Iron therapy in anaemic adults without chronic kidney disease.

Iron therapy in anaemic adults without chronic kidney disease (Review) Gurusamy KS, Nagendran M, Broadhurst JF, Anker SD, Richards T

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 12 http://www.thecochranelibrary.com

Iron therapy in anaemic adults without chronic kidney disease (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Oral iron vs inactive control, Outcome 1 Mortality. . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Oral iron vs inactive control, Outcome 2 Proportion requiring blood transfusion. . . . Analysis 1.3. Comparison 1 Oral iron vs inactive control, Outcome 3 Length of hospital stay. . . . . . . . . Analysis 1.4. Comparison 1 Oral iron vs inactive control, Outcome 4 Haemoglobin. . . . . . . . . . . . Analysis 1.5. Comparison 1 Oral iron vs inactive control, Outcome 5 Quality of life. . . . . . . . . . . . Analysis 1.6. Comparison 1 Oral iron vs inactive control, Outcome 6 Serious adverse events. . . . . . . . . . Analysis 2.1. Comparison 2 Parenteral iron vs inactive control, Outcome 1 Mortality. . . . . . . . . . . . Analysis 2.2. Comparison 2 Parenteral iron vs inactive control, Outcome 2 Proportion requiring blood transfusion. . Analysis 2.3. Comparison 2 Parenteral iron vs inactive control, Outcome 3 Haemoglobin. . . . . . . . . . . Analysis 2.4. Comparison 2 Parenteral iron vs inactive control, Outcome 4 Quality of life. . . . . . . . . . Analysis 2.5. Comparison 2 Parenteral iron vs inactive control, Outcome 5 Serious adverse events. . . . . . . . Analysis 3.1. Comparison 3 Parenteral iron vs oral iron, Outcome 1 Mortality. . . . . . . . . . . . . . . Analysis 3.2. Comparison 3 Parenteral iron vs oral iron, Outcome 2 Proportion requiring blood transfusion. . . . Analysis 3.3. Comparison 3 Parenteral iron vs oral iron, Outcome 3 Mean blood transfused. . . . . . . . . . Analysis 3.4. Comparison 3 Parenteral iron vs oral iron, Outcome 4 Haemoglobin. . . . . . . . . . . . . Analysis 3.5. Comparison 3 Parenteral iron vs oral iron, Outcome 5 Quality of life. . . . . . . . . . . . . Analysis 3.6. Comparison 3 Parenteral iron vs oral iron, Outcome 6 Serious adverse events. . . . . . . . . . Analysis 4.1. Comparison 4 Iron: different preparations, Outcome 1 Mortality. . . . . . . . . . . . . . Analysis 4.2. Comparison 4 Iron: different preparations, Outcome 2 Haemoglobin. . . . . . . . . . . . . Analysis 4.3. Comparison 4 Iron: different preparations, Outcome 3 Serious adverse events. . . . . . . . . . Analysis 5.1. Comparison 5 Subgroup analysis, Outcome 1 Mortality (parenteral iron vs inactive control stratified by clinical setting). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.2. Comparison 5 Subgroup analysis, Outcome 2 Mortality (parenteral iron vs inactive control stratified by erythropoietin use). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.3. Comparison 5 Subgroup analysis, Outcome 3 Mortality (parenteral iron vs oral iron stratified by clinical setting). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Iron therapy in anaemic adults without chronic kidney disease Kurinchi Selvan Gurusamy1 , Myura Nagendran2 , Jack F Broadhurst3 , Stefan D Anker4 , Toby Richards1 1

Department of Surgery, Royal Free Campus, UCL Medical School, London, UK. 2 UCL Division of Surgery and Interventional Science, Department of Surgery, London, UK. 3 Division of Medicine, University College London, London, UK. 4 Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany Contact address: Toby Richards, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK. [email protected]. Editorial group: Cochrane Injuries Group. Publication status and date: New, published in Issue 12, 2014. Review content assessed as up-to-date: 11 July 2013. Citation: Gurusamy KS, Nagendran M, Broadhurst JF, Anker SD, Richards T. Iron therapy in anaemic adults without chronic kidney disease. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD010640. DOI: 10.1002/14651858.CD010640.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Anaemia affects about a quarter of the world’s population. An estimated 50% of anaemic people have anaemia due to iron deficiency. Objectives To assess the safety and efficacy of iron therapies for the treatment of adults with anaemia who are not pregnant or lactating and do not have chronic kidney disease. Search methods We ran the search on 11 July 2013. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE (Ovid SP), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus (EBSCO Host), the Institute for Scientific Information Web of Science (ISI WOS) Scientific Citation Index (SCI)-EXPANDED (1970) and Conference Proceedings Citation Index (CPCI)-Science (1990) and Clinicaltrials.gov; we also screened reference lists. An updated search was run on 24 November 2014 but the results have not yet been incorporated into the review. Selection criteria Two review authors independently selected references for further assessment by going through all titles and abstracts. Further selection was based on review of full-text articles for selected references. Data collection and analysis Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence interval (CI) for binary outcomes and the mean difference (MD) or the standardised mean difference (SMD) with 95% CI for continuous outcomes. We performed meta-analysis when possible, when I2 was less than or equal to 80% using a fixed-effect or random-effects model, using Review Manager software. The range of point estimates for individual studies is presented when I2 > 80%. Iron therapy in anaemic adults without chronic kidney disease (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results We included in this systematic review 4745 participants who were randomly assigned in 21 trials. Trials were conducted in a wide variety of clinical settings. Most trials included participants with mild to moderate anaemia and excluded participants who were allergic to iron therapy. All trials were at high risk of bias for one or more domains. We compared both oral iron and parenteral iron versus inactive controls and compared different iron preparations. The comparison between oral iron and inactive control revealed no evidence of clinical benefit in terms of mortality (RR 1.05, 95% CI 0.68 to 1.61; four studies, N = 659; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged from 0.3 to 3.1 g/dL higher in the oral iron group than in the inactive control group. The proportion of participants who required blood transfusion was lower with oral iron than with inactive control (RR 0.74, 95% CI 0.55 to 0.99; three studies, N = 546; very low-quality evidence). Evidence was inadequate for determination of the effect of parenteral iron on mortality versus oral iron (RR 1.49, 95% CI 0.56 to 3.94; 10 studies, N = 2141; very low-quality evidence) or inactive control (RR 1.04, 95% CI 0.63 to 1.69; six studies, N = 1009; very low-quality evidence). Haemoglobin levels were higher with parenteral iron than with oral iron (MD -0.50 g/dL, 95% CI -0.73 to -0.27; six studies, N = 769; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged between 0.3 and 3.0 g/dL higher in the parenteral iron group than in the inactive control group. Differences in the proportion of participants requiring blood transfusion between parenteral iron and oral iron groups (RR 0.61, 95% CI 0.24 to 1.58; two studies, N = 371; very low-quality evidence) or between parenteral iron groups and inactive controls (RR 0.84, 95% CI 0.66 to 1.06; eight studies, N = 1315; very low-quality evidence) were imprecise. Average blood volume transfused was less in the parenteral iron group than in the oral iron group (MD -0.54 units, 95% CI -0.96 to -0.12; very low-quality evidence) based on one study involving 44 people. Differences between therapies in quality of life or in the proportion of participants with serious adverse events were imprecise (very low-quality evidence). No trials reported severe allergic reactions due to parenteral iron, suggesting that these are rare. Adverse effects related to oral iron treatment included nausea, diarrhoea and constipation; most were mild. Comparisons of one iron preparation over another for mortality, haemoglobin or serious adverse events were imprecise. No information was available on quality of life. Thus, little evidence was found to support the use of one preparation or regimen over another. Subgroup analyses did not reveal consistent results; therefore we were unable to determine whether iron is useful in specific clinical situations, or whether iron therapy might be useful for people who are receiving erythropoietin. Authors’ conclusions • Very low-quality evidence suggests that oral iron might decrease the proportion of people who require blood transfusion, and no evidence indicates that it decreases mortality. Oral iron might be useful in adults who can tolerate the adverse events, which are usually mild. • Very low-quality evidence suggests that intravenous iron results in a modest increase in haemoglobin levels compared with oral iron or inactive control without clinical benefit. • No evidence can be found to show any advantage of one iron preparation or regimen over another. • Additional randomised controlled trials with low risk of bias and powered to measure clinically useful outcomes such as mortality, quality of life and blood transfusion requirements are needed.

