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Iron therapy in anaemic adults without chronic kidney disease

  1. Kurinchi Selvan Gurusamy,
  2. Toby Richards*

Editorial Group: Cochrane Injuries Group

Published Online: 9 JUL 2013

DOI: 10.1002/14651858.CD010640


How to Cite

Gurusamy KS, Richards T. Iron therapy in anaemic adults without chronic kidney disease (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD010640. DOI: 10.1002/14651858.CD010640.

Author Information

  1. Royal Free Campus, UCL Medical School, Department of Surgery, London, UK

*Toby Richards, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital,, Rowland Hill Street, London, NW3 2PF, UK. toby.richards@ucl.ac.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 9 JUL 2013

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This is not the most recent version of the article. View current version (31 DEC 2014)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Oxygen is necessary for the efficient extraction of energy from food. Red blood cells carry oxygen in the blood, which is bound to a protein called haemoglobin (NCBI-Hemoglobins). Iron is an essential component of haemoglobin (NCBI-Iron).

Anaemia is the reduction in the number of circulating red cells in the blood or in the quantity of haemoglobin in the blood (NLM Anemia). The World Health Organization (WHO) definition of anaemia (WHO 2001) is shown in  Table 1. The global prevalence of anaemia in the general population is 24.8%, with an estimated 1.6 billion people affected by anaemia (WHO 2008). Regional variations and differences in anaemia prevalence have been noted in men, non-pregnant women, pregnant women and children of various ages (WHO 2001; WHO 2008).

Common causes of anaemia include:

  • nutritional deficiency (such as deficient iron, folic acid or vitamin B12; vitamin A deficiency and protein-energy malnutrition);
  • increased nutritional demand (as in pregnancy);
  • impaired production of red cells (as in chronic kidney disease);
  • genetic haemoglobin disorders resulting in increased destruction of red cells (such as thalassaemias);
  • infectious diseases (such as worm infestation and malaria);
  • malabsorption and disorders of the small intestine;
  • blood loss (acute blood loss as in surgery and chronic blood loss as in menstrual disorders or occult gastrointestinal bleeding); and
  • anaemia of chronic disease (also known as anaemia of inflammation).

These are due to a combination of defective incorporation of iron into developing red cells, decreased availability of iron stores as the result of increased uptake and retention of iron within the reticuloendothelial system, decreased erythropoietin and increased destruction of red cells caused by increased cytokines released as part of a chronic inflammatory response (examples include rheumatoid arthritis, malignancy, chronic infection and chronic kidney disease) (Balarajan 2011; Davis 2012; Goonewardene 2012; Fireman 2004; Weiss 2005).

In an estimated 50% of anaemic patients, iron deficiency is the cause of their condition (WHO 2001; WHO 2008) and may be due to insufficient intake, decreased absorption or blood loss greater than 5 to 10 mL per day (the amount of iron the gut can absorb from a normal diet) (Balarajan 2011; Liu 2012). Vegetarians have a high prevalence of iron deficiency (Waldmann 2004) and a higher prevalence of anaemia compared with non-vegetarians (Jain 2012). It is important to note that the etiopathogenesis of anaemia in nutritional deficiency and blood loss is iron deficiency, and that in chronic inflammatory disorders such as rheumatoid arthritis, it consists of defective incorporation of iron into developing red cells and increased destruction of red cells (Davis 2012; Fireman 2004). Because circulatory iron is low in patients with anaemia of chronic disease (Weiss 2005), and because erythropoietin deficiency is one of the mechanisms of anaemia of chronic disease (Davis 2012; Weiss 2005), patients with anaemia due to chronic disease are frequently treated with a combination of erythropoietin and iron (Davis 2012).

Anaemia can cause fatigue (Foubert 2006) and decreased work activity (Scholz 1997), and it worsens heart failure (Ghali 2009). Severe anaemia is associated with increased mortality in patients with chronic heart failure (von Haehling 2010). In patients undergoing an operation, preoperative anaemia increases mortality (Beattie 2009; Dunne 2002; Musallam 2011) and morbidity (Musallam 2011) and prolongs hospital stay (Leichtle 2011). In children, anaemia may cause developmental delays and cognitive impairment (Yadav 2011).

