg/L and/or TSAT>50%) rather than
included on the basis of likelihood of response to IV iron at lower ferritin and TSAT levels.
Participants will be allocated to the treatment arm using a randomly generated sequence.
Randomisation will be in variable block size and stratified by site. Allocation concealment will be
maintained by using sequentially numbered, sealed, opaque envelopes containing the numeric
code of the study arm to which the participant was randomised. The randomisation code will be
documented in the participants notes, the case report form (CRF) and provided to the ICU
nursing shift coordinator with access to the unblinding code for preparation of the intervention.
Active medication and re-dosing
60
There are substantial pharmacokinetic and pharmacodynamics differences between
commercially available IV iron preparation. These differences relate predominantly to the effect of
differences in the size of the iron core and composition of the carbohydrate shell on release and
distribution of the iron therapy 132. Given the lack of data for patients admitted to the ICU, the
choice of IV iron therapy and dosing schedule for the IRONMAN trial was based on the available
safety and efficacy extrapolated from non-critically ill patients. Although conclusive evidence is
lacking, there is some evidence from comparative studies that ferric carboxymaltose is more
effective and more cost-effective than iron sucrose, a commonly prescribed alternative iron
preparation 133 134.
Participants randomised to the intervention arm will receive 500mg of ferric carboxymaltose
(Ferrinject) as an IV infusion (figure 1). Ferric carboxymaltose is an iron-carbohydrate complex
licensed in Australia 135. It can be safely administered as a short IV infusion, without need for a
test dose, and provides controlled release of iron with a low risk of acute toxicity, infusion reaction
or immediate hypersensitivity. Previous large multicentre RCTs have used ferric carboxymaltose
in similar doses and reported efficacy with a low adverse event rate comparable to placebo 131 136.
Dosing schedule was 500mg ferric carboxymaltose prepared in 100ml sodium chloride 0.9%
infused over a total of 60 minutes. Given the lack of previous interventional studies in critically ill
patients, the choice of dose was based on the lowest dose associated with improved outcomes in
non-critically ill patients. Smaller, more frequent doses based on reassessment of iron saturation
may reduce the risk of oversaturation and may therefore also be more effective than single larger
doses.
Patients will be re-dosed with study medication if they remained in the ICU (or high dependency
unit that is under the supervision of an Intensivist) and are at least 4 days beyond their previous
dose, their Hb is less than 100g/L in the preceding 24 hours and they continue not to fulfill any of
the exclusion criteria. Initial study eligibility and re-dosing are dependent on excluding potential
iron overload (ferritin >1200ng/ml or transferrin saturations >50%). Previous RCTs demonstrating
the safety and efficacy of IV iron have used similar ferritin and transferrin saturation thresholds 136
137. Assessment for re-dosing will continue according these criteria until death, discharge from the
61
ICU or a maximum of 4 doses of study drug (total 2000mg IV iron or placebo) are administered,
whichever occurs first (figure 2).
Placebo
Participants randomised to the placebo arm will receive 100ml of sodium chloride 0.9% delivered
by an identical infusion pump over a total of 60 minutes, in addition to standard care. All aspects
of patient management other than the specific study-related procedures will be at the direction of
the treating clinician. Open-label oral or IV iron and open-label ESA will be discouraged and
considered a protocol violation in patients participating in the IRONMAN study. No formal RBC
transfusion will be specified as part of the study protocol. However, clinicians will be encouraged
to follow the critical care National Blood Authority transfusion guidelines including a restrictive
transfusion trigger 138.
Blinding
Study treatment will be blinded using an opaque sleeve covering the syringe and giving set
(figure 2). An un-blinded research nurse or pharmacist will draw up the study medication and the
bedside nurse will deliver the infusion. Outcome assessment and data collection will be
conducted by the blinded research coordinators at each study site. Analysis of the study results
will be conducted blinded by the primary investigator. The efficacy of blinding will be assessed
according to a sub-study questionnaire that asked the clinician responsible for the patient
whether they were aware of the study allocation.
Discontinuation of study treatment
Participants will be discontinued from receiving further study treatment on discharge from the ICU
or after the fourth dose of study treatment, whichever occurs first. Any participant that develops
sepsis (as defined by two or more SIRS criteria plus antibiotics started or changed by the treating
clinician for suspected or confirmed infection) will be discontinued from receiving further study
treatment for the duration of the period of sepsis. Participants that experience a suspected or
confirmed immediate hypersensitivity reaction temporarily related to delivery of the study
intervention will have delivery of the study treatment ceased immediately.
Sample Size
62
The assumption of a mean of 4 RBC transfusions in eligible patients remaining in the ICU >2
days was based on the findings of the observational study (Chapter 3), a standard deviation in
the intervention and control groups of 2 and a loss to follow up or incomplete data rate of 10%
(including those participants initially enrolled by the next of kin then declining to provide ongoing
participant consent), a study of 140 patients has 80% power to detect a decrease in mean
number of RBC transfusions of 1 unit at a significance level of 5%.
Statistical Analysis
All analyses will be conducted on an intention-to-treat basis without adjustment for baseline
variables. Differences in outcome variables will be compared using t-test and Chi-Squared test as
appropriate if normally distributed and using non-parametric equivalents if not normally
distributed. Analysis will be primarily conducted using STATA version 10.2 (College Station,
Texas 77845 USA). Data will be censored at 60 days post study enrolment for Hb, RBC
transfusion and vital status.
63
4.3 Data Management
All data will be collected by trained staff at each study site using a paper source document
developed by the management committee. Data will then be entered into a secured, password-
protected, web database (www.savant.net.au). Data queries will be automatically generated via
the electronic data collection database. Randomised patients will be followed up to death or
hospital discharge. A ‘day’ in ICU is defined as commencing at midnight. A list of study data is
provided in table 3.
Safety Monitoring
A drug safety and monitoring board (DSMB) will be convened comprising of three experienced
WA researchers including two Intensivists not associated with the study, along with a senior
Emergency Medicine clinician. Serious adverse events will be reported according to the Good
Clinical Practice Guidelines and the requirements of institutions in which the study will take place.
The DSMB will receive notification of all SAEs. No interim analysis is planned. However, the
DSMB reserves the right to request an interim analysis on the basis of un-blinded SAEs. In
keeping with the advice of Cook et al, events that are part of the natural history of the primary
disease process or expected complications of critical illness will not be reported as serious
adverse events unless thought to be causally related to the study intervention or otherwise
specified in the CRF 139.
Ethical Issues
The study will not proceed at any site until approval had been gained by the responsible Human
Research Ethics Committee (HREC). Prospective informed consent will be sought from eligible
patients wherever they retain capacity. However, the proportion of critically ill patients fulfilling
these characteristics is likely to be low and would not be representative of the patient population
most likely to benefit from the intervention under investigation. For eligible patients without
capacity to provide consent at the time of study eligibility, prospective informed consent will be
obtained prior to study enrolment from the designated next-of-kin. Consent for ongoing
participation will then be sought from participants who regained capacity as soon as practicable.
64
4.4 Conclusion
RBC transfusion is associated with increased morbidity and mortality in critically ill patients. RBCs
are also an increasingly costly and scarce resource. In the ICU, RBC transfusion occurs
predominantly for anaemia, and despite high compliance with recommended transfusion
thresholds, the incidence of RBC transfusion remains high. The aim of the IRONMAN
randomised controlled trial is to determine whether IV iron administered to anaemic patients
admitted to the ICU results in a decrease in mean RBC transfusion requirement.
65
4.5 Figures
Figure 1. Active Medication Kit
Figure 2. IRONMAN Trial Dosing Flow Chart
66
4.6 Tables
Table 1. Trial End Points Primary Outcome
Mean number of RBC units transfused from study enrolment to discharge from hospital
Secondary Outcomes
Proportion of participants who receive RBC transfusion from enrolment to ICU discharge
ICU and hospital mortality
Duration of admission to ICU and hospital
Organ-failure support-free days between enrolment and ICU discharge
Proportion of patients who develop nosocomial infection in ICU including all-
cause incident infection confirmed blood stream infection and incident
infection associated with new organ failure
Number of SAEs and proportion of patients who develop a SAE
Mean number of RBC units transfused and proportion of patients transfused from study enrolment to discharge
from hospital adjusted for baseline Hb, pre-enrolment transfusion, ferritin, transferrin saturation, hepcidin, soluble
transferrin receptors, renal replacement therapy
Subgroups
Mean number of RBC units transfused and proportion of patients transfused from study enrolment to discharge
from hospital in patients with baseline transferrin saturations <20%
Mean number of RBC units transfused and proportion of patients transfused from study enrolment to discharge
from hospital in patients with baseline ferritin <200ng/ml
Mean number of RBC units transfused and proportion of patients transfused from study enrolment to discharge
from hospital in patients receiving more than one dose of study drug
Mean Hb on discharge from ICU and hospital in patients not receiving RBC
transfusion in ICU after study enrolment
Duration from enrolment to time of first RBC transfusion in patients receiving at least one RBC unit after enrolment
67
Table 2. Trial Eligibility Criteria Inclusion Criteria
Admitted to an ICU for less than 48 hours
Anticipated to require ICU care beyond the next calendar day
Hb less than 100g/l at any time in the preceding 24 hours
Age 18 years or greater
Exclusion Criteria
Suspected or confirmed severe sepsis (two or more systemic inflammatory response syndrome criteria, suspected
or confirmed infection and one or more organ system failure)
Serum ferritin greater than 1200ng/ml or transferrin saturation greater than 50%
History of haemachromatosis or aceruloplasminaemia
Known prior administration of IV iron in the preceding 3 months
Jehovah’s Witness or other documented exclusion to receiving blood products
Receiving ESA (e.g. epoetin or darbepoeitin) in the preceding 3 months
Known hypersensitivity to IV iron
Pregnancy
Treatment intent is palliative
Death is imminent and inevitable
Weight less than 40kg
Participating in a competing study
68
Table 3. Data to be collected in the IRONMAN trial Baseline
Age and gender
Date of Hospital and ICU Admission
Number of RBC units transfused between arrival in hospital and ICU admission
First Hb and MCV on arrival to hospital
Episode of bleeding prior to ICU admission
Source of ICU admission
APACHE II score and diagnostic code on ICU admission
SOFA score and components on ICU admission
Hb closest to but prior to enrolment in study
Organ support on enrolment in study: mechanical ventilation, vasopressors, renal replacement therapy
Iron studies: serum iron, transferrin, transferrin saturation, ferritin, soluble transferrin receptors
Hepcidin and C-reactive protein
Daily
SOFA score and components
Hb
Hepcidin and C-reactive protein
Number of RBC units for which transfusion commenced during calendar day
Indication for transfusion
Organ support during calendar day: mechanical ventilation, vasopressors, renal replacement therapy
New infection
Organ failure associated with infection
New episode of bacteraemia
Redosing of study drug
Iron studies on days eligible for redosing: serum iron, transferrin, transferrin saturation, ferritin
Adverse events including anaphylaxis
Discharge
Date of discharge from ICU and hospital
Readmission to ICU
Survival status at ICU and hospital discharge
Number of RBCs transfused after ICU discharge
Received non-study-drug related iron
Hb on hospital discharge
Discharge destination
69
Chapter 5
Intravenous Iron or Placebo for Anaemia in Intensive Care: The
IRONMAN Multicentre Randomized Blinded Trial
70
5.1 Introduction
Anaemia is extremely common in patients admitted to the ICU and is the most common indication
for allogeneic RBC transfusion even when adherence with transfusion guidelines is high1 2. Both
anaemia and RBC transfusion may be harmful to critically ill patients. Anaemia is an independent
risk factor for mortality and major morbidity in patients undergoing major surgery and in general
ICU patients; RBC transfusion is associated with mortality, nosocomial infection, multi-organ
dysfunction syndrome and the acute respiratory distress syndrome (ARDS) in patients treated in
an ICU3 129 140 141.