PLAIN LANGUAGE SUMMARY Iron treatment in adults without kidney disease Background Anaemia is common, affecting about a quarter of the world’s population. Anaemia can be defined as a reduction in the number of circulating red cells or in the quantity of haemoglobin (both of which carry oxygen) in the blood. An estimated 50% of anaemic people have anaemia due to iron deficiency. We wanted to assess the safety and usefulness of iron treatment in adult men and adult women who were not pregnant and had not just given birth to a child, and who did not have kidney disease. To achieve this aim, we searched the medical literature in July 2013 for relevant studies. We included only randomised trials-a type of study in which the treatment received by participants is determined by chance, so that similar types of people are given the different treatments to be studied. This Iron therapy in anaemic adults without chronic kidney disease (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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allows evaluation of the effects of treatment on these people rather than examination of preexisting differences among people receiving different treatments. We included all trials irrespective of the year or language in which they were published. Two review authors independently selected the studies and recorded information from these studies to minimise error. Study characteristics We included 4745 participants from 21 trials who received iron injections, iron tablets or no treatment. Clinical settings of these trials included loss of blood, cancer, anaemia before surgery for various reasons and heart failure, among others. Most trials included participants with mild to moderate anaemia and excluded participants who were allergic to iron therapy. Key results Comparisons between iron tablets and no treatment revealed no evidence of clinical benefit in terms of a decrease in death or in quality of life. However, a reduction in the proportion of participants who required blood transfusion was noted among those who received iron tablets versus no treatment. Haemoglobin levels were higher in participants receiving iron tablets versus no treatment. With regards to iron injections, haemoglobin levels were higher after iron injections compared with levels reported after iron tablets or no treatment, but no evidence showed clinical benefit in terms of a decrease in death, in the number of participants requiring blood transfusion or in quality of life of participants. Although the average amount of blood transfused was less in the iron injection group than in the iron tablet group, only one trial reported this outcome, introducing significant doubt about this finding. Differences in serious complications between people who received iron versus no treatment were imprecise. No trials reported severe allergic reactions due to iron injections, suggesting that these are rare. Most of the adverse events related to iron tablet treatment were mild; effects such as nausea, diarrhoea and constipation were reported. Comparisons of the clinical benefit of one iron preparation over another were imprecise. We were unable to determine whether iron is useful in specific clinical situations because available information was not clearly presented. In summary, no evidence is currently available to support the routine use of iron injections in adult anaemic men and or in adult non-pregnant anaemic women who have not just given birth to a baby. Iron tablets might be useful in anaemic adult men and adult women who can tolerate the side effects. No evidence suggests any advantage of one iron preparation over another. Future research Additional randomised controlled trials are required to determine whether iron treatment decreases death and blood transfusion requirements and improves quality of life. Such trials should be appropriately designed and should include a sufficiently large number of participants, to decrease the chance of erroneous conclusions.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Oral iron vs inactive control for anaemic patients Patient or population: patients with anaemia Settings: variable Intervention: oral iron vs inactive control Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

Number of participants (studies)

Quality of the evidence (GRADE)

Assumed risk

Corresponding risk

Inactive control

Oral iron

100 per 1000

105 per 1000 (68 to 161)

RR 1.05 (0.68 to 1.61)

659 (4 studies)

⊕

Very lowa,b,c,d

Proportion requiring blood 279 per 1000 transfusion

206 per 1000 (153 to 276)

RR 0.74 (0.55 to 0.99)

546 (3 studies)

⊕

Very lowa,d

Mortality

Length of hospital stay

Mean hospital stay in control Mean hospital stay in intervengroups was tion groups was 21.3 days 2.50 lower (6.82 lower to 1.82 higher)

300 (1 study)

⊕

Very lowa,d,e

Haemoglobin g/dL

Mean haemoglobin in control Point estimate of haemoglobin groups ranged between 11.4 in intervention groups in the individual studies was 0.30 to g/dL and 12.4 g/dL 3.10 higher

402 (4 studies)

⊕

Very lowa,d,f

Quality of life

-

276 (1 study)

⊕

Very lowa,d,g

Mean quality of life in intervention groups was 0.13 standard deviations lower (0.37 lower to 0.1 higher)

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Serious adverse events

205 per 1000

197 per 1000 (156 to 250)

RR 0.96 (0.76 to 1.22)

731 (5 studies)

⊕

Very lowa,b,c,d

*The basis for the assumed risk is the average risk among controls. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a Trial(s)

reporting this outcome was/were at high risk of bias. than 300 events in either group. c Confidence intervals overlapped 1 and either 0.75 or 1.25 or both. d Several trials did not report this outcome. e Mean difference overlapped minimal clinically important difference. f Significant heterogeneity was noted by lack of overlap of confidence intervals and by I2 . So, point estimates in the studies are presented. g Standardised mean difference overlapped 0 and -0.25 or +0.25 or both. b Fewer

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BACKGROUND

Description of the condition Oxygen is necessary for 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 can be defined as a reduction in the number of circulating red cells or in the quantity of haemoglobin in the blood (NLM Anemia). The definition of anaemia (WHO 2001) provided by the World Health Organization (WHO) 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 worldwide (WHO 2008). Regional variations and differences in anaemia prevalence have been noted in men, nonpregnant 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 causes are associated with 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 resulting from 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). For an estimated 50% of anaemic people, 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 in chronic inflammatory disorders such as rheumatoid arthritis 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 people 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), people with anaemia due to chronic disease can be treated with a combination of erythropoietin and iron (Davis 2012). Anaemia can cause fatigue (Foubert 2006) and decreased work activity (Scholz 1997). Anaemia can worsen heart failure (Ghali 2009) and is associated with increased mortality in people with chronic heart failure (von Haehling 2010). In people undergoing an operation, preoperative anaemia is associated with increased mortality (Beattie 2009; Dunne 2002; Musallam 2011) and morbidity (Musallam 2011) and prolonged 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, iron isomaltoside, ferumoxytol and ferric carboxymaltose) (Goddard 2011). Serious 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 one million units (one unit is equivalent to 100 mg of iron, otherwise called 100 mg dose equivalent) of iron sucrose sold in the United States (Bailie 2012). Serious and major adverse events for other intravenous iron preparations from this database include 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 generally are made from chemicals, not from animal products; hence they are acceptable for vegetarians.