 

Description of the intervention

Iron therapy can be administered orally (ferrous sulphate, ferrous fumarate and ferrous gluconate), intramuscularly (iron dextran) or intravenously (iron dextran, iron sucrose and ferric carboxymaltose) (Goddard 2011). Adverse events related to intravenous iron are rare and include death, pulmonary embolism, anaphylaxis, unresponsiveness, loss of consciousness, circulatory collapse, hypotension, anaphylactoid reaction, dyspnoea, pruritus, hypersensitivity and urticaria (Bailie 2012). According to the US Food and Drug Administration (FDA) database, on average, four major or serious adverse events have been reported for every 1 million units (1 unit is equivalent to 100 mg of iron, otherwise called 100 mg dose equivalent) of iron sucrose sold in the United States (Bailie 2012). The serious and major adverse events for other intravenous iron preparations from this database are 184 per million units for ferumoxytol, 10 per million units for sodium ferric gluconate and 27 per million units for iron dextran (Bailie 2012). The adverse effects of oral iron are usually gastrointestinal and include heartburn, nausea, vomiting, diarrhoea and constipation (Hyder 2002). Iron preparations are generally made from chemicals, not from animal products; hence they are acceptable for vegetarians.

 

How the intervention might work

Iron supplementation provides iron to the circulation. The amount of iron that reaches the blood circulation varies with different routes of administration, the form of iron and other factors specific to the route of administration. Bioavailability indicates the proportion of administered iron that reaches the general body circulation. Oral iron in the form of bivalent iron (ferrrous form) is preferable to the trivalent form (ferric) because of the better bioavailability of ferrous form. On average, the bioavailability of ferrous form is about 10% to 15% that of ferrous, and that of ferric form is 3 to 4 times less (Santiago 2012). The bioavailability of oral iron depends on various factors, including the iron stores of the individual, fasting state at the time of iron consumption, the chemical to which the iron is bound (e.g. ferrous sulphate vs ferrous fumarate) and the addition of vitamin C (Santiago 2012). The bioavailability of intramuscular iron is unpredictable; this fact, combined with other factors such as painful injection and staining of the skin at the injection site, has generally made intramuscular iron the least preferable route (Silverstein 2004). Intravenous iron directly enters the circulation and reaches the reticuloendothelial system, where it is used for haemoglobin production (Danielson 2004). Iron therapy acts by replenishing the iron stores in the body in the case of nutritional iron deficiency or chronic blood loss. Iron is an essential component of haemoglobin; therefore replenishing iron stores may increase the production of haemoglobin. In the case of anaemia of chronic disease, increasing circulatory iron may increase the iron that is available for the production of haemoglobin.

 

Why it is important to do this review

Cochrane reviews about the role of iron therapy in patients with chronic kidney disease, in renal transplant patients, in pregnant women and in postpartum women and children are available or have been registered as in progress (Albaramki 2012; Dodd 2004; Reveiz 2011; Zeng 2009). However, no systematic review of randomised controlled trials (RCTs) has assessed the clinical benefits of iron therapy in anaemic patients without chronic kidney disease or pregnancy, or during the postpartum period. It is important to obtain evidence of the effectiveness of iron therapy in different clinical conditions. Hence, the findings of this review can influence the care of a large number of people.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To assess the safety and efficacy of iron therapies in the treatment of non-pregnant and non-lactating anaemic adults without chronic kidney disease.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

RCTs, irrespective of blinding, language, publication status, date of publication, study setting or sample size, will be included. We will include cluster randomised trials provided that the effect size has been adjusted for clustering.

Studies in which the treatment group allocation can be predicted, such as allocation by hospital number or date of birth, will be excluded.