Progressive anaemia and subsequent RBC transfusion are predictable at the time of ICU
admission142. In selected patients, novel interventions implemented shortly after ICU admission
could reduce the incidence and severity of anaemia, the need for RBC transfusion, and therefore
the burden of associated morbidity and mortality. Intravenous (IV) iron decreases both the
severity of anaemia and incidence of RBC transfusion in non-critically ill patients 116. However,
there is a theoretical risk of causing or worsening infection and older preparations are associated
with anaphylactic reactions 24 116 143. High quality safety and efficacy data for IV iron in the critical
care setting are lacking.
The multicentre Intravenous Iron or Placebo for Anaemia in Intensive Care (IRONMAN) RCT was
designed to test the hypothesis that, in critically ill patients admitted to the ICU who are anaemic,
early administration of IV ferric carboxymaltose, compared with placebo, reduces the mean
number of RBC units transfused between randomisation and hospital discharge.
71
5.2 Methods
Study Design and Oversight
Between 20 June 2013 and 6 June 2015, a randomized, placebo-controlled, blinded trial was
conducted in four ICUs in Perth, Western Australia. The study protocol was registered
prospectively on the Australian New Zealand Clinical Trials Registry
(ANZCTRN12612001249842), was approved by the ethics committee at each participating site,
and has been published previously126. Prospective consent was obtained from all participants or
their legal surrogates. The trial was overseen by an independent Data Safety Monitoring
Committee. Study drug was supplied by Vifor Pharma© which had no other role in the design or
conduct of the study or analysis and reporting of the results.
Study Population
Patients were eligible to participate if they were 18 years of age or older, within 48 hours of
admission to ICU, anticipated to require ICU care beyond the next calendar day and had a
haemoglobin (Hb) less than 100 g/L at any time in the preceding 24 hours. Exclusion criteria
included suspected or confirmed severe sepsis, a ferritin greater than 1200 ng/ml or transferrin
saturation greater than 50%. A complete list of the exclusion criteria are provided in the
supplementary appendix.
Randomization and blinding
Eligible patients were randomly assigned in a 1:1 ratio to receive either IV iron or placebo. The
randomization sequence was generated by an online resource was stratified according to study
centre144. Allocation concealment was maintained by using permuted block randomisation and
sealed, opaque, consecutively numbered envelopes at each study site that had been generated
centrally by staff unrelated to the study or ICU. Randomisation was to a study number. Study
medication was then prepared by a clinical nurse or pharmacist not involved in the care of the
patient. An opaque sleeve covering the study drug infusion syringe and giving set was used to
maintain blinding of the participants, treating, site researchers and data collectors 126. The
adequacy of blinding was assessed by conducting a blinding sub-study measuring inter-rater
72
agreement between the study intervention actually delivered and the opinion of the intervention
arm according to the attending clinician using Cohen’s Kappa.
Study Treatments
Patients randomized to the IV iron group received 500mg of ferric carboxymaltose in 100 ml of
0.9% saline delivered in two consecutive 50ml syringes. Details of the study treatment including a
photo of the blinding set up have been published previously126. Patients in the placebo group
received 100ml of 0.9% saline alone. Four days after receiving the initial or subsequent dose of
study drug, patients remaining in the ICU were assessed for repeat dosing. Participants were
eligible for re-dosing if they continued to fulfill the study eligibility criteria, including repeated
ferritin and transferrin saturation parameters and an Hb<100g/L. Assessment for suitability for re-
dosing continued until the patient was discharged from the ICU, received four doses of study drug
or died, whichever occurred first.
The IV iron formulation was chosen on the basis of data supporting superiority of ferric
carboxymaltose at fixed dose compared with an alternate IV iron formulation and low reported
side effect profile 131 135. The ferritin and transferrin saturation (TSAT) cutoffs were chosen on the
basis of the higher end of the effective reported range (ferritin <1200mn/ml) and lack of
interaction between TSAT and IV iron on RBC transfusion 116 137.
All aspects of patient management, including decision for RBC transfusion and ICU discharge,
were administered according to local practice and at the direction of the treating ICU clinician.
There were no RBC transfusion policies in any of the participating centres. Open-label IV iron and
erythropoiesis-stimulating agents were strongly discouraged and use of these agents were a
protocol violation.
Study Outcomes
The primary study outcome was number of RBC units transfused per patient between
randomisation and hospital discharge reported according to an intention-to-treat analysis.
Secondary outcomes included Hb at hospital discharge, proportion of patients receiving RBC
transfusion, ICU and hospital length of stay and mortality and infection. Infection was defined as
the commencement, escalation or change of IV antibiotics for a confirmed or strongly suspected
73
infection and was adjudicated locally by blinded clinical staff. Clinically confirmed deep vein
thrombosis (DVT) and pulmonary embolism (PE) were explicitly collected as SAEs. Bleeding
definitions are provided in the supplementary appendix. Admission diagnoses were based on
acute physiology and chronic health evaluation (APACHE) II diagnostic codes. Events were
deemed to be part of the natural history of the primary disease process or expected
complications of critical illness were not reported as SAEs unless thought to be causally related
to the study intervention.
Statistical Analysis
All analyses were conducted on an intention-to-treat basis. No imputation was made for missing
data. Continuous variables were reported as mean (±SD) or median and interquartile range
(IQR), with between group differences analysed using Student’s t-test or the Wilcoxon rank-sum
test for apparently normal and non-normally distributed data respectively. Categorical variables
were reported as proportion and analysed using the Chi2 test or Fischer exact test as appropriate.
Data was censored at 60 days after enrolment for Hb level, RBC transfusion and vital status. A
two-sided P value of 0.05 or less was considered to be statistically significant. All analyses were
conducted with Stata Version 14 StataCorp College Station, TX77845, USA. No interim analyses
were planned or conducted.
Although the analyses were conducted according to a previously reported statistical analysis
plan126, the number of RBC units was not normally distributed and, in conjunction with advice
from an independent statistician (Centre for Applied Statistics, University of Western Australia),
the primary outcome has been reported as median and IQR instead of the prespecified mean and
standard deviation (SD). The data has then been analysed using negative binomial regression
with incidence-rate ratios reported. This analysis satisfied the assumptions as count data with
over-dispersion (variance greater than the mean). The sample size of 140 participants was based
on a baseline mean of four RBC transfusions in eligible patients, determined from an
observational study conducted in one of the participating study sites, with a SD in the intervention
and control groups of two and a loss to follow-up of 10%142. This provided 80% power to detect a
decrease in the mean number of RBC transfusions of 1 unit at a significance level of 5%.
74
Additional sensitivity analyses of the primary outcome variable adjusted for predefined covariates
(enrollment Hb, RBC transfusion prior to enrollment, transferrin saturation, ferritin, soluble
transferrin receptor and renal replacement therapy) were performed using negative binomial
regression for count data. The effect of IV iron on incidence-rate ratio of RBC transfusion was
performed for predefined subgroups including transferrin saturation (<20% or ≥20%) and ferritin
(<200ng/ml or ≥200ng/ml).
75
5.3 Results
The study enrolled 140 patients, with 70 assigned to IV iron and 70 to placebo. All participants
received the intervention to which they were randomly allocated and all patients were followed up
to discharge from index hospitalisation. One patient declined consent to ongoing participation at
time of ICU discharge but consented to data use. Repeat dosing of study drug occurred in 17
patients in the IV iron group (15 patients received two doses, three patients received three doses)
and 26 patients in the placebo group (23 patients received two doses, three patients received
three doses). Seven participants in the IV iron group and three participants in the placebo group
received non-study-drug IV iron either in ICU (n=1) or post-ICU discharge (n=9). There was no
missing data for the primary or prespecified secondary outcomes (figure 1). Demographic and
clinical characteristics at baseline were similar between the groups (table 1), and there was no
significant association between perceived and actual study group allocation (McNemar’s test chi2
2.37, p=0.12).
Primary Outcome
The IV iron group was transfused 97 RBC units versus 136 RBC units in the placebo group. The
number of RBC units transfused in the ICU was 79 (81%) and 121 (89%) for the IV iron and
placebo groups respectively. The median (IQR) RBC transfusion in the IV iron and placebo
groups [1 unit (0-2) vs. 1 unit (0-3) P=0.53], incidence rate ratio (IRR) [0.71 (95% confidence
interval (CI) 0.43-1.18) P=0.19]. (table 2). There was no significant between-group difference in
RBC transfusion with the use of multivariable binomial regression adjusting for predefined
baseline covariates (P=0.77), or according to a per protocol analysis (P=0.15). Between-group
RBC transfusion was also similar in the predefined subgroups (Table 3). RBC transfusion (figure
3) and median Hb (figure 4) by day whilst in ICU are provided in the supplementary appendix.
Secondary Outcomes
Overall, the median Hb at hospital discharge was significantly higher in the IV iron group
compared with the placebo group (107 g/L (IQR 97-115) vs. 100 g/L (IQR 89-111), P=0.02). The
histograms for the Hb on hospital discharge for the two groups are provided in the supplementary
appendix (figure 2). In a post-hoc analysis, the proportion of patients discharged from hospital
76
with an Hb<100g/L was significantly lower in the IV iron compared with placebo groups (21/70
(30%) vs. 33/70 (47%), p=0.04). The IV iron and placebo groups had similar median lengths of
stay in ICU and hospital, and no significant differences in ICU and hospital mortality were
observed (table 2).
Safety
There was no statistical difference between the iron and placebo groups in infection, infection
associated with organ failure, or bacteraemia. The number of serious adverse events (SAEs) did
not differ significantly between groups. There were no immediate study-drug-related adverse
events in the IV iron group and one in the placebo group where shivering post study drug
administration was thought to be possibly related to study drug (table 4).
77
5.4 Discussion
In this multicentre randomized trial of patients admitted to the ICU who were anaemic, it was
found that IV iron, compared with placebo, did not result in a significant difference in number of
RBC units transfused. IV iron did however result in a significantly higher Hb concentration at
hospital discharge. Safety outcomes, specifically mortality, infection, clinically diagnosed venous
thrombosis and immediate infusion-related adverse events were not significantly different in those
receiving IV iron compared with placebo.
Outside of the critical care setting, trials enrolling patients with similar baseline Hb and
haematinics have shown a significant decrease in RBC transfusion associated with IV iron
therapy 116. Although the point estimate for the primary outcome in our study favored IV iron, the
difference was not significant. One possible reason is that IV iron is simply ineffective in patients
admitted to the ICU due to the modulating effects of severe inflammation on the erythropoietic
response to IV iron119 145. Given that the point estimate of the primary outcome favors IV iron with
a clinically meaningful decrease in incidence rate ratio of 0.71, and the statistically significant
increase in Hb at hospital discharge associated with IV iron, this would appear unlikely. Perhaps
more likely is the effect of the mean number of RBC units transfused being substantially lower
(1.9 units in the placebo group) than anticipated. The IRONMAN study was powered to detect a
one unit reduction from a baseline of four units transfused; the observed reduction was 0.5 units.
The study was underpowered to detect such a difference leading to the possibility of a type II
error (see supplementary appendix for a power calculation for a future trial of IV iron).
Whilst our study attempted to identify a cohort of patients at high risk of progressive anaemia and
subsequent RBC transfusion, characteristics associated with an erythropoiesis response to IV
iron in the critical care setting are poorly understood and require further consideration. For
example, the relative efficacy of IV iron in patients with anaemia at least partly due to absolute
iron deficiency, compared with anaemia of inflammation alone, remains uncertain, and
measurement of hepcidin may be of value 119. Future trials of IV iron in critical illness should
consider adopting a lower Hb threshold for enrolment, only enrolling patients with a longer
predicted length of stay, and targeting the intervention at those most likely to mount an
78
erythropoeitic response. This would have the simultaneous effect of identifying a population at
higher risk of RBC transfusion and prolonged ICU stay and greater risk of adverse outcomes.