How the intervention might work Iron supplementation provides iron to the blood circulation system. The amount of iron that reaches the blood circulation varies with different routes of administration, the form of iron given and other factors specific to the route of administration. Bioavailability indicates the proportion of administered iron that reaches the


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general body circulation. Oral iron in the form of bivalent iron (ferrrous form) is preferable to the trivalent form (ferric) because the ferrous form is more bioavailable. On average, the bioavailability of the ferrous form is about 10% to 15% that of total iron, and that of the ferric form is three to four times less (Santiago 2012). The bioavailability of oral iron depends on various factors, including 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 and lysine (Santiago 2012). Oral iron absorption is reduced in infection, inflammation and chronic disease (Weiss 2005). 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 obsolete (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 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 people with chronic kidney disease, in people undergoing renal transplant, 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 people 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 To assess the safety and efficacy of iron therapies for the treatment of adults with anaemia who are not pregnant or lactating and do not have chronic kidney disease.

METHODS

Criteria for considering studies for this review

Types of studies Randomised controlled trials, irrespective of blinding, language, publication status, date of publication, study setting and sample size, were included. We planned to include cluster-randomised trials provided that the effect size had been adjusted for clustering; however, we did not find any such trials. Studies in which treatment group allocation could be predicted, such as allocation by hospital number or date of birth, were excluded. Trials at unclear or at high risk of bias due to allocation concealment were also excluded from the review.

Types of participants Any non-pregnant and non-lactating anaemic adult without chronic kidney disease was included in this review, irrespective of the setting and the degree of anaemia. We included the following broad categories of participants (this is not an exhaustive list). • Blood loss. • Cancer. • Preoperative anaemia. • Chronic heart failure. • Autoimmune disorders. We excluded four important categories of people with anaemia. • Patients with chronic kidney disease and renal transplant, because these participants were included in the review, ’Parenteral versus oral iron therapy for adults and children with chronic kidney disease’ (Albaramki 2012). • Pregnant women because these participants were included in the review, ’Treatments for iron-deficiency anaemia in pregnancy’ (Reveiz 2011). • Postpartum women because these participants were included in the review, ’Treatment for women with postpartum iron deficiency anaemia’ (Dodd 2004). • Children because they were included in another review, ’Iron supplementation for iron deficiency anaemia in children’ (Zeng 2009). We made efforts to exclude children in cases in which their data were described in detail; however, if no detailed description was provided, the trial was included with the knowledge that a small quantity of data from children may be included in the review. We accepted any definition of anaemia used by study authors, provided that all male participants had less than 13 g/dL and all female participants had less than 12 g/dL of haemoglobin (i.e. all participants must have met 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 a trial because it used a different level of haemoglobin or another measure to diagnose anaemia (e.g. 11 g/dL haemoglobin).


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Types of interventions • Oral iron versus placebo or no iron therapy. • Parenteral iron versus placebo or no iron therapy. • Parenteral iron versus oral iron. • Different oral iron formulations (and doses). • Different parenteral iron formulations (and routes (intramuscular vs intravenous) and doses). Co-interventions were allowed if they were provided equally in study 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 study authors). • Mean difference in haemoglobin levels. • Mean difference (or standardised mean difference if different scales were used) in quality of life (as defined by study authors). • Risk of serious adverse events: Serious adverse events are defined as any events that would increase mortality; are life threatening; or required inpatient hospitalisation or resulted in persistent or significant disability; and any important medical events that might have jeopardised participants or required 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 To reduce publication and retrieval bias, we did not restrict our search by language, date or publication status. We included appropriate studies regardless of whether they are published or unpublished. Electronic searches We searched the following electronic databases. • Cochrane Central Register of Controlled Trials (The Cochrane Library) (Issue 7, 2013); • MEDLINE (Ovid) (1950 to July 2013); • EMBASE (Ovid) (1980 to July 2013);

• CINAHL (Cumulative Index to Nursing and Allied Health Literature) Plus (EBSCO) (1957 to July 2013); • ISI Web of Science: Science Citation Index Expanded (SCIEXPANDED) (1970 to July 2013); • ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (1990 to July 2013). Search strategies are listed in Appendix 1. An updated search was run on 24 November 2014 but the results have not yet been incorporated into the review. The studies identified are listed in Studies awaiting classification. Searching other resources We searched the reference lists of all included studies and previously published reviews for additional studies. We contacted study authors and experts in the field to request additional published or unpublished study information. We had planned to search Google Scholar and to investigate the following online trial registers using the search strategy provided in Appendix 1. • ClinicalTrials.gov (www.clinicaltrials.gov). • WHO International Clinical Trials Registry Platform (ICTRP) portal (http://apps.who.int/trialsearch/). However because of the number of reports retrieved (tens of thousands of reports), we searched only the ClinicalTrials.gov trial register.

Data collection and analysis We performed this systematic review in accordance with instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Selection of studies Two review authors (KSG and TR or MN) identified trials for inclusion independently of each other. We listed the excluded studies along with reasons for exclusion. We resolved differences through discussion. Data extraction and management KSG and MN independently extracted the following data from each included study report. • Year and language of publication. • Country of participant recruitment. • Year of conduct of the trial. • Inclusion and exclusion criteria. • Sample size. • Population characteristics. • Details of iron supplementation, including dose, route, frequency and duration.


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• Outcomes reported and times the outcomes were measured. • Outcomes included in this review. • Risk of bias (as described later).

• High risk of bias: No blinding or incomplete blinding was applied, and the outcome or the outcome measurement was likely to be influenced by lack of blinding.

We obtained this information from all reports if multiple reports described a particular trial. We sought unclear or missing information by contacting the authors of individual trials. If we had any doubt about whether trials shared the same participants, completely or partially (with common authors and centres), we contacted the study authors to clarify whether the trial report had been duplicated. We resolved differences in opinion through discussion. For cluster-randomised trials, we planned to extract effect estimates of the outcomes adjusted for a cluster effect. However, we identified no cluster-randomised trials.

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

Assessment of risk of bias in included studies

Incomplete outcome data

We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). According to empirical evidence (Kjaergard 2001; Lundh 2012; Moher 1998; Schulz 1995; Wood 2008), the risk of bias of included trials was assessed on the basis of the following bias risk domains. Sequence generation

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

• Low risk of bias: The method used (e.g. central allocation) was unlikely to induce bias on the final observed effect. • Uncertain risk of bias: Information was insufficient to allow assessment of whether the method used was likely to induce bias on the estimate of effect. • High risk of bias: The method used (e.g. open random allocation schedule) was 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 was not likely to be influenced by lack of blinding. • Uncertain risk of bias: Information was insufficient to allow assessment of whether the type of blinding used was likely to induce bias on the estimate of effect.