 

Types of participants

Any non-pregnant and non-lactating anaemic adult without chronic kidney disease will be included in this review, irrespective of the setting and the degree of anaemia. We anticipate the following broad categories of participants; this is not an exhaustive list.

  • Blood loss.
  • Cancer.
  • Preoperative anaemia.
  • Chronic heart failure.
  • Autoimmune disorders.

We will exclude four important categories of patients with anaemia. We are excluding patients with chronic kidney disease and renal transplant because such participants have been included in another review, 'Parenteral versus oral iron therapy for adults and children with chronic kidney disease' (Albaramki 2012). We are excluding pregnant women because such participants were included in the review, 'Treatments for iron-deficiency anaemia in pregnancy' (Reveiz 2011). We are excluding postpartum women because such participants were included in the review, 'Treatment for women with postpartum iron deficiency anaemia' (Dodd 2004). We are excluding children because they will be included in another review, 'Iron supplementation for iron deficiency anaemia in children' (Zeng 2009). We will make efforts to exclude children in cases where their data have been described in detail; however, jf no detailed description is provided, the trial will be included in the knowledge that a small quantity of data from children may be included in the review.

We will accept any definition of anaemia used by the authors, provided that all participants have less than 13 g/dL for males and 12 g/dL for females of haemoglobin (i.e. all participants will have to meet the WHO criteria for anaemia for adult males and non-pregnant females. We are aware that some potential participants who meet the WHO criteria may not be included in the trial because the trial used a different level of haemoglobin or another measure to diagnose anaemia (e.g. 11 g/dL haemoglobin).

 

Types of interventions

  • Oral iron versus placebo or no iron therapy.
  • Parenteral iron versus placebo or no iron therapy.
  • Parenteral iron versus oral iron.
  • Comparison of different oral iron formulations (and doses).
  • Comparison of different parenteral iron formulations (and routes (intramuscular vs intravenous) and doses).

Co-interventions will be allowed if performed equally in both groups.

 

Types of outcome measures

 

Primary outcomes

  • Mortality. Risk of death at one year (all-cause mortality).

 

Secondary outcomes

  • Mortality. Hazard ratio of all-cause mortality at different periods of follow-up (short, medium and long, depending on available follow-up periods of studies).
  • Risk of requiring blood transfusion.
  • Mean difference in blood transfused (as defined by authors).
  • Mean difference in haemoglobin levels.
  • Mean difference (or standardised mean difference if different scales are used) in quality of life (as defined by authors).
  • Risk of serious adverse events. Serious adverse events are defined as any events that would increase mortality; are life-threatening; require inpatient hospitalisation or result in persistent or significant disability; or any important medical events that might have jeopardised the participant or that require intervention to prevent them (ICH-GCP 1996) (within 30 days of cessation of treatment).
  • Narrative summary of length of hospital stay.

 

Search methods for identification of studies

We will not restrict the search for studies by date or language of publication. We aim to include appropriate studies regardless of whether they are published or unpublished.

 

Electronic searches

We will search the following electronic databases.

  • Cochrane Injuries Group specialised register (present version).
  • Cochrane Central Register of Controlled Trials (The Cochrane Library) (latest issue).
  • MEDLINE (Ovid) (1950 to present).
  • EMBASE (Ovid) (1980 to present).
  • CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCO) (1980 to present).
  • ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to present).
  • ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (1990 to present).

As the review progresses and we run the searches, we will modify the search strategies (Appendix 1) where necessary.

 

Searching other resources

We will search the reference lists of all included studies and previously published reviews for additional studies. We will also contact authors and experts in the field to identify additional published or unpublished study information.

We will search Google Scholar and will investigate the following online trials registers using the search strategy provided in Appendix 1.

 

Data collection and analysis

We will perform the systematic review in accordance with the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011; Higgins 2011a; Higgins 2011b; Sterne 2011).

 

Selection of studies

Two review authors (KSG and TR) will identify the trials for inclusion independently of each other. We will list excluded studies with the reasons for exclusion. Any differences will be resolved through discussion.