Pieracci et al conducted an RCT of IV iron sucrose in trauma patients admitted to the ICU and
found no difference in Hb concentration125. In contrast, the IRONMAN study found that IV iron
resulted in a statistically significant increase in Hb at hospital discharge and a greater proportion
of patients discharged with an Hb>100g/l, although the clinical significance of these findings is
uncertain.
Compared with Pieracci et al, our study used a higher dose of iron, and an alternative preparation
previously shown to be associated with greater erythropoietic response 131. The IRONMAN study
also enrolled patients at higher risk of RBC transfusion (Hb threshold for enrollment 100 g/l vs.
120 g/l) and included a broader range of critically ill patients, potentially at greater risk of
preexisting iron deficiency.
It is plausible that a higher Hb during recovery from critical illness may be of clinical benefit,
including more rapid functional recovery and decreased LOS. Although the IRONMAN study did
not find a significant decrease in hospital LOS associated with IV iron, the median duration from
initiation of IV iron to hospital discharge was 11 days, whereas maximal therapeutic effect may
not occur for three to four weeks. Whether the observed difference was greater post-discharge,
and the clinical benefits of a higher Hb in a cohort of patients with a longer estimated LOS require
further consideration.
Bateman et al found that moderately severe anaemia at the time of ICU discharge was
associated with a markedly reduced health-related quality of life score at three and six months
compared with a non-selected ICU cohort, and that over half remained anaemic at six months10.
Postoperative rehabilitation studies suggest that anaemia is associated with fatigue, reduced
exercise capacity, muscle strength and performance in activities of daily living and may impair
recovery 146. Furthermore, Froessler et al, found that IV iron prior to major abdominal surgery
was associated with a significant decrease in hospital length of stay and a significant increase in
Hb at four weeks, suggesting a role for IV iron in enhancing recovery147.
79
The IRONMAN study found no association between IV iron and infection. New infection was
defined in terms of the commencement, escalation or change of antibiotics. This definition was
pragmatic, reflective of clinical practice, and assessed by blinded clinicians. Future studies may
consider blinded adjudication by independent experts and powering the study to exclude a
clinically important difference in infection.
The formulation and dosing of IV iron in the IRONMAN study resulted in no immediate adverse
events. Given the lack of data in for IV iron use in ICU, a cautious dosing approach was chosen
and it is plausible that in future studies, a higher, weight-based dosing and/or continued dosing
after ICU discharge, may result in a greater response to IV iron. The comparative efficacy of other
IV iron preparations in this context remains uncertain.
Strengths
The IRONMAN study has a number of strengths including a pragmatic design, effective blinding,
administration of the study drug to all participants according to the assigned study group,
complete follow up to discharge from index hospitalisation and the use of a restrictive RBC
transfusion approach
Limitations
The data distribution for the primary outcome required a change to the planned statistical
analysis, adding to the possibility of a type II error. Baseline transfusion was lower than planned,
reducing the power of our study to detect a difference in RBC units. A small proportion of patients
received non-study IV iron; however, the number were not significantly different between groups
and did not change the findings when the groups were analysed per protocol. The significant
increase in Hb at discharge was a secondary outcome and there is a risk that this is a chance
finding due to multiple testing. However, the point estimate for RBC transfusion also favors IV
iron, so a false positive result is considered less likely. Fewer patients required transfusion for
major haemorrhage in the IV iron compared with placebo groups, although the difference was not
statistically significant. Although a differential effect of mortality or hospital LOS may affect
interpretation of the primary end-point, neither were significantly different between groups and so
this is considered unlikely. Finally, threshold for RBC transfusion was at the discretion of the
80
treating clinician and not specified as part of the study. Treating clinicians were however blinded
to the study allocation and median Hb prior to transfusion was within published guidelines and not
significantly different between groups138.
81
5.5 Conclusion
In patients admitted to the ICU who were anaemic, IV iron compared with placebo, did not result
in a significant difference in RBC transfusion at hospital discharge. Patients who received IV iron
had a significantly higher Hb at hospital discharge.
82
5.6 Figures
Figure 1. Participant Flow
83
5.7 Tables Table 1 Baseline Characteristics Characteristic*
IV Iron (n=70)
Placebo (n=70)
Age – years
58.5 (18.8) 56.0 (21.1)
Male gender – no. (%)
44 (63) 52 (74)
APACHE II score
12.2 (5.7) 13.8 (6.1)
SOFA score
6.1 (2.5) 6.6 (3.3)
ICU admission source – no (%) Emergency department Hospital ward Operating theater Other hospital
14 (20) 5 (7) 50 (71) 1 (1)
13 (19) 4 (6) 50 (71) 3 (4)
ICU admission type – no (%) Surgical Medical
61 (87) 9 (13)
60 (86) 10(14)
ICU admission subtype – no (%) Surgical subgroups - General surgical - Cardiothoracic - Trauma Neurosurgical Medical subgroups - Congestive cardiac failure - Cardiac ischaemia - Cardiogenic shock - Pulmonary embolism - Gastrointestinal bleeding - Acute kidney injury - Metabolic - Neurological (undefined) - Overdose - COAD - Respiratory (undefined)
9 (13) 30 (43) 20 (29) 2 (3) 2 (3) 1 (1) 0 (0) 2 (3) 2 (3) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0)
13 (19) 19 (27) 25 (36) 3 (4) 3 (4) 1 (1) 1 (1) 0 (0) 0 (0) 1 (1) 0 (0) 1 (1) 1 (1) 1 (1) 1 (1)
Mechanical ventilation – no. (%)
45 (64) 48 (69)
Vasoactive infusion – no. (%)
51 (73) 48 (69)
Renal replacement therapy – no. (%)
3 (4) 5 (7)
Haemoglobin – median g/l (IQR)
89 (81-94) 87 (79-95)
Ferritin –ng/ml+
317 (218) 365 (436)
Transferrin saturation - %
13 (10) 14 (12)
C reactive protein – mg/l 111 (83)
122 (85)
RBC transfusion – median units (IQR)
0.5 (0-4) 1.5 (0-4)
RBC transfusion prior to randomisation –no (%)
13 (19) 18 (26)
Time from ICU admission to initiation of study – hours
28 (13) 31 (13)
*Mean and standard deviation (SD) unless otherwise reported. +ng/ml has a conversion factor of 1 to the standard international units mcg/ml
84
Table 2. Study Outcomes Variable* IV Iron
(n=70)
Placebo (n=70)
P Value Risk ratio^
or median difference$ for IV iron compared with placebo (95% CI)
Primary outcome – total RBC units/participants
97/70 136/70
RBC units 1 (0-2) 1 (0-3) 0.53
0.71^ (0.43-1.18)
Received RBC transfusion – participants transfused/total participants (%)
38/70 (54)
39/70 (56) 0.87 0.97^ (0.72-1.31)
RBC units per transfused patient
2 (1-3) 2 (1-5) 0.25 0.73^ (0.50-1.06)
RBC units transfused in ICU – RBC units ICU/ total RBC units (%)
79/97 (81) 121/136 (89) 0.10
Indication for RBC transfusion in ICU – no participants (% total participants transfused in ICU) Major bleeding Minor bleeding Anaemia Low cardiac output Other
1 (3) 7 (21) 28 (85) 2 (6) 0 (0)
3 (8) 8 (21) 31 (82) 3 (8) 1 (3)
0.62 0.79 0.61 1.0 1.0
0.33^ (0.04-3.13) 0.88^ (0.34-2.28) 0.90^ (0.61-1.33) 0.67^ (0.11-3.87)
Hb prior to transfusion g/L
76 (71-81) 75 (69-84) 0.74 1$ (-3.13-5.13)
Hb at hospital discharge g/L
107 (97-115) 100 (89-111) 0.02 7$ (1.89-12.11)
Duration from study drug to first RBC transfusion – days
2 (1-3) 1 (1-2) 0.22 1$ (0.29-1.71)
Duration from study drug to determination of Hb at hospital discharge – days
11 (7-24) 15 (8-24) 0.51 -4$ (-8.98-1.98)
ICU mortality – no/total (%)
5/70 (7) 3/70 (4)
0.47 1.67^ (0.41-6.71)
Hospital mortality – no/total (%)
7/70 (10)
6/70 (9)
0.77 1.17^ (0.41-3.30)
Duration of stay ICU - days Hospital - days
6 (5-9) 15 (11-28)
6 (5-9) 18 (11-25)
0.70 0.75
0$ (-1.07-1.07) -3$ (-7.95-1.95)
ICU organ failure support-free days
2 (1-3) 2 (1-3) 0.89 0$ (-0.68-0.68)
*Median and interquartile range (IQR) unless otherwise reported.
85
Table 3. Subgroup Analysis – Effect of IV Iron on Incidence-Rate Ratio for RBC Transfusion* Incidence-rate ratio
(95% Confidence interval)
P value P value for interaction
Transferrin saturation≤20% Yes (n=113) 0.73 (0.42-1.29)
0.29 0.92
No (n=27)
0.78 (0.31-1.94) 0.60
Ferritin≤200ng/ml Yes (n=54)
0.65 (0.25-1.70) 0.38 0.75
No (n=86)
0.77 (0.43-1.36) 0.36
*Negative binomial univariate regression. An incidence-rate ratio of less than one favors intravenous iron. Table 4. Safety Variable* IV Iron
(n=70)
Placebo (n=70)
P Value Relative risk (95% CI)
Nosocomial infection – no. (%)
20 (28.6) 16 (22.9) 0.44 1.25 (0.71-2.21)
Nosocomial infection associated with organ failure – no. (%)
2 (2.9) 0 (0) 0.50
Bacteraemia – no. (%)
2 (2.9) 1 (1.4) 1.0 2.0 (0.19-21.56)
Immediate study-drug related AEs – no. (%)
0 (0) 1 (1.4) 1.0
SAEs – no. (%)
4 (6) DVT=2 PE=2
4 (6) DVT=1 PE=3
1.0 1.0 (0.26-3.84)
*Mean and standard deviation (SD) unless otherwise reported.
86
5.8 Supplementary data Additional IRONMAN RCT investigators Dr Andy Chapman, Ms Janet Ferrier, Dr Stuart Baker, Prof Wendy Erber, A/Prof Craig French, Dr David Hawkins, Ms Alisa Higgins, Dr Axel Hoffmann, Dr Bart De Keulenaer, Mr Shannon Farmer, Dr Julie McMorrow, Prof John Olynyk, Ms Anne-Marie Palermo, Mr Toby Richards, Ms Brigit Roberts, Dr Simon Towler, Prof Steve Webb Trial Eligibility Criteria
Inclusion criteria
1. Admitted to an ICU for less than 48 hours
2. Anticipated to require ICU care beyond the next calendar day
3. Hb less than 100 g/L at any time during the preceding 24 hours
4. Age 18 years or greater
Exclusion criteria
1. Suspected or confirmed severe sepsis (two or more Systemic Inflammatory Response
Syndrome (SIRS) criteria, suspected or confirmed infection, and one or more organ system
failure)
2. Serum ferritin greater than 1200ng/ml or transferrin saturation greater than 50%
3. History of haemochromatosis or aceruloplasminaemia
4. Known prior administration of IV iron in the preceding 3 months
5. Jehovah’s Witness or other documented exclusion to receiving blood products
6. Receiving ESA (e.g. epoietin or darbepoeitin) in the 3 months prior to ICU admission
7. Known hypersensitivity to intravenous iron
8. Pregnancy
9. Treatment intent is palliative
10. Death is deemed imminent and inevitable
11. Weight less than 40kg
12. Participating in competing study
Minor and Major Bleeding Definitions
Minor bleeding = overt or suspected bleeding or bleeding apparent on imaging studies without
haemodynamic compromise (SBP<90mmHg) and not requiring transfusion or fluid resuscitation,
specific diagnostic tests or interventions or initiation or escalation in vasopressor requirement
Major bleeding = overt or suspected bleeding or bleeding apparent on imaging studies with
haemodynamic compromise (SBP<90mmhg) or requiring transfusion or fluid resuscitation,
specific diagnostic tests or interventions or initiation or escalation in vasopressor requirement
87
Power calculation for a future trial of IV iron
On the basis of the results of this study (baseline mean RBC transfusion of 1.9 units, standard
deviation 3, mean difference 0.5 RBC units), a future trial of 567 participants per group would
have 80% power to detect a change in RBC units transfused of 0.5 (alpha=0.05). The sample
size calculation would then have to be inflated to account for non-normal distribution (20%),
potential decrease in baseline RBC use over time (5%) and loss to follow up (10%). This would
give a final trial sample size of approximately 1572 participants.