Blinding of outcome assessors

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

• Low risk of bias: The trial protocol was available, and all of the trial’s prespecified outcomes that are of interest for the review had been reported; if the trial protocol was not available, mortality and serious adverse events were reported. • Uncertain risk of bias: Information was insufficient to allow assessment of whether the magnitude and the direction of the observed effect were related to selective outcome reporting. • High risk of bias: Not all of the trial’s prespecified primary outcomes had been reported or were similar. Source of funding bias

• Low risk of bias: The trial protocol was available, and the trial was carried out according to the protocol; or if the trial protocol was not available, the trial was funded by a sponsor who had no vested interest in the results of the trial. • Uncertain risk of bias: Information was insufficient to allow assessment of whether the magnitude and the direction of the observed effect were related to the source of funding. • High risk of bias: Violation of trial protocol occurred, and information on the funder was insufficient; or if the trial


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protocol was not available, the trial was funded by a sponsor who had vested interest in the results of the trial, such as an iron manufacturer. We considered all trials that were classified as having low risk of bias in all of the previously listed domains as low risk of bias trials.

Measures of treatment effect For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). For continuous variables, we calculated 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 (when different scales were used). For time-to-event outcomes such as mortality at maximal follow-up, we planned to calculate the hazard ratio (HR) with 95% CI.

Assessment of heterogeneity We anticipated that major sources of clinical heterogeneity would be associated with 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 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 explored heterogeneity within each meta-analysis using a Chi2 test with significance set at a P value of 0.10, and we expressed the percentage of heterogeneity due to variation rather than to chance as I2 (Higgins 2002). We considered heterogeneity to be moderate if I2 > 50%. If considerable heterogeneity was noted (I2 > 80%), we did not perform a meta-analysis.

Assessment of reporting biases Unit of analysis issues The unit of analysis was the individual anaemic person undergoing treatment. In the case of cluster-randomised trials, we planned to obtain the effect estimate adjusted for the cluster effect.

We used 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 used the linear regression approach described by Egger 1997 to determine funnel plot asymmetry. Selective reporting was also considered as evidence of reporting bias.

Dealing with missing data We performed an intention-to-treat analysis (Newell 1992) when possible. We planned to impute data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best-case scenario and worst-case scenario, if more than 25% was missing (Gurusamy 2009). For continuous outcomes, we used available-case analysis. If the mean and the standard deviation were not available from the trial report, we sought this information from the trial authors. If this information still was not available, we imputed the standard deviation from P values in keeping with instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and we used the median for the meta-analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the confidence intervals, we imputed the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation would decrease the weight of the study for calculation of mean differences and would 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 interval were not reported, we planned to 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.

Data synthesis We performed the meta-analyses using the software package Review Manager version 5.2 (RevMan 2012) and in accordance with recommendations of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We compared the results of a random-effects model (DerSimonian 1986) versus those of a fixedeffect model (DeMets 1987) to assess the effects of small studies. However, we reported the results of the random-effects model. We planned to use the generic inverse variance method to pool (separately) hazard ratios, while 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 planned to use generic inverse variance methods to pool unadjusted effect estimates calculated from simple parallel RCTs with effect estimates adjusted for cluster effect obtained from cluster RCTs. For continuous outcomes, we pooled mean differences or standardised mean differences accordingly by using the inverse variance method. For the mean amount of blood transfused, we analysed separately trials using different methods of measurement of transfused blood (e.g. amount of blood transfused reported in millilitres, amount of blood transfused reported in units of blood transfusion).


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Subgroup analysis and investigation of heterogeneity We planned to perform the following subgroup analyses in the presence of at least two trials under at least two subgroups for the primary outcome (mortality). • Different iron preparations. • Different types of participants (blood loss, cancer, preoperative anaemia, chronic heart failure, autoimmune disorders and infectious disease). • Trials in which erythropoietin was used as a co-intervention in both groups versus trials in which erythropoietin was not used as a co-intervention. We used the ’Test for subgroup differences’ available in Review Manager software to identify differences between subgroups. A P value < 0.05 was considered statistically significant. Because of the different iron preparations and dosage regimens used in different trials, we did not perform a subgroup analysis of different iron preparations.

• 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 used 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 (Grades of Recommendation, Assessment, Development and Evaluation) approach (Schünemann 2011). We considered 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.

Sensitivity analysis We planned to perform a sensitivity analysis by excluding trials with unclear or high risk of bias for random sequence generation; 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. However, all trials had at least one domain with unclear or high risk of bias. We planned to 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 was missing. None of the trials met this criterion. We performed a sensitivity analysis by excluding trials in which the mean and the standard deviation were imputed in the presence of at least two trials for the outcome. Summary of findings We have presented the main results of the review in a ‘Summary of findings’ table. We included the following outcomes. • Risk of mortality. • Risk of requiring blood transfusion.

RESULTS

Description of studies Results of the search We identified a total of 16,331 references through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (n = 1825), MEDLINE (n = 8473), EMBASE (n = 3661), Science Citation Index-Expanded (n = 1042) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus (n = 1330). From ClinicalTrials.gov, we identified 30 trials that potentially met the inclusion criteria. We have shown the flow of references in Figure 1. We excluded 5678 duplicates, then 10,501 clearly irrelevant references, by reading titles and abstracts. The full-text copy of two references could not be obtained (Izuel-Rami 2006; Kang 2006). Neither of these references is likely to provide additional information for the systematic review, but we are looking for them so we can be absolutely sure. We identified a further 82 references upon updating the searches on 24 November 2014; these references are awaiting classification.


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Figure 1. Study flow diagram.


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A total of 180 references were retrieved for further assessment. No references were identified by reference searching. Of 180 study reports retrieved in full text, we excluded 55 references (to 54 studies) for the reasons listed in the Characteristics of excluded studies table. In all, 77 references (62 studies including 30 potentially eligible trials identified from trial registers) are awaiting classification, as more information is required, although we contacted the authors of every study listed in August 2012. Although many of these studies mention that they were randomised, the method of allocation concealment was not stated, and because this is one of the inclusion criteria for our review, we cannot include these studies until further information is received. It was not clear whether many of the trials identified from the ClinicalTrials.gov register included participants with chronic kidney disease, children and pregnant or lactating women. People with these characteristics are excluded from this review. In total, 48 publications describing 21 randomised trials fulfilled the inclusion criteria. All 21 randomised controlled trials provided quantitative data for this review, but only 19 trials could be included in the meta-analysis. Data from two trials could not be included in a meta-analysis, as there was no other similar study, but the results are shown on a forest plot (Evstatiev 2011; Hetzel 2012).

of the trials included participants with mild to moderate anaemia and excluded participants who were allergic to iron therapy. The clinical settings in the different included trials were blood loss (five trials) (Abrahamsen 1965; Karkouti 2006; Parker 2010; Sutton 2004; Van Wyck 2009); cancer (six trials) (Auerbach 2010; Bastit 2008; Dangsuwan 2010; Hedenus 2007; Maccio 2010; Steensma 2010); preoperative anaemia of varied aetiology (three trials) (Edwards 2009; Lidder 2007; Madi-Jebara 2004); chronic heart failure (two trials) (Anker 2009; Beck-da-Silva 2013); autoimmune disorders (two trials) (Evstatiev 2011; Lindgren 2009); and others (three trials) (Hetzel 2012; Pieracci 2009; Vadhan-Raj 2013). Further details of participants are shown in the Characteristics of included studies table and in Table 2.