 

Data extraction and management

Both review authors will independently extract the following data.

  • Year and language of publication.
  • Country.
  • Year of conduct of the trial.
  • Inclusion and exclusion criteria.
  • Sample size.
  • Population characteristics.
  • Details of iron supplementation, including dose, route, frequency and duration.
  • Outcomes reported in the trials.
  • Outcomes (included in this review).
  • Risk of bias (described later).

We will obtain the information from all reports if multiple reports pertain to a trial. We will seek unclear or missing information by contacting the authors of the individual trials. If there is any doubt whether the trials share the same participants-completely or partially (by identifying common authors and centres)-we will contact the study authors to clarify whether the trial report has been duplicated. We will resolve any differences in opinion through discussion.

In cluster randomised trials, we will extract the effect estimate of the outcomes adjusted for a cluster effect.

 

Assessment of risk of bias in included studies

We will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011b). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), the risk of bias of the trials will be assessed on the basis of the following bias risk domains.

 

Sequence generation

  • Low risk of bias: The method used is either adequate (e.g. computer generated random numbers, table of random numbers) or unlikely to introduce confounding.
  • Uncertain risk of bias: Information is insufficient to allow assessment of whether the method used is likely to introduce confounding.
  • High risk of bias: The method used (e.g. quasi-randomised studies) is improper and is likely to introduce confounding. Such studies will be excluded.

 

Allocation concealment

  • Low risk of bias: The method used (e.g. central allocation) is unlikely to induce bias on the final observed effect.
  • Uncertain risk of bias: Information is insufficient to allow assessment of whether the method used is likely to induce bias on the estimate of effect.
  • High risk of bias: The method used (e.g. open random allocation schedule) is likely to induce bias on the final observed effect.

 

Blinding of participants, personnel

  • Low risk of bias: Blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding.
  • Uncertain risk of bias: Information is insufficient to allow assessment of whether the type of blinding used is likely to induce bias on the estimate of effect.
  • High risk of bias: No blinding or incomplete blinding is applied, and the outcome or the outcome measurement is likely to be influenced by lack of blinding.

 

Blinding of outcome assessors

  • Low risk of bias: Blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding.
  • Uncertain risk of bias: Information is insufficient to allow assessment of whether the type of blinding used is likely to induce bias on the estimate of effect.
  • High risk of bias: No blinding or incomplete blinding is applied, and the outcome or the outcome measurement is likely to be influenced by lack of blinding.

 

Incomplete outcome data

  • Low risk of bias: The underlying reasons for missingness are unlikely to make treatment effects a departure from plausible values, or proper methods have been employed to handle missing data.
  • Uncertain risk of bias: Information is insufficient to allow assessment of whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect.
  • High risk of bias: The crude estimate of effects (e.g. complete case estimate) will clearly be biased because of the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory.

 

Selective outcome reporting

  • Low risk of bias: The trial protocol is available, and all of the trial's prespecified outcomes that are of interest in the review have been reported as similar; if the trial protocol is not available, all primary outcomes in this review are reported.
  • Uncertain risk of bias: Information is insufficient to allow assessment of whether the magnitude and direction of the observed effect are related to selective outcome reporting.
  • High risk of bias: Not all of the trial's prespecified primary outcomes have been reported or are similar.

 

Source of funding bias

  • Low risk of bias: The trial protocol is available, and the trial is carried out according to the protocol; or if the trial protocol is not available, the trial is funded by a sponsor who has no vested interest in the results of the trial.
  • Uncertain risk of bias: Information is insufficient to allow assessment of whether the magnitude and the direction of the observed effect are related to the source of funding.
  • High risk of bias: Violation of trial protocol occurs, and information on the funder is insufficient; or if the trial protocol is not available, the trial is funded by a sponsor who has vested interest in the results of the trial, such as an iron manufacturer.

We will consider as low bias-risk trials all trials that are classified as having low risk of bias in all of the previously listed domains.