Figure 2 Histogram of Hb at Hospital Discharge for IV Iron and Placebo Groups
88
Figure 3. Total RBC units by Study Day for Patients Remaining in ICU
Figure 4. Median Hb by Study Day for Patients Remaining in ICU
89
Chapter 6
Utility of Hepcidin in Predicting Risk of Red Blood Cell Transfusion
and Response to IV Iron Therapy in Patients Admitted to the
Intensive Care Unit: A Nested Cohort Study
90
6.1 Introduction
RBC transfusion occurs in approximately one third of patients admitted to the ICU, and is
associated with increased morbidity and mortality 148. IV iron reduces RBC transfusion
requirement in the acute care setting and has recently been shown to increase haemoglobin in
patients admitted to the ICU 116 149.
Anaemia is the most common indication for RBC transfusion in critically patients. However, acute
inflammation makes diagnosis of iron deficiency unreliable. In contrast, hepcidin may be down-
regulated by iron insufficiency even in the presence of inflammation. Whether hepcidin
concentration can predict risk of RBC transfusion and response to IV iron therapy in critically ill
patients, in whom iron-restricted erythropoiesis and inflammation frequently coexist, remains
uncertain 150.
The primary aim of this nested cohort study, was to assess the association between hepcidin
concentration in patients within 48 hours of ICU admission and subsequent RBC transfusion
requirement during the index hospitalisation, and to determine whether hepcidin concentration
could be used to identify a group of patients in whom IV iron therapy compared to placebo, would
decrease RBC transfusion 149.
91
6.2 Methods
The study received Human Research Ethics Committee approval at all sites prior to
commencement and prospective consent was obtained from all participants or their legal
surrogates. The protocol and primary results of the IRONMAN RCT have been presented in
Chapters 4 and 5 126 149. Briefly, the IRONMAN RCT enrolled adult patients in four centres in
Perth, Western Australia between 20 June 2013 and 6 June 2015 who were within 48 hours of
admission to ICU, had a haemoglobin (Hb) of less than 100 g/L, and were anticipated to require
ICU care beyond the next calendar day. Exclusion criteria included suspected or confirmed
severe sepsis, a ferritin greater than 1200 ng/ml or transferrin saturation greater than 50%.
Participants were randomised in a 1:1 ratio to receive either 500mg IV ferric carboxymaltose or
placebo and were followed up to hospital discharge.
Baseline blood was collected at the time of enrolment, prior to study drug administration.
Hepcidin-25 was isolated from for quantitation by liquid chromatography-quadrupole time-of-flight
mass spectrometry (LC-qTOF-MS), using a Waters Synapt G2S (Waters, Manchester, UK) as
previously described 151 152. Briefly, the hepcidin was isolated by solid phase extraction (SPE)
following the initial addition of a synthetic human hepcidin (13C18,15N3) peptide internal standard
(Peptides International, Kentucky, USA), and removal of the more abundant polypeptides by
organic solvent precipitation and centrifugation. The accurate mass measurement of the
precursor hepcidin-25 [M+5H]5+ ion was confirmed against a hepcidin-25 standard (Peptides
International, Kentucky, USA); and further by MS/MS. Quantitation was by reference to a human
hepcidin-25(13C18,15N3) calibration, prepared in human serum.
Statistical Analysis
Continuous variables were reported as mean (±SD) or median and interquartile range (IQR), with
between group differences analysed using Student’s t-test or the Wilcoxon rank-sum test for
apparently normal and non-normally distributed data respectively. Categorical variables were
reported as proportion and analysed using the Chi2 test or Fischer exact test as appropriate. Data
was censored at 60 days after enrolment for RBC transfusion Hb concentration and vital status.
92
The relationship between hepcidin concentration, and other baseline risk factors, and subsequent
RBC transfusion quantity was assessed using negative binomial univariate and multivariate
analyses. Variables with a P value of <0.3 on univariate analysis were included in a multivariable
analysis with stepwise removal of variables with a P value >0.05. Interaction was assessed using
multivariable fractional polynomials to account for potential non-linear relationships. Significant
interactions (P value of <0.05) were examined graphically and a final model then produced. The
relative prognostic value with and without baseline hepcidin concentration included was assessed
using Akaike information criterion (AIC).
The methodology used in this study to examine the predictive value of hepcidin concentration
was similar to that used in a previously published RCT of IV iron in patients with chemotherapy-
induced anaemia 153. After first stratifying patients by tertile of baseline hepcidin concentration,
the incident risk ratio for RBC transfusion (as the primary outcome measure of response to IV
iron) was compared between those who were randomised to receive IV iron versus those who
received placebo. The relationship between IV iron therapy and RBC transfusion quantity across
the range of hepcidin values was further explored by locally-weighted scatterplot smoothing
(LOWESS) 154.
Data was censored at 60 days after enrolment for Hb level, RBC transfusion and vital status. A
two-sided P value of 0.05 or less was considered to be statistically significant. In order to assess
whether the association between hepcidin and RBC transfusion varied according to baseline Hb
and/or use of IV iron, interaction terms were added to the multivariate analysis. The performance
of the model with and without hepcidin as a predictor was compared using Akaike information
criterion. Assessment of the predictors of Hb at hospital discharge were determined in a similar
way, using linear regression. All analyses were conducted with Stata Version 14 StataCorp
College Station, TX77845, USA.
93
6.3 Results
Baseline hepcidin levels were available for 133 (95%) out of the 140 participants enrolled in the
IRONMAN RCT. The flow of participants is presented in figure 1. The mean time from ICU
admission to collection was 29 hours [Standard Deviation (SD) 13] and median hepcidin value
was 34.9 µg/L [interquartile range (IQR) 17.3-69.2, range 0-163.5]. The baseline characteristics
of the population are provided in table 1. There was no significant correlation between hepcidin
concentration and other baseline values including C reactive protein and standard iron indices
(Hb -0.09, P=0.308. Ferritin 0.13, P=128. Transferrin saturation -0.15, P=0.09. Soluble transferrin
receptor -0.15, P=0.10. C reactive protein -0.09, P= 0.308).
Prediction of RBC transfusion quantity
The complete list of variables assessed on univariate analysis and those added to the initial
multivariable model are provided in table 3. ICU admission related to trauma, baseline Hb,
transferrin saturation and hepcidin concentration were found to be significant independent
predictors of risk of RBC transfusion and retained in the final multivariable model. There was a
significant interaction between Hb and hepcidin concentrations in predicting the risk of RBC
transfusion (likelihood ratio test for significance of interaction p=0.0462), see figure 2. For
patients with a Hb ≥80g/L, increasing each 10 µg/ml increase in hepcidin concentration was
associated with a risk ratio of RBC transfusion of 1.09 (95%CI 1.01-1.18, P=0.034). However, for
patients with a Hb <80g/L there was no significant association between hepcidin concentration
and risk of RBC transfusion [IRR 0.95 (95%CI 0.84-1.07), p=0.387]. The variables included in the
final model are provided in table 4. Akaike information criterion (AIC) with hepcidin in the model
was 415.14 versus 468.16 with hepcidin removed.
Hepcidin and prediction of response to IV iron
The association between IV iron therapy and both RBC transfusion and Hb at hospital discharge
by tertile of hepcidin concentration are provided in table 2. For the 88 patients in the lower two
tertiles of hepcidin values, there was a significant decrease in risk of RBC transfusion associated
with IV iron therapy (38 RBC units, n=44) compared with placebo (79 RBC units, n=44), (incident
rate ratio [IRR 0.475 (95%CI 0.26-0.85), p=0.013]. However, no significant association was
94
found between IV iron therapy and risk of transfusion for the 45 patients in the highest tertile of
hepcidin value [IRR 1.33 (95%CI 0.57-3.08), p=0.518]. The LOWESS plot describing the
association between hepcidin concentration and RBC transfusion quantity in patients who
received IV iron compared with placebo is provided in figure 3.
IV iron therapy compared with placebo was not associated with a significant increase in Hb for
those in the lower two tertiles of hepcidin values [mean increase Hb 3g/L (95%CI -3-10),
p=0.361]. However, IV iron therapy was associated with a significant increase in Hb at hospital
discharge for patients in the highest tertile of hepcidin value [mean increase Hb 9 g/L (95%CI 2-
14), p=0.01]. There was no significant difference in iron, transferrin saturation, ferritin or
transferrin receptor levels associated with lower versus higher hepcidin tertile (table 5).
95
6.4 Discussion
In this study, elevated hepcidin levels, measured within 48 hours of ICU admission in critically ill
patients who were also anaemic, was an independent predictor of subsequent RBC transfusion
prior to hospital discharge. This effect was modified by Hb levels, and strongest above a cut-off
Hb of 80g/L, likely due to the high risk of RBC transfusion below this level. Importantly, IV iron
therapy compared to placebo was associated with a significant decrease in RBC transfusion
requirement when excluding patients in the upper tertile of hepcidin levels.
Lasocki et al found that hepcidin levels may be suppressed in critically ill patients with anaemia,
even in the setting of inflammation 150. Steesma et al conducted a secondary analysis of a RCT
and found that hepcidin levels predicted response to IV iron therapy in patients with
chemotherapy-induced anaemia also receiving an erythroid-stimulating agent (ESA) 153. These
results, together with our findings in which no ESA therapy was used, suggest that in the
presence of inflammation, measurement of hepcidin is useful in identifying patients in whom IV
iron therapy is likely to reduce RBC transfusion requirement.
Hepcidin levels have been shown to be the predominant predictor of erythrocyte iron
incorporation in African children with anaemia 155. Amongst adult patients admitted to the ICU,
Tacke et al have demonstrated an association between markers of increased iron availability and
mortality, predominantly amongst patients with sepsis 156. It is plausible that targeting IV iron
therapy to critically ill patients with lower hepcidin concentration, has the benefit not only of
significantly reducing RBC transfusion requirement, but may also reduce any potential risk of
initiating or exacerbating infection related to free iron.
Hepcidin synthesis is finely regulated including induction by both inflammation and iron overload
119. In our study, the median CRP concentration was 110 mg/L in patients in the lower two tertiles
of hepcidin concentration and there was no significant difference in iron indices between levels of
hepcidin. These results suggest that IV iron may be effective in reducing RBC transfusion
requirement even in the setting of substantial inflammation in the majority of patients admitted to
the ICU with an Hb of <100g/L and in whom sepsis has been excluded. The role of hepcidin
antagonists in patients with elevated hepcidin levels requires further consideration157.
96
In order for future studies to examine the utility of hepcidin for critically ill patients admitted to the
ICU, several obstacles must be overcome. First, substantial variation currently exists in hepcidin
assays and reference ranges, making comparison between studies difficult 157. Second, point of
care testing is necessary, to allow access to test results in a clinically useful timeframe. Finally, a
greater understanding is required in the changes in hepcidin levels over time and interaction with
key interventions including RBC transfusion and response to IV iron therapy.