Intervention

Most trials used the intravenous route as the form of parenteral administration of iron. Intramuscular iron was used as parenteral iron in one trial (Abrahamsen 1965). Most trials using intravenous iron gave it as a divided dose (undiluted or diluted in normal saline). Total dose infusion was provided in one of the arms of one trial (Evstatiev 2011). Further details of interventions are given in the Characteristics of included studies table and in Table 2.

Included studies Four trials compared oral iron with inactive control (Lidder 2007; Parker 2010; Pieracci 2009; Sutton 2004). Six trials compared parenteral iron versus inactive control (Anker 2009; Edwards 2009; Hedenus 2007; Karkouti 2006; Madi-Jebara 2004; Vadhan-Raj 2013). Two trials compared parenteral iron with standard practice, which consisted of oral iron or no intervention (Auerbach 2010; Bastit 2008). Four trials compared parenteral iron versus oral iron (Dangsuwan 2010; Lindgren 2009; Maccio 2010; Van Wyck 2009). Three trials compared parenteral iron, oral iron and inactive control (Abrahamsen 1965; Beck-da-Silva 2013; Steensma 2010). Two trials compared different preparations of intravenous iron (Evstatiev 2011; Hetzel 2012). None of the trials that compared different preparations of oral iron met all of the eligibility criteria of this review (allocation concealment at low risk of bias).

Control

The inactive control for the comparison between oral iron versus inactive control was oral placebo in two trials (Pieracci 2009; Sutton 2004). The inactive control for the comparison between intravenous iron versus inactive control was placebo in five trials (Anker 2009; Edwards 2009; Karkouti 2006; Madi-Jebara 2004; Vadhan-Raj 2013). One trial comparing intravenous iron, oral iron and inactive control used an intravenous placebo and an oral placebo, so that adequate blinding could be achieved (Beck-daSilva 2013). Another trial comparing intravenous iron, oral iron and inactive control used a oral placebo to blind the comparison between oral iron and inactive control but used no intravenous placebo to blind the comparison between intravenous iron with oral iron and inactive control (Steensma 2010).

Participants

Overall, 4799 participants took part in the 21 trials included in this systematic review. The average age of participants in these trials ranged from 39 to 82 years in the trials that provided this information. The proportion of females ranged from 23.8% to 100% in the trials that provided this information. The proportion of postrandomisation dropouts ranged from 0% to 19.2%. After postrandomisation dropouts occurred, 4745 participants were included in the various analyses in this systematic review. Most

Co-interventions

Supplementary erythropoietin was used in all arms of five trials (Auerbach 2010; Bastit 2008; Hedenus 2007; Maccio 2010; Steensma 2010). In the remaining trials, supplementary erythropoietin was not used for the participants included in this review. Supplementary oral iron was used as a co-intervention in both arms of one trial comparing parenteral iron versus inactive control (Karkouti 2006). Supplementary oral iron was allowed as part of


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standard practice (i.e. investigators were allowed to continue their standard practice, and some participants in the control group received oral iron while others did not receive this, depending upon investigators’ preference) in two trials comparing parenteral iron versus control (Auerbach 2010; Bastit 2008).

Excluded studies

Reasons for exclusion are shown in the Characteristics of excluded studies table.

Risk of bias in included studies None of the included studies was of low risk of bias in every domain. Risk of bias in individual trials is shown in Figure 2, and the proportions of trials with low risk, unclear risk and high risk of bias in each of the domains are shown in Figure 3.

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies. Twenty-one studies are included in this review.


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Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation Random sequence generation was adequate in 15 trials ( Abrahamsen 1965; Anker 2009; Beck-da-Silva 2013; Dangsuwan 2010; Edwards 2009; Evstatiev 2011; Hedenus 2007; Hetzel 2012; Karkouti 2006; Lindgren 2009; Maccio 2010; Parker 2010; Steensma 2010; Sutton 2004; Van Wyck 2009). As trials that were at unclear or high risk of bias due to allocation concealment were excluded from the review, allocation concealment was adequate in all 21 trials. Overall, 15 trials were at low risk of selection bias (Abrahamsen 1965; Anker 2009; Beck-da-Silva 2013; Dangsuwan 2010; Edwards 2009; Evstatiev 2011; Hedenus 2007; Hetzel 2012; Karkouti 2006; Lindgren 2009; Maccio 2010; Parker 2010; Steensma 2010; Sutton 2004; Van Wyck 2009).

Blinding Seven trials were free from performance bias and detection bias because of use of placebo and blinding of participants, healthcare providers and outcome assessors to the groups to which participants were randomly assigned (Anker 2009; Beck-da-Silva 2013; Edwards 2009; Karkouti 2006; Pieracci 2009; Sutton 2004; Vadhan-Raj 2013).

Other potential sources of bias Five trials were free from source of funding bias and were considered to be free from other potential sources of bias (Abrahamsen 1965; Dangsuwan 2010; Maccio 2010; Parker 2010; Sutton 2004).

Effects of interventions See: Summary of findings for the main comparison Oral iron vs inactive control for anaemic patients; Summary of findings 2 Parenteral iron vs inactive control for anaemic patients; Summary of findings 3 Parenteral iron vs oral iron for anaemic patients Although the risk of mortality at one year was the primary outcome for this review, only short-term mortality was reported in all trials. None of the trials reported long-term mortality; therefore hazard ratio was not calculated for any of the comparisons. All references to mortality indicate the risk ratio of short-term mortality within one year, with mortality measured in most trials a few weeks after the start of therapy.

Oral iron versus inactive control Results are summarised in Summary of findings for the main comparison.

Incomplete outcome data No postrandomisation dropouts were reported in 10 trials; these trials were considered free from risk of attrition bias (Abrahamsen 1965; Anker 2009; Beck-da-Silva 2013; Dangsuwan 2010; Hedenus 2007; Hetzel 2012; Maccio 2010; Madi-Jebara 2004; Parker 2010; Pieracci 2009).

Selective reporting We were able to locate a published protocol for only one trial (Beck-da-Silva 2013). This trial reported the main outcomes of interest as stated in its protocol and was considered to be at low risk of selective outcome reporting bias. Fifteen trials reported mortality and serious adverse events, which are expected to be reported as per International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines for clinical trials of pharmaceutical agents (ICH-GCP 1996). These trials were considered at low risk of selective outcome reporting bias, and the remaining trials were considered at high risk of selective outcome reporting bias (Abrahamsen 1965; Anker 2009; Auerbach 2010; Bastit 2008; Dangsuwan 2010; Hedenus 2007; Hetzel 2012; Karkouti 2006; Maccio 2010; Madi-Jebara 2004; Parker 2010; Steensma 2010; Sutton 2004; Vadhan-Raj 2013; Van Wyck 2009).

Mortality

Four trials reported this outcome (Abrahamsen 1965; Beck-daSilva 2013; Parker 2010; Steensma 2010). No statistically significant differences in mortality were observed between oral iron and inactive control groups (RR 1.05, 95% CI 0.68 to 1.61; I2 = 0%; Chi2 test for heterogeneity P value 0.45) (Analysis 1.1). No significant change in results with use of the fixed-effect model or the random-effects model would have changed the conclusions.