 

Measures of treatment effect

For dichotomous variables, we will calculate the risk ratio (RR) with 95% confidence interval (CI). For continuous variables, we will calculate the mean difference (MD) with 95% CI for outcomes such as hospital stay and standardised mean difference (SMD) with 95% CI for quality of life (where different scales might be used). For time-to-event outcomes such as mortality at maximal follow-up, we will calculate the hazard ratio (HR) with 95% CI.

 

Unit of analysis issues

The unit of analysis will be individual anaemic participants who are undergoing treatment. In the case of cluster randomised trials, we will obtain the effect estimate adjusted for the cluster effect.

 

Dealing with missing data

We will perform an intention-to-treat analysis (Newell 1992) whenever possible. We will impute data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best-case scenario and worst-case scenario (Gurusamy 2009).

For continuous outcomes, we will use available-case analysis. If the mean and the standard deviation are not available from the trial report, we will seek this information from the trial authors. If this information is not available, we will impute the standard deviation from P values in keeping with the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and we will use the median for the meta-analysis when the mean is not available. If it is not possible to calculate the standard deviation from the P value or the confidence intervals, we will impute the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation will decrease the weight of the study for calculation of mean differences and will bias the effect estimate to no effect in case of a standardised mean difference (Higgins 2011).

For time-to-event outcomes, if the hazard ratio and the 95% confidence intervals are not reported, we will obtain the logarithm of hazard ratios (ln(HR)) and the standard error (SE) of ln(HR) according to the methods described by Parmar 1998, using the Excel sheet provided by Tierney 2007.

 

Assessment of heterogeneity

We anticipate that major sources of clinical heterogeneity would be due to different iron preparations (including different doses, frequencies and durations of administration), inclusion of different types of participants (blood loss, cancer, preoperative anaemia, chronic heart failure and autoimmune disorders) and the use of erythropoietin as a co-intervention. Methodological diversity (trials with low risk of bias vs trials with high risk of bias) may be another source of heterogeneity.

We will explore heterogeneity within each meta-analysis with a Chi2 test with significance set at a P value of 0.10, and we will express the percentage of heterogeneity due to variation rather than to chance as I2 (Higgins 2002). We will consider heterogeneity to be moderate if I2 > 50%. If considerable heterogeneity is noted (I2 > 80%), we will not perform meta-analysis.

 

Assessment of reporting biases

We will use visual asymmetry on a funnel plot to explore reporting bias in the presence of at least 10 trials for the outcome (Egger 1997; Macaskill 2001). We will perform the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry. Selective reporting will be considered as evidence of reporting bias.

 

Data synthesis

We will perform the meta-analyses using the software package Review Manager version 5.2 (RevMan 2012) and in accordance with the recommendations of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will compare the results of a random-effects model (DerSimonian 1986) versus those of a fixed-effect model (DeMets 1987) to assess small study effects.

We will, however, report the results of the random-effects model. We will use the generic inverse variance method to pool (separately) hazard ratios, carrying out separate analyses for short-term (less than one year), medium-term (longer than one year but less than three years), and long-term follow-up (longer than three years).

Similarly, for risk ratios, in the presence of cluster randomised trials, we will use generic inverse variance methods to pool the unadjusted effect estimates calculated from simple parallel RCTs, with the effect estimate adjusted for cluster effect obtained from cluster RCTs.

For continuous outcomes, we will pool the mean differences or the standardised mean differences accordingly by using the inverse variance method. For the mean amount of blood transfused, we will analyse separately trials with different methods of measurement of transfused blood (e.g. amount of blood transfused reported in milliliters, amount of blood transfused reported in units of blood transfusion). We will additionally present the results of the primary outcomes in a 'Summary of finding table'.

 

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses in the presence of at least two trials under at least two subgroups.