Limitations
This study included only patients with an Hb<100g/L and did not include patients with sepsis at
the time of enrolment. The utility of hepcidin in these groups remains uncertain. Although soluble
transferrin receptor levels were assessed and found not to be predictive of RBC transfusion
requirement, other assay with potential diagnostic benefit including zinc protophoryn were not.
However, given the central role of hepcidin in iron metabolism, it is unlikely that other assays
provide superior diagnostic utility.
97
6.5 Conclusion
In critically ill patients with anaemia admitted to an ICU baseline hepcidin concentration predicts
RBC transfusion requirement and is able to identify a group of patients in whom IV iron compared
with placebo is associated with a significant decrease in RBC transfusion requirement.
98
6.6 Figures
Figure 1 Derivation of the Cohort
Figure 2 Effect of Hb Level on Association Between Baseline Hepcidin Concentration and Log
Prediction of RBC Transfusion Quantity
99
Figure 3. LOWESS Plot – Association Between Hepcidin Concentration and Subsequent RBC
Transfusion Quantity for IV iron and Placebo
100
6.7 Tables
Table 1 Baseline Characteristics
Characteristic*
Outcome
(n=133)
Age – years 62 (41-73)
Male gender – no. (%) 91 (68)
ICU admission source – no (%)
Emergency department
Hospital ward
Operating theater
Other hospital
24 (18)
8 (6)
97 (73)
4 (3)
ICU admission type – no (%)
Medical
General surgical
Cardiothoracic
Trauma
Neurosurgical
17 (13)
20 (15)
49 (37)
42 (32)
5 (4)
APACHE II score 12 (9-17)
SOFA Score 6 (4-9)
Prior RBC transfusion–no (%) 30 (23)
Haemoglobin – g/l 88 (81-94)
Mean corpuscular volume 91 (88-94)
C Reactive protein 110 (48-170)
Iron – 3 (2-6)
Ferritin –ng/ml+ 260 (161-437)
Transferrin 17 (15-20)
Transferrin saturation - % 9 (6-16)
Soluble transferrin receptor – mg/L 1.81 (1.28-2.44)
Hepcidin – µg/mL
Tertile 1 – (0-20.08)
Tertile 2 – (20.09-53.00)
Tertile 3 – (53.01- 163.46)
34.9 (17.3-69.2)
10.6 (4.2-15.6)
34.9 (27.1-48.5)
81.2 (69.2-97.9)
*Median and interquartile range (IQR) unless otherwise reported. ICU intensive care unit, +ng/ml
has a conversion factor of 1 to the standard international units mcg/ml
101
Table 2 Tertiles of Hepcidin and RBC transfusion
IV iron No IV iron IRR or mean
difference*
(95% CI)
P value
Median RBC transfusion
Hepcidin 1st tertile (0-20.1µg)
number units/number patients
median (IQR)
23/22
1 (0-2)
35/21
0 (0-2)
0.63 (0.26-1.50)
0.293
Hepcidin 2nd tertile (20.1-53.0µg)
number units/number patients
median (IQR)
15/22
0 (0-1)
45/23
1 (0-3)
0.35 (0.16-0.77)
0.009
Hepcidin 3rd tertile (53.0-163.5µg)
number units/number patients
median (IQR)
43/22
1 (0-3)
34/23
1 (0-3)
1.32 (0.57-3.08)
0.518
Mean Hb at hospital discharge
Hepcidin 1st tertile (0-20.1µg) 102 (16) 96 (16) 7 (-3-17) 0.181
Hepcidin 2nd tertile (20.1-53.0µg) 107 (14) 107 (17) 0 (-9-9) 0.972
Hepcidin 3rd tertile (53.0-163.5µg) 110 (10) 101 (11) 9 (2-14) 0.010
102
Table 3. Univariate analysis of variables associated with risk of RBC transfusion
Characteristic*
(n=133)
Coefficient (95%CI)
P Value
Age -0.013 (-0.026 - -0.002) 0.027
Male gender 0.148 (-0.401 – 0.697) 0.530
ICU admission type – trauma vs non trauma
0.997 (0.508 – 1.487)
<0.001
APACHE II score -0.001 (-0.40 – 0.038) 0.954
SOFA Score 0.051 (-0.021 – 0.124) 0.165
Renal replacement therapy 0.382 (-0.665 – 1.429) 0.475
Prior RBC transfusion 0.571 (-0.008 – 1.149) 0.053
Haemoglobin -0.016 (-0.038 – 0.006) 0.145
Mean corpuscular volume
0.003 (-0.039 – 0.045) 0.901
C Reactive protein 0 (-0.003 – 0.002) 0.823
Iron 0.061 (0.007 – 0.115) 0.027
Ferritin 0.001 (-0.0 – 0.002) 0.257
Transferrin -0.043 (-0.085 - -0.0) 0.049
Transferrin saturation 0.031 (0.010 – 0.051) 0.003
Soluble transferrin receptor -0.013 (-0.163 – 0.136) 0.860
Thomas plot (soluble transferrin receptor/log
ferritin)
-0.183 (-1.028-0.663) 0.672
Hepcidin (mcg/L) 0.003 (-0.003 – 0.010) 0.286
Received IV iron -0.338 0.188
103
Table 4 Final Multivariate Model – Independent predictors of RBC transfusion
Characteristic*
(n=133)
Coefficient (95%CI)
Risk ratio (95%CI) P Value
ICU admission type
– trauma vs non trauma
0.833 (0.382 – 1.285)
2.30 (1.46-3.61)
<0.001
Haemoglobin >80 g/L
– yes vs no
-0.99 (-1.493 to -0.493)
0.37 (0.22-0.61)
<0.001
Transferrin saturation
– per 10% increase
0.237 (0.082– 0.391)
1.27 (1.09-1.48)
0.003
Hepcidin
– per 10 µg/ml increase
0.086 (0.030 – 0.142)
1.09 (1.03-1.15)
0.002
Constant for model 0.088 (95%CI -0.398-0.575)
Table 5. Iron indices according to hepcidin levels
lowest two hepcidin tertiles Highest hepcidin tertile P value
Iron 3 (2-7) 3 (2-6) 0.363
Transferrin saturation 9 (6-17) 8 (6-16) 0.649
Ferritin 247 (152-424) 263 (177-463) 0.291
Soluble transferrin receptors 1.82 (1.34-2.54) 1.63 (1.24-2.13) 0.225
C reactive Protein 110 (63-170) 70 (36-150) 0.100
Median and interquartile range unless otherwise specified
104
Chapter 7
Conclusion
105
7.1 Thesis overview
This project was designed to test the hypothesis that intravenous iron therapy is effective in
reducing allogeneic RBC transfusion requirement in critically ill patients with anaemia who are
admitted to the ICU. In order to test this hypothesis, the project included a systematic review, a
prospective observational study, a multicentre RCT and a nested cohort study within the RCT.
The main findings of the project are that: 1. IV iron is effective in decreasing RBC transfusion
requirement in a number of acute care settings outside of the ICU, but may increase the risk of
infection, 2. Simple clinical characteristics available early in the ICU admission period can identify
patients at high risk of subsequent RBC transfusion and that, in this setting, standard measures
of iron metabolism may be more useful in excluding iron overload than diagnosing IRE likely to
result in RBC transfusion, 3. IV iron therapy is biologically active in critically ill patients admitted to
the ICU as evidenced by a significant increase in Hb at hospital discharge, but further, larger,
and/or more targeted trials are required to determine whether this is associated with change in
RBC transfusion requirement, incident infection or patient-centered outcome, 4. Baseline
hepcidin concentration may be useful in identifying patients admitted to the ICU in whom IV iron
therapy will reduce RBC transfusion.
106
7.2 Limitations
There are several limitations to this project. First, the central question of whether IV iron in
critically ill patients with anaemia reduces RBC transfusion requirement has not been definitively
answered, primarily because the IRONMAN study was underpowered. The results of the
IRONMAN study suggest biological activity of IV iron in this patient group. However, although the
effect size was within the plausible range estimated from the systematic review, the baseline
RBC transfusion rate was lower than anticipated and the primary outcome was not significant. In
the systematic review, IV iron was associated with a significant increased risk of infection. This
finding may be of particular relevance in critically ill patients. The IRONMAN study did not find a
significant increase in infection risk associated with IV iron. However, the confidence interval
around the point estimate was wide and the sample size was insufficient to exclude a clinically
important difference in either infection risk or severity.
Second, the project tested a specific formulation, dose and timing of IV iron therapy in critically ill
patients and it is uncertain whether the results can be generalised to other dosing schedules or IV
iron formulations. In the IRONMAN study, the majority of RBC transfusion occurred during the
ICU stay rather than after discharge to the hospital ward. However, the results of the nested
hepcidin sub-study suggest that the benefit of IV iron therapy may be modulated by hepcidin
concentration. It is plausible that hepcidin concentration decreases as the acute inflammatory
response diminishes during recovery from critical illness. The timing of IV iron therapy in critically
ill patients may therefore have a substantial impact on the effect and this was not tested in the
IRONMAN study.
Third, although the project was designed to investigate whether IV iron reduced the requirement
for RBC transfusion, data collection in the IRONMAN study was censored at hospital discharge
and a substantial proportion of patients remained anaemic at last follow up. This project did not
address whether IV iron therapy administered early in the ICU admission results in ongoing
effects beyond hospital discharge.
Finally, this project did not directly examine the potential cost effectiveness of IV iron in critically ill
patients with anaemia. Although this was not an aim of the project the issue does bear
107
consideration given that it may be reasonable to introduce into widespread practice a therapy that
is more cost effective if harm can first be excluded.
108
7.3 Significance & Future research
IV iron therapy is increasingly being incorporated in Patient Blood Management Guidelines and
International Consensus Statements on the basis of increasing evidence of allogeneic blood-
sparing effects in non-critically ill populations 158 159. Both anaemia and RBC transfusion are
common in ICU and associated with increased morbidity and mortality. Whether IV iron therapy
has a role in critically ill patients is therefore of substantial public health interest. However, critical
illness is also associated with substantial changes to iron metabolism and the generalisability of
findings of the safety and efficacy of IV iron therapy in non-critically ill patients remains uncertain.
Although this project was not designed to, and did not find, definitive evidence of improvement in
patient-centered outcomes associated with IV iron therapy in critically ill patients admitted to the
ICU, the findings suggest biological activity and provides a pathway and rationale for further
evaluation.
There are several areas of further research to highlight. First, there is a strong rationale to
conduct a multicentre RCT powered for difference in RBC transfusion quantity based on the
baseline event rate found in the IRONMAN RCT and with the eligibility criteria modified to
increase RBC transfusion risk for enrolled patients, for example, by lowering the threshold for
inclusion to an Hb less than 90 g/L rather than less than 100g/L and/or extending the recruitment
window. This RCT should also be powered to exclude a clinically important increase in infection
associated with IV iron. If IV iron was found to decrease RBC transfusion without increase in
infection or other signal of harm, it is reasonable to consider that this therapy may be introduced
on the basis of cost and scarcity associated with allogeneic RBC transfusion alone. Whether or
not prior dose-finding studies are necessary is debatable. Given the biological effect
demonstrated in the IRONMAN RCT and potential risk for oversaturation, a conservative
approach, continuing the same regime may be warranted. In addition, given the potential
synergistic effect of ESA therapy in addition to IV iron demonstrated in the systematic review
(Chapter 2), further consideration should also be given to studying ESA in combination with IV
iron as part of either a two or three-armed RCT (IV iron + placebo vs. IV iron + ESA vs. placebo +
placebo).
109
A larger RCT of IV iron in critically ill patients could also evaluate longer-term functional outcomes
based on the significant increase in Hb found at hospital discharge. There is an unmet need to
identify treatments associated with improvements in functional outcomes of patients admitted to
the ICU. IV iron therapy has potential beneficial effects both on physical and cognitive function
and as such, is a plausible candidate intervention to improve functional outcomes in survivors of
critical illness.