Blood transfusion requirements

Three trials reported the proportions of participants who required blood transfusion (Lidder 2007; Pieracci 2009; Steensma 2010). The proportion of participants who required blood transfusion was statistically significantly lower in the oral iron group than in the inactive control group when the random-effects model was used (RR 0.74, 95% CI 0.55 to 0.99; I2 = 0%; Chi2 test for heterogeneity P value 0.57) (Analysis 1.2). No statistically significant differences were noted in the proportions of participants who required blood transfusion when the fixed-effect model was used (RR 0.76, 95% CI 0.56 to 1.02). None of the trials reported mean blood transfused.


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Haemoglobin levels

Parenteral iron versus inactive control

Four trials reported haemoglobin levels. Three trials reported final haemoglobin levels (Beck-da-Silva 2013; Parker 2010; Sutton 2004) and one trial reported change in haemoglobin (Abrahamsen 1965). As considerable heterogeneity was noted (I2 = 89%), we did not perform the meta-analysis (Analysis 1.4). The point estimate of the mean difference in haemoglobin levels in individual studies ranged from 0.3 to 3.1 g/dL higher in the oral iron group than in the inactive control group (Analysis 1.4). Mean or standard deviation or both were imputed in two trials (Abrahamsen 1965; Sutton 2004), but we did not perform a sensitivity analysis, as a meta-analysis was not performed.

Results are summarised in Summary of findings 2.

Mortality

Ten trials reported mortality (Abrahamsen 1965; Anker 2009; Auerbach 2010; Bastit 2008; Beck-da-Silva 2013; Hedenus 2007; Karkouti 2006; Madi-Jebara 2004; Steensma 2010; Vadhan-Raj 2013). No statistically significant differences in mortality were observed between parenteral iron and inactive control groups (RR 1.04, 95% CI 0.63 to 1.69; I2 = 8%; Chi2 test for heterogeneity P value 0.37) (Analysis 2.1). The conclusions are not changed with use of the fixed-effect model or the random-effects model.

Quality of life

One trial (Steensma 2010) used the Fatigue Linear Analog Scale Assessment (LASA) (Steensma 2010). No statistically significant difference in quality of life was noted between oral iron and inactive control groups (SMD 0.13, 95% CI -0.10 to 0.37) (Analysis 1.5). Serious adverse events

Five trials reported this outcome (Abrahamsen 1965; Beck-daSilva 2013; Parker 2010; Steensma 2010; Sutton 2004), and no serious adverse events were observed in either group in four trials (Abrahamsen 1965; Beck-da-Silva 2013; Parker 2010; Sutton 2004). No statistically significant differences in serious adverse events were noted between oral iron and inactive control groups in the remaining trial (Steensma 2010) (RR 0.96, 95% CI 0.76 to 1.22) (Analysis 1.6). Adverse events related to oral iron included nausea, diarrhoea or constipation; most reported cases were mild. Length of hospital stay

One trial (Parker 2010) found no statistically significant difference in length of hospital stay between the two groups (MD -2.50 days, 95% CI -6.82 to 1.82). Subgroup analysis (primary outcome)

Subgroup analysis was not possible, as a minimum of two trials is needed.


Eight trials reported the proportions of participants who required blood transfusion (Anker 2009; Auerbach 2010; Bastit 2008; Edwards 2009; Hedenus 2007; Karkouti 2006; Madi-Jebara 2004; Steensma 2010). No statistically significant differences were noted in the proportions of participants who required blood transfusion between parenteral iron and inactive control groups (RR 0.84, 95% CI 0.66 to 1.06; I2 = 0%; Chi2 test for heterogeneity P value 0.67) (Analysis 2.2). No significant change in results with use of the fixed-effect model or the random-effects model would have changed the conclusions. No trials reported the amount of blood transfused.

Haemoglobin levels

Eight trials reported haemoglobin levels. Six trials reported final haemoglobin levels (Anker 2009; Beck-da-Silva 2013; Edwards 2009; Hedenus 2007; Karkouti 2006; Madi-Jebara 2004) and three trials reported change in haemoglobin from the baseline measurement (Abrahamsen 1965; Auerbach 2010; Vadhan-Raj 2013). As considerable heterogeneity was noted (I2 = 95%), we did not perform the meta-analysis (Analysis 2.3). The point estimate of the mean difference in haemoglobin levels in individual studies ranged from 0.3 to 3.0 g/dL higher in the parenteral iron group than in the inactive control group (Analysis 2.3). Mean or standard deviation or both were imputed in two trials (Abrahamsen 1965; Hedenus 2007), but we did not perform a sensitivity analysis, as a meta-analysis was not performed.

Sensitivity analysis

No imputation of mean or standard deviation was performed for length of hospital stay or quality of life. Reporting bias

As fewer than 10 trials provided information for each of the outcomes under this comparison, we did not explore reporting bias using a funnel plot.

Quality of life

Four trials reported on quality of life (Anker 2009; Bastit 2008; Steensma 2010; Vadhan-Raj 2013). The scales used were self-reported Patient Global Assessment (Anker 2009), Functional Assessment of Cancer Therapy-Fatigue (FACT-F) (Bastit 2008), Fatigue Linear Analog Scale Assessment (LASA) (Steensma 2010) and Functional Assessment of Chronic Illness Therapy Fatigue


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(FACITFatigue) (Vadhan-Raj 2013). As considerable heterogeneity was noted (I2 = 81%), we did not perform the meta-analysis. Statistical heterogeneity was high (I2 = 81%). The point estimate of the standardised mean difference in quality of life in individual studies ranged from 0.04 lower to 0.44 higher in the parenteral iron group than in the inactive control group (Analysis 2.4). No mean or standard deviation for quality of life was imputed.

Mortality

Six trials reported mortality (Abrahamsen 1965; Beck-da-Silva 2013; Dangsuwan 2010; Maccio 2010; Steensma 2010; Van Wyck 2009). No statistically significant differences in mortality between parenteral iron and oral iron groups were reported (RR 1.49, 95% CI 0.56 to 3.94; I2 = 0%; Chi2 test for heterogeneity P value 0.52) (Analysis 3.1). No significant change in results with use of the fixed-effect model or the random-effects model would have changed the conclusions.


Seven trials provided information on serious adverse events (Abrahamsen 1965; Anker 2009; Bastit 2008; Beck-da-Silva 2013; Hedenus 2007; Steensma 2010; Vadhan-Raj 2013). No statistically significant differences in serious adverse events were noted between parenteral iron and inactive control groups (RR 1.00, 95% CI 0.74 to 1.34; I2 = 25%; Chi2 test for heterogeneity P value 0.25) (Analysis 2.5). None of the trials reported severe allergic reactions due to parenteral iron, suggesting that these are rare. No significant change in results with use of the fixed-effect model or the random-effects model would have changed the conclusions.


This outcome was not reported in any of the trials.