  • Different iron preparations.
  • Different types of participants (blood loss, cancer, preoperative anaemia, chronic heart failure, autoimmune disorders, and infectious diseases).
  • Trials in which erythropoietin was used as co-intervention in both groups versus trials in which erythropoietin was not used as co-intervention.

We will use the 'Test for subgroup differences' available in Review Manager software to identify differences between subgroups. A P value of < 0.05 will be considered statistically significant.

 

Sensitivity analysis

We will perform a sensitivity analysis by excluding trials with unclear or high risk of bias for random sequence generation or allocation concealment, unclear or high risk of bias due to lack of blinding of participants, healthcare providers or outcome assessors (for subjective outcomes such as proportion requiring blood transfusion, amount of blood transfused, quality of life, serious adverse events and length of hospital stay) and unclear or high risk of bias due to incomplete outcome data.

We will perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best-case scenario and worst-case scenario (Gurusamy 2009), if more than 25% of data is missing. We will perform a sensitivity analysis by excluding trials in which the mean and the standard deviation were imputed.

 

Summary of findings    [Explanations]

We will present the main results of the review in a ‘Summary of findings’ table. We will include the following outcomes:

  • Risk of mortality.
  • Risk of requiring blood transfusion.
  • Mean difference in blood transfused.
  • Mean difference in haemoglobin levels.
  • Mean difference (or standardised mean difference if different scales are used) in quality of life.
  • Risk of serious adverse events.

We will use GRADEpro software to prepare the summary of findings table. We will judge the overall quality of the evidence for each outcome as ‘high’, ‘moderate’, ‘low’ or ‘very low’ according to the GRADE approach (Schünemann 2011). We will consider the following:

• Impact of risk of bias of individual trials;
• Precision of pooled estimate;
• Inconsistency or heterogeneity (clinical, methodological and statistical);
• Indirectness of evidence;
• Impact of selective reporting and publication bias on effect estimate.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The Cochrane Wounds Group.

The peer reviewers.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. Search strategies

The Cochrane Central Register of Controlled Trials (CENTRAL)

#1 MeSH descriptor Iron Compounds explode all trees
#2 MeSH descriptor Ferric Compounds explode all trees
#3 MeSH descriptor Ferrous Compounds explode all trees
#4 iron OR ferrous OR ferric
#5 (#1 OR #2 OR #3 OR #4)
#6 MeSH descriptor Anemia explode all trees
#7 anemi* OR anaemi*
#8 (#6 OR #7)
#9 (#5 AND #8)

MEDLINE (PubMed)

("Iron Compounds"[Mesh] OR "Ferric Compounds"[Mesh] OR "Ferrous Compounds"[Mesh] OR iron OR ferrous OR ferric) AND ("Anemia"[Mesh] OR anemi* OR anaemi*) AND ((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Embase (OvidSP)

1 exp iron therapy/
2 (iron or ferrous or ferric).af.
3 1 or 2
4 exp anemia/
5 (anemi* OR anaemi*).af.
6 4 or 5
7 exp crossover-procedure/ or exp double-blind procedure/ or exp randomized controlled trial/ or single-blind procedure/
8 (random* or factorial* or crossover* or placebo*).af.
9 7 or 8
10 3 and 6 and 9

ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to present)

ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) (1990 to present)

# 1 TS=(iron OR ferrous OR ferric)
# 2 TS=(anemi* OR anaemi*)
# 3 TS=(random* OR rct* OR crossover OR masked OR blind* OR placebo* OR meta-analysis OR systematic review* OR meta-analys*)
# 4 #3 AND #2 AND #1

Trial registries

(anemi* OR anaemi*)  AND (iron OR ferrous OR ferric)

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Both authors contributed to the protocol.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

KSG: None known.

TR: UCL received in 2009 an educational grant from Vifor Pharma. This funded a research fellow who undertook an audit of anaemia in surgical patients and helped set up a pre-assessment anaemia treatment clinic using intravenous iron before colorectal surgery. These data have been presented at national and international meetings.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • UCL Department of Surgery, Not specified.

 

External sources

  • No sources of support supplied

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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