The role of hepcidin in predicting RBC transfusion requirement and response to IV iron is
currently limited by the lack of a widely available, validated, point of care test as well as a detailed
understanding of the effects of interventions, including IV iron, on hepcidin concentration over
time. The development of a validated point of care test would allow hepcidin concentration to be
included as part of screening for future pragmatic RCTs of IV iron therapy, and, if successful,
incorporated into clinical practice.
Finally, the association between iron and infection in critical illness also requires further
consideration. Although a more recent systematic review and meta-analysis did not find a
significant increase in infection risk associated with IV iron, the direction of the estimate favored
harm and the confidence intervals included the point estimate of increased risk found in the
systematic review conducted for this project160. These findings have substantial implications for
the use of IV iron therapy in a number of clinical settings and, together with the lack of significant
decrease in RBC transfusion quantity found in the IRONMAN RCT, suggest that IV iron therapy
in the ICU should only be considered on a case by case basis in patients at low risk of developing
nosocomial infection. Further observational research quantifying free iron concentrations over
time and association both with iron therapy and infective outcomes are warranted.
110
References
1. Westbrook A, Pettila V, Nichol A, et al. Transfusion practice and guidelines in Australian and New Zealand intensive care units. ICM 2010;36(7):1138-46. doi: 10.1007/s00134-010-1867-8
2. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002;288(12):1499-507.
3. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States. CCM 2004;32(1):39-52. doi: 10.1097/01.CCM.0000104112.34142.79
4. Australian Red Cross Annual Report. http://wwwredcrossorgau/annual-reportsaspx 2011 5. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic
review of the literature. CCM 2008;36(9):2667-74. doi: 10.1097/CCM.0b013e3181844677 6. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of
transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. NEJM 1999;340(6):409-17. doi: 10.1056/NEJM199902113400601
7. Tinmouth A, Fergusson D, Yee IC, et al. Clinical consequences of red cell storage in the critically ill. Transfusion 2006;46(11):2014-27. doi: 10.1111/j.1537-2995.2006.01026.x
8. Leahy MF, Mukhtar SA. From blood transfusion to patient blood management: a new paradigm for patient care and cost assessment of blood transfusion practice. IMJ 2012;42(3):332-8. doi: 10.1111/j.1445-5994.2012.02717.x
9. Hayden SJ, Albert TJ, Watkins TR, et al. Anemia in critical illness: insights into etiology, consequences, and management. AJRCCM 2012;185(10):1049-57. doi: 10.1164/rccm.201110-1915CI
10. Bateman AP, McArdle F, Walsh TS. Time course of anemia during six months follow up following intensive care discharge and factors associated with impaired recovery of erythropoiesis. CCM 2009;37(6):1906-12. doi: 10.1097/CCM.0b013e3181a000cf
11. Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. GO 2010;116(3):522-5. doi: 10.1016/j.ygyno.2009.12.004 [published Online First: 2010/01/07]
12. Gaffney-Stomberg E, McClung JP. Inflammation and diminished iron status: mechanisms and functional outcomes. COCNMC 2012;15(6):605-13. doi: 10.1097/MCO.0b013e328357f63b
13. van Iperen CE, Gaillard CA, Kraaijenhagen RJ, et al. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. CCM 2000;28(8):2773-8.
14. Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. NEJM 2007;357(10):965-76. doi: 10.1056/NEJMoa071533
15. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. TO 2007;12(2):231-42. doi: 10.1634/theoncologist.12-2-231
16. Agarwal R, Rizkala AR, Bastani B, et al. A randomized controlled trial of oral versus intravenous iron in chronic kidney disease. AJN 2006;26(5):445-54. doi: 10.1159/000096174 [published Online First: 2006/10/13]
17. II. Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. AJKD 2006;47(5 Suppl 3):S16-85. doi: 10.1053/j.ajkd.2006.03.012 [published Online First: 2006/05/09]
18. Notebaert E, Chauny JM, Albert M, et al. Short-term benefits and risks of intravenous iron: a systematic review and meta-analysis. Transfusion 2007;47(10):1905-18. doi: 10.1111/j.1537-2995.2007.01415.x
19. Auerbach M, Coyne D, Ballard H. Intravenous iron: from anathema to standard of care. AJH 2008;83(7):580-8. doi: 10.1002/ajh.21154
111
20. Suffredini DA, Xu W, Sun J, et al. Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia. Transfusion 2017;57(10):2338-47. doi: 10.1111/trf.14214
21. Fleming RE, Ponka P. Iron overload in human disease. NEJM 2012;366(4):348-59. doi: 10.1056/NEJMra1004967
22. Fishbane S. Review of issues relating to iron and infection. AJKD 1999;34(4 Suppl 2):S47-52. doi: 10.1053/AJKD034s00047
23. Maynor L, Brophy DF. Risk of infection with intravenous iron therapy. AP 2007;41(9):1476-80. doi: 10.1345/aph.1K187
24. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. JN 2001;131(2S-2):616S-33S; discussion 33S-35S.
25. Maynor L, Brophy DF. Risk of infection with intravenous iron therapy. AP 2007;41(9):1476-80. doi: 10.1345/aph.1K187 [published Online First: 2007/08/02]
26. Torres S, Kuo YH, Morris K, et al. Intravenous iron following cardiac surgery does not increase the infection rate. SI 2006;7(4):361-6. doi: 10.1089/sur.2006.7.361
27. Heming N, Letteron P, Driss F, et al. Efficacy and toxicity of intravenous iron in a mouse model of critical care anemia*. CCM 2012;40(7):2141-8. doi: 10.1097/CCM.0b013e31824e6713
28. Hill GE, Frawley WH, Griffith KE, et al. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis. JT 2003;54(5):908-14. doi: 10.1097/01.TA.0000022460.21283.53
29. Locatelli F, Del Vecchio L. New erythropoiesis-stimulating agents and new iron formulations. CN 2011;171:255-60. doi: 10.1159/000327328
30. Mclean E. Worldwide prevalence of anaemia 1993-2005. World Health Organisation 2008 31. Isbister JP, Shander A, Spahn DR, et al. Adverse blood transfusion outcomes: establishing
causation. TMR 2011;25(2):89-101. doi: 10.1016/j.tmrv.2010.11.001 32. Goodnough LT. Iron deficiency syndromes and iron-restricted erythropoiesis (CME).
Transfusion 2012;52(7):1584-92. doi: 10.1111/j.1537-2995.2011.03495.x 33. Hofmann A, Farmer S, Towler SC. Strategies to preempt and reduce the use of blood
products: an Australian perspective. COA 2012;25(1):66-73. doi: 10.1097/ACO.0b013e32834eb726
34. Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? Transfusion 2010;50(3):719-32. doi: 10.1111/j.1537-2995.2009.02492.x
35. Lyseng-Williamson KA, Keating GM. Ferric carboxymaltose: a review of its use in iron-deficiency anaemia. Drugs 2009;69(6):739-56. doi: 10.2165/00003495-200969060-00007
36. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. AIM 2009;151(4):264-9, W64.
37. Friedrich JO, Adhikari NK, Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data. BMC MRM 2007;7:5. doi: 10.1186/1471-2288-7-5
38. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. doi: 10.1136/bmj.d5928
39. Neeru S, Nair NS, Rai L. Iron sucrose versus oral iron therapy in pregnancy anemia. IJCM 2012;37(4):214-8. doi: 10.4103/0970-0218.103467 [published Online First: 2013/01/08]
40. Adhikary L, Acharya S. Efficacy of IV iron compared to oral iron for increment of haemoglobin level in anemic chronic kidney disease patients on erythropoietin therapy. JNMA 2011;51(183):133-6. [published Online First: 2012/08/28]
41. Aggarwal HK, Nand N, Singh S, et al. Comparison of oral versus intravenous iron therapy in predialysis patients of chronic renal failure receiving recombinant human erythropoietin. JAPI 2003;51:170-4. [published Online First: 2003/05/03]
42. Al RA, Unlubilgin E, Kandemir O, et al. Intravenous versus oral iron for treatment of anemia in pregnancy: a randomized trial. OG 2005;106(6):1335-40. doi: 10.1097/01.AOG.0000185260.82466.b4 [published Online First: 2005/12/02]
112
43. al-Momen AK, al-Meshari A, al-Nuaim L, et al. Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy. EJOGRB 1996;69(2):121-4. [published Online First: 1996/11/01]
44. Allen RP, Adler CH, Du W, et al. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial. SM 2011;12(9):906-13. doi: 10.1016/j.sleep.2011.06.009
45. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. NEJM 2009;361(25):2436-48. doi: 10.1056/NEJMoa0908355 [published Online First: 2009/11/19]
46. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. JCO 2004;22(7):1301-7. doi: 10.1200/JCO.2004.08.119 [published Online First: 2004/03/31]
47. Auerbach M, Silberstein PT, Webb RT, et al. Darbepoetin alfa 300 or 500 mug once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. AJH 2010;85(9):655-63. doi: 10.1002/ajh.21779 [published Online First: 2010/07/28]
48. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. JCO 2008;26(10):1611-8. doi: 10.1200/JCO.2006.10.4620 [published Online First: 2008/04/01]
49. Bayoumeu F, Subiran-Buisset C, Baka NE, et al. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. AJOG 2002;186(3):518-22. [published Online First: 2002/03/21]
50. Beck-da-Silva L, Piardi D, Soder S, et al. IRON-HF study: A randomized trial to assess the effects of iron in heart failure patients with anemia. IJC 2013 doi: 10.1016/j.ijcard.2013.04.181 [published Online First: 2013/05/18]
51. Bencaiova G, von Mandach U, Zimmermann R. Iron prophylaxis in pregnancy: intravenous route versus oral route. EJOGRB 2009;144(2):135-9. doi: 10.1016/j.ejogrb.2009.03.006 [published Online First: 2009/05/02]
52. Bhandal N, Russell R. Intravenous versus oral iron therapy for postpartum anaemia. BJOG 2006;113(11):1248-52. doi: 10.1111/j.1471-0528.2006.01062.x
53. Birgegard G, Schneider K, Ulfberg J. High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron. VS 2010;99(4):354-61. doi: 10.1111/j.1423-0410.2010.01368.x [published Online First: 2010/07/06]
54. Breymann C, Gliga F, Bejenariu C, et al. Comparative efficacy and safety of intravenous ferric carboxymaltose in the treatment of postpartum iron deficiency anemia. IJGO 2008;101(1):67-73. doi: 10.1016/j.ijgo.2007.10.009 [published Online First: 2008/02/01]
55. Charytan C, Qunibi W, Bailie GR. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. NCP 2005;100(3):c55-62. doi: 10.1159/000085049 [published Online First: 2005/04/13]
56. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study JASN 2007;18(3):975-84. doi: 10.1681/asn.2006091034 [published Online First: 2007/02/03]
57. Edwards TJ, Noble EJ, Durran A, et al. Randomized clinical trial of preoperative intravenous iron sucrose to reduce blood transfusion in anaemic patients after colorectal cancer surgery. BJS 2009;96(10):1122-8. doi: 10.1002/bjs.6688
58. Evstatiev R, Alexeeva O, Bokemeyer B, et al. Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease. CGH 2013;11(3):269-77. doi: 10.1016/j.cgh.2012.10.013 [published Online First: 2012/10/20]
59. Friel JK, Andrews WL, Hall MS, et al. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. JPEN 1995;19(2):114-8. [published Online First: 1995/03/01]
113
60. Froessler B, Cocchiaro C, Saadat-Gilani K, et al. Intravenous iron sucrose versus oral iron ferrous sulfate for antenatal and postpartum iron deficiency anemia: a randomized trial. JMFN 2013;26(7):654-9. doi: 10.3109/14767058.2012.746299 [published Online First: 2012/11/08]
61. Garrido-Martin P, Nassar-Mansur MI, de la Llana-Ducros R, et al. The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: a randomized clinical trial. ICTS 2012;15(6):1013-8. doi: 10.1093/icvts/ivs344 [published Online First: 2012/09/04]
62. Grote L, Leissner L, Hedner J, et al. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. MO 2009;24(10):1445-52. doi: 10.1002/mds.22562 [published Online First: 2009/06/03]
63. Hedenus M, Birgegard G, Nasman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 2007;21(4):627-32. doi: 10.1038/sj.leu.2404562 [published Online First: 2007/01/26]
64. Hulin S, Durandy Y. [Post-haemodilution anaemia in paediatric cardiac surgery: benefit of intravenous iron therapy]. AFAR 2005;24(10):1262-5. doi: 10.1016/j.annfar.2005.05.023 [published Online First: 2005/07/12]
65. Karkouti K, McCluskey SA, Ghannam M, et al. Intravenous iron and recombinant erythropoietin for the treatment of postoperative anemia. CJA 2006;53(1):11-9. doi: 10.1007/bf03021522 [published Online First: 2005/12/24]
66. Kasper SM, Lazansky H, Stark C, et al. Efficacy of oral iron supplementation is not enhanced by additional intravenous iron during autologous blood donation. Transfusion 1998;38(8):764-70. [published Online First: 1998/08/26]
67. Khalafallah A, Dennis A, Bates J, et al. A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy. JIM 2010;268(3):286-95. doi: 10.1111/j.1365-2796.2010.02251.x [published Online First: 2010/06/16]
68. Kim YH, Chung HH, Kang SB, et al. Safety and usefulness of intravenous iron sucrose in the management of preoperative anemia in patients with menorrhagia: a phase IV, open-label, prospective, randomized study. AH 2009;121(1):37-41. doi: 10.1159/000210062 [published Online First: 2009/04/01]
69. Kim YT, Kim SW, Yoon BS, et al. Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy. GO 2007;105(1):199-204. doi: 10.1016/j.ygyno.2006.11.014 [published Online First: 2007/01/20]
70. Kochhar PK, Kaundal A, Ghosh P. Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial. JOGR 2013;39(2):504-10. doi: 10.1111/j.1447-0756.2012.01982.x [published Online First: 2012/08/29]
71. Krayenbuehl PA, Battegay E, Breymann C, et al. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Blood 2011;118(12):3222-7. doi: 10.1182/blood-2011-04-346304 [published Online First: 2011/06/28]
72. Kulnigg S, Stoinov S, Simanenkov V, et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. AJG 2008;103(5):1182-92. doi: 10.1111/j.1572-0241.2007.01744.x [published Online First: 2008/03/29]
73. Abou Turk C, Williams AL, Lasky RE. A randomized clinical trial evaluating silicone earplugs for very low birth weight newborns in intensive care. JP 2009;29(5):358-63. doi: 10.1038/jp.2008.236
74. Lindgren S, Wikman O, Befrits R, et al. Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients: A randomized, controlled, evaluator-blind, multicentre study. SJG 2009;44(7):838-45. doi: 10.1080/00365520902839667 [published Online First: 2009/03/31]
114
75. Maccio A, Madeddu C, Gramignano G, et al. Efficacy and safety of oral lactoferrin supplementation in combination with rHuEPO-beta for the treatment of anemia in advanced cancer patients undergoing chemotherapy: open-label, randomized controlled study. TO 2010;15(8):894-902. doi: 10.1634/theoncologist.2010-0020
76. Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. KI 1996;50(5):1694-9.