Two trials reported the proportions of participants who required blood transfusion (Dangsuwan 2010; Steensma 2010). No statistically significant differences between parenteral iron and oral iron were noted in the proportions of participants who required blood transfusion (RR 0.61, 95% CI 0.24 to 1.58; I2 = 72%; Chi 2 test for heterogeneity P value 0.06) (Analysis 3.2). No significant change in results with use of the fixed-effect model or the randomeffects model would have changed the conclusions. Only one trial reported mean blood transfused (Dangsuwan 2010). Mean blood transfused was statistically significantly less in the parenteral iron group than in the oral iron groups (MD -0.54 units, 95% CI -0.96 to -0.12) (Analysis 3.3). No mean or standard deviation for quantity of blood transfused was imputed.

Subgroup analysis

The test for subgroup differences was not statistically significant for subgroup analysis based on clinical setting or for erythropoietin use (P values of 0.93 and 0.34, respectively) (Analysis 5.1; Analysis 5.2).

Sensitivity analysis

In one of the trials included in this comparison, some participants in the control group received oral iron based on investigators’ preference (Bastit 2008). No important change was noted in interpretation of results for comparisons for which meta-analysis was performed after this trial was excluded. This was a post hoc sensitivity analysis.

Reporting bias

As fewer than 10 trials provided information for each of the outcomes under this comparison, we did not explore reporting bias by funnel plot.

Haemoglobin levels

Six trials reported haemoglobin levels. Three trials reported final haemoglobin levels (Beck-da-Silva 2013; Dangsuwan 2010; Lindgren 2009) and three trials reported change in haemoglobin (Abrahamsen 1965; Maccio 2010; Van Wyck 2009). Haemoglobin levels were statistically significantly higher with parenteral iron than with oral iron (MD -0.50 g/dL, 95% CI -0.73 to -0.27; I 2 = 0%; Chi2 test for heterogeneity P value 0.53) (Analysis 3.4). Negative signs ensured that better outcomes in intervention were shown when the summary estimate was to the left of the line of no effect. No significant change in results with use of the fixed-effect model or the random-effects model would have changed the conclusions. Mean or standard deviation or both were imputed in two trials (Abrahamsen 1965; Lindgren 2009). Excluding these trials did not alter the point estimate, nor did it change the statistical significance, although confidence intervals became wider (i.e. the results became less precise; MD -0.49 g/dL, 95% CI -0.86 to 0.12).

Quality of life

Parenteral iron versus oral iron Results are summarised in Summary of findings 3.

Three trials reported on quality of life (Dangsuwan 2010; Steensma 2010; Van Wyck 2009). The scales used were Functional Assessment of Cancer Therapy-Anemia (Fact-An) (Dangsuwan


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2010), Short-Form 36 (SF-36) (Van Wyck 2009) and Fatigue Linear Analog Scale Assessment (LASA) (Steensma 2010). No statistically significant differences in quality of life were observed between parenteral iron and oral iron groups (SMD -0.02, 95% CI -0.16 to 0.13; I2 = 0%; Chi2 test for heterogeneity P value 0.47) (Analysis 3.5). No significant change in results with use of the fixed-effect model or the random-effects model would have changed the conclusions. No mean or standard deviation for quality of life was imputed.


Seven trials reported serious adverse events (Abrahamsen 1965; Beck-da-Silva 2013; Dangsuwan 2010; Lindgren 2009; Maccio 2010; Steensma 2010; Van Wyck 2009). No statistically significant differences in serious adverse events between parenteral iron and oral iron groups were reported (RR 1.23, 95% CI 0.99 to 1.54; I2 = 0%; Chi2 test for heterogeneity P value 0.57) (Analysis 3.6). No trials reported severe allergic reactions due to parenteral iron, suggesting that these are rare. Adverse events related to oral iron treatment included effects such as nausea, diarrhoea or constipation; most cases were mild. No significant change in results with use of the fixed-effect model or the random-effects model would have changed the conclusions.


This outcome was not reported in any of the trials.

Subgroup analysis

Subgroup differences were not statistically significant for subgroup analysis based on clinical setting (P value 0.52) (Analysis 5.3)-the only subgroup analysis with at least two subgroups and at least two trials.


None of the trials reported the proportions of participants who required blood transfusion or mean blood transfused.

Haemoglobin levels

Both trials-one comparing intravenous ferric carboxymaltose versus intravenous iron sucrose (Evstatiev 2011) and one comparing intravenous ferric carboxymaltose versus intravenous iron sucrose (Hetzel 2012)-reported haemoglobin levels. Both trials reported final haemoglobin levels. No statistically significant differences in haemoglobin levels were reported for either comparison (MD 0.20 g/dL, 95% CI -0.68 to 0.28, and MD -0.30 g/dL, 95% CI -1.11 to 0.51, respectively) (Analysis 4.2). No mean or standard deviation was imputed for these two trials.

Quality of life

No trials reported this outcome.


Two trials-one comparing intravenous ferric carboxymaltose versus intravenous iron sucrose (Evstatiev 2011) and one comparing intravenous ferric carboxymaltose versus intravenous iron sucrose (Hetzel 2012)-reported serious adverse events. One participant with serious adverse events was described in the intravenous carboxymaltose group, and no serious adverse events were reported in the intravenous iron sucrose group (Evstatiev 2011). This difference was not statistically significant (Analysis 4.3). No statistically significant differences in the proportions of participants who developed serious adverse events were noted in the comparison between intravenous ferrumoxytol and iron sucrose (RR 1.67, 95% CI 0.62 to 4.45) (Analysis 4.3).

Reporting bias

As fewer than 10 trials provided information for each of the outcomes under this comparison, we did not explore reporting bias using a funnel plot. Iron: different preparations


Length of hospital stay was not reported for any of the trials.

Subgroup analysis

Subgroup analysis was not possible because too few trials were included under each comparison.

Mortality

Only one trial reported mortality (Hetzel 2012). This trial compared two intravenous iron preparations (ferrumoxytol vs iron sucrose) and reported no statistically significant differences in mortality between the two intravenous iron preparations (RR 1.47, 95% CI 0.06 to 36.03) (Analysis 4.1).

Reporting bias

As fewer than 10 trials provided information for each of the outcomes under each comparison, we did not explore reporting bias by funnel plot.


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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Parenteral iron vs inactive control for anaemic patients Patient or population: patients with anaemia Settings: variable Intervention: parenteral iron vs inactive control Outcomes

Mortality





Assumed risk

Corresponding risk

Inactive control

Parenteral iron

46 per 1000

47 per 1000 (29 to 77)

RR 1.04 (0.63 to 1.69)

2141 (10 studies)

⊕

Very lowa,b,c,d

153 per 1000 (120 to 193)

RR 0.84 (0.66 to 1.06)

1315 (8 studies)

⊕

Very lowa,b,c

Proportion requiring blood 182 per 1000 transfusion Haemoglobin g/dL

Mean haemoglobin in control The point estimate of haemogroups ranged between 11.2 globin in intervention groups g/dL and 13.0 g/dL in the individual studies was from 0.30 to 3.00 higher

1371 (9 studies)

⊕

Very lowa,e

Quality of life

-

The point estimate of haemoglobin in intervention groups in the individual studies was between 0.04 standard deviations lower and 0.44 standard deviations higher

1629 (4 studies)

⊕

Very lowa,d,e,f,g


184 per 1000

184 per 1000

1802 (7 studies)