77. Madi-Jebara SN, Sleilaty GS, Achouh PE, et al. Postoperative intravenous iron used alone or in combination with low-dose erythropoietin is not effective for correction of anemia after cardiac surgery. JCVA 2004;18(1):59-63. [published Online First: 2004/02/20]
78. McMahon LP, Kent AB, Kerr PG, et al. Maintenance of elevated versus physiological iron indices in non-anaemic patients with chronic kidney disease: a randomized controlled trial. NDT 2010;25(3):920-6. doi: 10.1093/ndt/gfp584 [published Online First: 2009/11/13]
79. Meyer MP, Haworth C, Meyer JH, et al. A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin. JP 1996;129(2):258-63. [published Online First: 1996/08/01]
80. Na HS, Shin SY, Hwang JY, et al. Effects of intravenous iron combined with low-dose recombinant human erythropoietin on transfusion requirements in iron-deficient patients undergoing bilateral total knee replacement arthroplasty. Transfusion 2011;51(1):118-24. doi: 10.1111/j.1537-2995.2010.02783.x [published Online First: 2010/07/14]
81. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. JACC 2008;51(2):103-12. doi: 10.1016/j.jacc.2007.09.036 [published Online First: 2008/01/15]
82. Olijhoek G, Megens JG, Musto P, et al. Role of oral versus IV iron supplementation in the erythropoietic response to rHuEPO: a randomized, placebo-controlled trial. Transfusion 2001;41(7):957-63. [published Online First: 2001/07/14]
83. Onken JE, Bregman DB, Harrington RA, et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion 2013 doi: 10.1111/trf.12289 [published Online First: 2013/06/19]
84. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. JCO 2008;26(10):1619-25. doi: 10.1200/jco.2007.12.2051 [published Online First: 2008/04/01]
85. Pollak A, Hayde M, Hayn M, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics 2001;107(1):78-85. [published Online First: 2001/01/03]
86. Provenzano R, Schiller B, Rao M, et al. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. CJASN 2009;4(2):386-93. doi: 10.2215/CJN.02840608 [published Online First: 2009/01/30]
87. Qunibi WY, Martinez C, Smith M, et al. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients. NDT 2011;26(5):1599-607. doi: 10.1093/ndt/gfq613 [published Online First: 2010/10/12]
88. Schaller G, Scheiber-Mojdehkar B, Wolzt M, et al. Intravenous iron increases labile serum iron but does not impair forearm blood flow reactivity in dialysis patients. KI 2005;68(6):2814-22. doi: 10.1111/j.1523-1755.2005.00754.x [published Online First: 2005/12/01]
89. Schindler E, Scholz S, Boldt J, et al. [Effectiveness of oral versus parenteral iron substitution in autologous blood donors]. ITM 1994;21(4):236-41. [published Online First: 1994/08/01]
90. Schroder O, Mickisch O, Seidler U, et al. Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease--a randomized, controlled, open-label, multicenter study. AJG 2005;100(11):2503-9. doi: 10.1111/j.1572-0241.2005.00250.x [published Online First: 2005/11/11]
115
91. Seid MH, Derman RJ, Baker JB, et al. Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical trial. AJOG 2008;199(4):435 e1-7. doi: 10.1016/j.ajog.2008.07.046 [published Online First: 2008/10/22]
92. Serrano-Trenas JA, Ugalde PF, Cabello LM, et al. Role of perioperative intravenous iron therapy in elderly hip fracture patients: a single-center randomized controlled trial. Transfusion 2011;51(1):97-104. doi: 10.1111/j.1537-2995.2010.02769.x
93. Shafi D, Purandare SV, Sathe AV. Iron deficiency anemia in pregnancy: intravenous versus oral route. JOGI 2012;62(3):317-21. doi: 10.1007/s13224-012-0222-0
94. Singh H, Reed J, Noble S, et al. Effect of intravenous iron sucrose in peritoneal dialysis patients who receive erythropoiesis-stimulating agents for anemia: a randomized, controlled trial. CJASN 2006;1(3):475-82. doi: 10.2215/cjn.01541005
95. Singh K, Fong YF, Kuperan P. A comparison between intravenous iron polymaltose complex (Ferrum Hausmann) and oral ferrous fumarate in the treatment of iron deficiency anaemia in pregnancy. EJH 1998;60(2):119-24. [published Online First: 1998/03/21]
96. Sloand JA, Shelly MA, Feigin A, et al. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. AJKD 2004;43(4):663-70. [published Online First: 2004/03/26]
97. Spinowitz BS, Kausz AT, Baptista J, et al. Ferumoxytol for treating iron deficiency anemia in CKD. JASN 2008;19(8):1599-605. doi: 10.1681/ASN.2007101156 [published Online First: 2008/06/06]
98. Steensma DP, Sloan JA, Dakhil SR, et al. Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia. JCO 2011;29(1):97-105. doi: 10.1200/jco.2010.30.3644 [published Online First: 2010/11/26]
99. Stoves J, Inglis H, Newstead CG. A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. NDT 2001;16(5):967-74. [published Online First: 2001/05/01]
100. Toblli JE, Lombrana A, Duarte P, et al. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. JACC 2007;50(17):1657-65. doi: 10.1016/j.jacc.2007.07.029 [published Online First: 2007/10/24]
101. van Iperen CE, Gaillard CA, Kraaijenhagen RJ, et al. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. CCM 2000;28(8):2773-8. [published Online First: 2000/08/31]
102. Van Wyck DB, Martens MG, Seid MH, et al. Intravenous ferric carboxymaltose compared with oral iron in the treatment of postpartum anemia: a randomized controlled trial. OG 2007;110(2 Pt 1):267-78. doi: 10.1097/01.AOG.0000275286.03283.18
103. Van Wyck DB, Mangione A, Morrison J, et al. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion 2009;49(12):2719-28. doi: 10.1111/j.1537-2995.2009.02327.x
104. Van Wyck DB, Roppolo M, Martinez CO, et al. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. KI 2005;68(6):2846-56. doi: 10.1111/j.1523-1755.2005.00758.x [published Online First: 2005/12/01]
105. Verma S. Intravenous iron therapy versus oral iron in postpartum patients in rural areas. JSAFOG 2011;3(2):67-70.
106. Warady BA, Kausz A, Lerner G, et al. Iron therapy in the pediatric hemodialysis population. PN 2004;19(6):655-61. doi: 10.1007/s00467-004-1457-5 [published Online First: 2004/04/06]
107. Weisbach V, Skoda P, Rippel R, et al. Oral or intravenous iron as an adjuvant to autologous blood donation in elective surgery: a randomized, controlled study. Transfusion 1999;39(5):465-72. [published Online First: 1999/05/21]
108. Westad S, Backe B, Salvesen KA, et al. A 12-week randomised study comparing intravenous iron sucrose versus oral ferrous sulphate for treatment of postpartum anemia.
116
AOGS 2008;87(9):916-23. doi: 10.1080/00016340802317802 [published Online First: 2008/08/23]
109. Fleming RE, Ponka P. Iron overload in human disease. NEJM 2012;366(4):348-59. doi: 10.1056/NEJMra1004967 [published Online First: 2012/01/27]
110. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010;116(23):4754-61. doi: 10.1182/blood-2010-05-286260
111. Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. NEJM 2007;357(10):965-76. doi: 10.1056/NEJMoa071533 [published Online First: 2007/09/07]
112. Ang O, Gungor M, Aricioglu F, et al. The effect of parenteral iron administration on the development of Staphylococcus aureus-induced experimental pyelonephritis in rats. IJEP 1990;71(4):507-11. [published Online First: 1990/08/01]
113. Moore RA, Gaskell H, Rose P, et al. Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data. BMC BD 2011;11:4. doi: 10.1186/1471-2326-11-4 [published Online First: 2011/09/29]
114. Gafter-Gvili A, Rozen-Zvi B, Vidal L, et al. Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials. AO 2013;52(1):18-29. doi: 10.3109/0284186X.2012.702921 [published Online First: 2012/08/11]
115. Stewart GB, Altman DG, Askie LM, et al. Statistical analysis of individual participant data meta-analyses: a comparison of methods and recommendations for practice. PO 2012;7(10):e46042. doi: 10.1371/journal.pone.0046042 [published Online First: 2012/10/12]
116. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ 2013;347:f4822. doi: 10.1136/bmj.f4822
117. Beris P, Munoz M, Garcia-Erce JA, et al. Perioperative anaemia management: consensus statement on the role of intravenous iron. BJA 2008;100(5):599-604. doi: 10.1093/bja/aen054
118. Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. BJH 2013;161(5):639-48. doi: 10.1111/bjh.12311
119. Lasocki S, Longrois D, Montravers P, et al. Hepcidin and anemia of the critically ill patient: bench to bedside. Anesthesiology 2011;114(3):688-94. doi: 10.1097/ALN.0b013e3182065c57
120. Patteril MV, Davey-Quinn AP, Gedney JA, et al. Functional iron deficiency, infection and systemic inflammatory response syndrome in critical illness. AIC 2001;29(5):473-8.
121. Ferrari P, Kulkarni H, Dheda S, et al. Serum iron markers are inadequate for guiding iron repletion in chronic kidney disease. CJASN 2011;6(1):77-83. doi: 10.2215/CJN.04190510
122. Investigators N-SS, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. NEJM 2009;360(13):1283-97. doi: 10.1056/NEJMoa0810625
123. Brissot P, Ropert M, Le Lan C, et al. Non-transferrin bound iron: a key role in iron overload and iron toxicity. BEBA 2012;1820(3):403-10. doi: 10.1016/j.bbagen.2011.07.014
124. Hod EA, Brittenham GM, Billote GB, et al. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. Blood 2011;118(25):6675-82. doi: 10.1182/blood-2011-08-371849
125. Pieracci FM, Stovall RT, Jaouen B, et al. A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness. CCM 2014 doi: 10.1097/CCM.0000000000000408
126. Litton E, Baker S, Erber W, et al. The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia. CCR 2014;16(4):285-90.
117
127. McQuilten ZK, Schembri N, Polizzotto MN, et al. Hospital blood bank information systems accurately reflect patient transfusion: results of a validation study. Transfusion 2011;51(5):943-8. doi: 10.1111/j.1537-2995.2010.02931.x
128. Shander A, Hofmann A, Gombotz H, et al. Estimating the cost of blood: past, present, and future directions. BPRCA 2007;21(2):271-89.
129. Musallam KM, Tamim HM, Richards T, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet 2011;378(9800):1396-407. doi: 10.1016/S0140-6736(11)61381-0
130. Authority NB. Patient Blood Management Guidelines:Module 4 Critical Care. ISBN 978-0-9872519-9-2 2012;http://www.nba.gov.au
131. Evstatiev R, Marteau P, Iqbal T, et al. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology 2011;141(3):846-53 e1-2. doi: 10.1053/j.gastro.2011.06.005
132. Munoz M, Martin-Montanez E. Ferric carboxymaltose for the treatment of iron-deficiency anemia. [corrected]. EOP 2012;13(6):907-21. doi: 10.1517/14656566.2012.669373
133. Sharma N, Thiek JL, Natung T, et al. Comparative Study of Efficacy and Safety of Ferric Carboxymaltose Versus Iron Sucrose in Post-partum Anaemia. JOGI 2017;67(4):253-57. doi: 10.1007/s13224-017-0971-x
134. Calvet X, Gene E, AngelRuiz M, et al. Cost-minimization analysis favours intravenous ferric carboxymaltose over ferric sucrose or oral iron as preoperative treatment in patients with colon cancer and iron deficiency anaemia. THC 2016;24(1):111-20. doi: 10.3233/THC-151074
135. MIMS. Ferinject Product Information. MIMS Australia Pty Ltd & CMPMedica Australia Pty Ltd. New South Wales Australia. http: //www-mimsonline-com-au 2012, Accessed: 07/04/2012 2012
136. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. NEJM 2009;361(25):2436-48. doi: 10.1056/NEJMoa0908355
137. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study. JASN 2007;18(3):975-84. doi: 10.1681/ASN.2006091034
138. Patient Blood Management Guidelines: Module 4 Critical Care. NBA ;ISBN 978-0-9872519-9-2
139. Cook D, Lauzier F, Rocha MG, et al. Serious adverse events in academic critical care research. CMAJ : 2008;178(9):1181-4. doi: 10.1503/cmaj.071366
140. Engoren M, Schwann TA, Habib RH, et al. The independent effects of anemia and transfusion on mortality after coronary artery bypass. ATS 2014;97(2):514-20. doi: 10.1016/j.athoracsur.2013.09.019
141. Holst LB, Petersen MW, Haase N, et al. Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis. BMJ 2015;350:h1354. doi: 10.1136/bmj.h1354
142. Litton E, Xiao J, Allen CT, et al. Iron-restricted erythropoiesis and risk of red blood cell transfusion in the intensive care unit: a prospective observational study. AIC 2015;43(5):612-6.
143. Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012;338(6108):768-72. doi: 10.1126/science.1224577
144. Urbaniak GCP, S. Research Randomizer (version 4.0) [Computer software]. http:wwwrandomizerorg/, 2013.
145. Piagnerelli M, Cotton F, Herpain A, et al. Time course of iron metabolism in critically ill patients. ACB 2013;68(1):22-7. doi: 10.2143/ACB.68.1.2062715
146. Carson JL, Terrin ML, Jay M. Anemia and postoperative rehabilitation. CJA 2003;50(6 Suppl):S60-4.
147. Froessler B, Palm P, Weber I, et al. The Important Role for Intravenous Iron in Perioperative Patient Blood Management in Major Abdominal Surgery: A Randomized Controlled Trial. AS 2016 doi: 10.1097/SLA.0000000000001646
118
148. Lelubre C, Vincent JL. Red blood cell transfusion in the critically ill patient. AIC 2011;1:43. doi: 10.1186/2110-5820-1-43
149. Investigators I, Litton E, Baker S, et al. Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial : A randomized trial of IV iron in critical illness. ICM 2016;42(11):1715-22. doi: 10.1007/s00134-016-4465-6
150. Lasocki S, Baron G, Driss F, et al. Diagnostic accuracy of serum hepcidin for iron deficiency in critically ill patients with anemia. ICM 2010;36(6):1044-8. doi: 10.1007/s00134-010-1794-8
151. Gummer J, Trengove R, Pascoe EM, et al. Association between Serum Hepcidin-25 and Primary Resistance to Erythropoiesis Stimulating Agents in Chronic Kidney Disease: A Secondary Analysis of the HERO Trial. Nephrology 2016 doi: 10.1111/nep.12815
152. van Rijnsoever M, Galhenage S, Mollison L, et al. Dysregulated Erythropoietin, Hepcidin, and Bone Marrow Iron Metabolism Contribute to Interferon-Induced Anemia in Hepatitis C. JICR 2016;36(11):630-34. doi: 10.1089/jir.2016.0043
153. Steensma DP, Sasu BJ, Sloan JA, et al. Serum hepcidin levels predict response to intravenous iron and darbepoetin in chemotherapy-associated anemia. Blood 2015;125(23):3669-71. doi: 10.1182/blood-2015-03-636407
154. May S, Bigelow C. Modeling nonlinear dose-response relationships in epidemiologic studies: statistical approaches and practical challenges. DR 2006;3(4):474-90. doi: 10.2203/dose-response.003.04.004
155. Prentice AM, Doherty CP, Abrams SA, et al. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Blood 2012;119(8):1922-8. doi: 10.1182/blood-2011-11-391219
156. Tacke F, Nuraldeen R, Koch A, et al. Iron Parameters Determine the Prognosis of Critically Ill Patients. CCM 2016;44(6):1049-58. doi: 10.1097/CCM.0000000000001607
157. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood 2016;127(23):2809-13. doi: 10.1182/blood-2015-12-639112
158. Patient Blood Management Guidelines: Module 2 Perioperative. NBA 159. Munoz M, Acheson AG, Auerbach M, et al. International consensus statement on the peri-
operative management of anaemia and iron deficiency. Anaesthesia 2017;72(2):233-47. doi: 10.1111/anae.13773
160. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron preparations: systematic review and meta-analysis. MCP 2015;90(1):12-23. doi: 10.1016/j.mayocp.2014.10.007
119
Appendix 1 – Human Research Ethics Approvals
120
121
122
123
124
125
Appendix 2 – Publications, Presentations and Prizes Publications
1. Litton et al Safety and efficacy of intravenous iron therapy in reducing requirement for
allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials
BMJ 2013;347;f4822 Impact Factor 19.7 (Google Scholar 136 Citations), (Other: NEJM Journal
Watch 31/10/2013 http://www.jwatch.org/na32026/2013/10/31/intravenous-vs-oral-iron-patients-
with-anemia, BMJ Rapid Responses http://www.bmj.com/content/347/bmj.f4822/rapid-
responses, Reactions Weekly, Balancing the risks and benefits of IV iron
https://link.springer.com/article/10.1007/s40278-013-5442-2)
2. Litton et al The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trail
of intravenous iron in intensive care unit patients with anaemia Critical Care & Resuscitation 2014
16(4) 285-90 Impact Factor 3.2 (Google Scholar 14 Citations)
3. Litton et al Iron-restricted erythropoiesis and risk of red blood cell transfusion in the intensive
care unit: a prospective observational study Anaesthesia and Intensive Care 2015; 43(5) 612-6
Impact Factor 1.28 (Google Scholar 3 Citations)
4. Litton RE: The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trail
of intravenous iron in intensive care unit patients with anaemia Critical Care & Resuscitation 2015
17(2) 144-5 Impact Factor 3.2
5. Litton et al Intravenous iron or placebo for anaemia in intensive care: the IRONMAN
multicentre randomized blinded trial: A randomized trail of IV iron in critical illness Intensive Care
Medicine 2016 42(11) 1715-1722 Impact Factor 10.2 (Google Scholar 3 Citations)
6. Litton et al Intravenous iron or placebo for anaemia in intensive care: the IRONMAN
multicentre randomized blinded trial Critical Care Medicine 2016 44(12) 225
Presentations
1. https://www.youtube.com/watch?v=_m-H9mjplQg The Safety and Efficacy of Intravenous Iron
Therapy in Reducing Requirement for Allogeneic Blood Transfusion: A Systematic Review and
Meta-Analysis of Randomised Clinical Trials BMJ Youtube Channel 15/08/2013
126
2. Best of ANZICS Transfusion in ICU Invited Speaker 7-9/06/2013 Delhi and Mumbai, India
3. Australia and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group (CTG)
Annual Meeting Intravenous Iron for Anaemia in Intensive Care: the IRONMAN Study 07/03/2014
Noosa, Australia
4. Haematology Society of Australia and New Zealand, the Australian & New Zealand Society of
Blood Transfusion and the Thrombosis and Haemostasis Society of Australia and New Zealand
(HAA) The role of intravenous iron in critical illness Invited Speaker 19/10/2014, Perth, Australia
5. Social Media and Critical Care Gold Iron, is it fools gold? Invited Speaker 20/03/2014
Southport, Australia
6. ANZICS Annual Scientific Meeting Iron-restricted erythropoiesis in ICU: A Prospective
Observational Study 11/10/2014, Melbourne, Australia
7. Indian Ocean Rim Laboratory Haematology Congress IRONMAN – IV Iron in ICU Invited
Speaker 15/10/2015 Fremantle, Australia
8. ANZICS CTG Spring Forum IRONMAN RCT Study Results 28/10/2015 Auckland, New
Zealand
9. Australia and New Zealand Intensive Care Society Clinical Trials Group Annual Meeting
IRONMAN Updated Results 8/03/2016 Noosa, Australia
10. European Society of Intensive Care Medicine (ESICM) LIVES2016 The IRONMAN Study
Invited Speaker 2/10/2016 Milan, Italy
11. ESICM Webinar Intravenous Iron or Placebo for Anaemia in Intensive Care: The IRONMAN
Study 10/11/2016
Prizes
Society of Critical Care Medicine Research Snapshot Bronze Award Intravenous Iron or Placebo
for Anaemia in ICU: The IRONMAN Multicentre Randomized Blinded Trial 23/1/2017
Raine Research Prize for best publication by a WA researcher/clinician The IRONMAN
Multicentre Randomized Blinded Trial
top related