⊕

Very lowa,b,c,d,g

RR 1 (0.74 to 1.34)

20


*The basis for the assumed risk is the average risk among controls. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a Trial(s)

reporting this outcome was/were at high risk of bias. than 300 events in either group. c Confidence intervals overlapped 1 and either 0.75 or 1.25 or both. d Publication bias could not be explored because fewer than 10 trials were included. e Heterogeneity was significant, as was noted by lack of overlap of confidence intervals and by I2 . So, point estimates in the studies are presented. f Standardised mean difference overlapped 0 and -0.25 or +0.25 or both. g Several trials did not report this outcome. b Fewer

21


Parenteral iron vs oral iron for anaemic patients Patient or population: patients with anaemia Settings: variable Intervention: parenteral iron vs oral iron Outcomes





Assumed risk

Corresponding risk

Oral iron

Parenteral iron

12 per 1000

18 per 1000 (7 to 47)

RR 1.49 (0.56 to 3.94)

1009 (6 studies)

⊕

Very lowa,b,c,d

Proportion requiring 189 per 1000 blood transfusion

115 per 1000 (45 to 299)

RR 0.61 (0.24 to 1.58)

371 (2 studies)

⊕

Very lowa,b,c,d,e

Mean blood transfused units

Mean mean blood transfused in control groups was 0.86 unit

Mean blood transfused in intervention groups was 0.54 lower (0.96 to 0.12 lower)

44 (1 study)

⊕

Very lowa,d

Haemoglobin g/dL

Mean haemoglobin in control groups was between 9.5 g/dL and 12.5 g/dL

Mean haemoglobin in intervention groups was 0.5 lower (0.73 to 0.27 lower)

769 (6 studies)

⊕⊕

Lowa,d

Quality of life

-

Mean quality of life in intervention groups was 0.02 standard deviations lower (0.16 lower to 0.13 higher)

771 (3 studies)

⊕

Very lowa,d,f

Mortality

Comments

SMD 0.09 (-0.04 to 0.22)

22



131 per 1000

162 per 1000 (130 to 202)

RR 1.23 (0.99 to 1.54)

1100 (7 studies)

⊕

Very lowa,b,c

*The basis for the assumed risk is average risk among controls. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a Trial(s)

reporting this outcome was/were at high risk of bias. than 300 events in either group. c Confidence intervals overlapped 1 and either 0.75 or 1.25 or both. d Publication bias could not be explored because fewer than 10 trials were included. e Heterogeneity was significant, as was noted by lack of overlap of confidence intervals and by I2 . f Standardised mean difference overlapped 0 and -0.25 or +0.25 or both. b Fewer

23

DISCUSSION

Summary of main results In this systematic review, we examined the utility of iron therapy in the treatment of individuals with anaemia (non-peripartal anaemic adults without chronic kidney disease). We compared parenteral iron versus oral iron; parenteral iron versus inactive control; oral iron versus inactive control and different iron preparations. Most trials included participants with mild to moderate anaemia. In these participants, haemoglobin levels were statistically significantly higher among participants receiving parenteral iron than among those who received oral iron or inactive control. However these trials demonstrate no clinical benefit in terms of mortality, proportions of participants requiring blood transfusion or quality of life-outcomes that would determine whether an intervention could be recommended routinely. Although the mean blood transfused was less in the parenteral iron group than in the oral iron group, only one trial reported this outcome (Dangsuwan 2010). Advantages gained as a result of iron therapy for clinical outcomes such as mortality, quality of life or blood transfusion requirements must be balanced against adverse events. No statistically significant differences were reported among proportions of participants who developed serious adverse events as a result of parenteral iron therapy. According to the Food and Drug Administration (FDA) database, on average, four major or serious adverse events have been reported for every one million units (one unit is equivalent to 100 mg of iron, otherwise called 100 mg dose equivalent) of iron sucrose sold in the USA (Bailie 2012). Serious and major adverse events reported for other intravenous iron preparations from this database include 184 per million units for ferumoxytol; 10 per million units for sodium ferric gluconate; and 27 per million units for iron dextran (Bailie 2012). Most trials reporting serious adverse events found no allergic or anaphylactic reactions or serious reactions, suggesting that these are rare. No justification is apparent for routine use of parenteral iron in the absence of significant clinical benefit, as merely an improvement in haemoglobin level (with no clinical improvement or benefit) is not a reason for iron therapy. Comparisons between oral iron and inactive control again revealed no clinical benefit in terms of mortality and quality of life. A statistically significant reduction in the proportion of participants who required blood transfusion was reported among those who received oral iron therapy as compared with those who received no iron therapy. No statistically significant differences in the proportions of participants who developed serious adverse events as a result of oral iron therapy were reported. Adverse events related to oral iron therapy were gastrointestinal side effects such as nausea, diarrhoea or constipation; most cases were mild. Although the balance of benefits and harms of oral iron therapy appear to favour routine oral iron therapy in anaemic people, the quality of

evidence is very low, as is shown in Summary of findings for the main comparison. Eleven studies compared different preparations or regimens of oral iron (Adsul 2005; Black 1981; Chen 2002; Devasthali 1991; Ferrari 2012; Gordeuk 1987; Jacobs 2000; Langstaff 1993; Li 2005; Mimura 2008; Pedrazzoli 1988). Although these studies were stated to be randomised controlled trials, study authors did not report the method of allocation concealment used; therefore we could not be sure whether they were randomised controlled trials. Thus no trials that compared different oral iron preparations are included in this review. No significant clinical benefits of one intravenous iron preparation over another were revealed in the two comparisons included in this review. Thus, little evidence is available on which one preparation or regimen can be recommended over another. Various subgroup analyses were performed to determine whether iron would be useful in specific clinical situations, or whether iron therapy might be useful in people receiving erythropoietin. Trials included under each of these subgroups were few, and the results were not consistent; therefore we were not able to determine whether iron therapy might be useful in any specific situation.

Overall completeness and applicability of evidence This review is applicable only for non-pregnant and non-lactating anaemic adults without chronic kidney disease who have mild to moderate anaemia. It should be noted that most trials excluded participants who were allergic to iron therapy and measured ferritin and transferrin levels to ensure that participants had iron deficiency anaemia. Iron therapy should be provided only after appropriate medical consultation.

Quality of the evidence Overall, the quality of evidence was very low as indicated in Summary of findings 3 Summary of findings 2 and Summary of findings for the main comparison. Many trials did not report important clinical outcomes, although it is likely that such clinical outcomes were measured. This has resulted in assignment of high risk of selective outcome reporting bias. Overall, the quality of evidence was very low for measured outcomes, most often because of high risk of bias, imprecision and inconsistency.

Potential biases in the review process We searched most of the medical literature databases. We did not search trial registers except ClinicalTrials.gov, as the search resulted in over sixteen thousand references, making it impossible to complete a review for which the searches are current. The main purpose of searching trial registers is to identify any trial that was not


24

reported in the medical literature because of trial results. However, we did not find significant clinical benefit in most comparisons. It should be noted that we did not restrict the articles by language of publication or by whether trials were reported in full text, decreasing the possibility of reporting bias. Two review authors went through the lists of articles independently and extracted data independently to minimise the risk of missing any trials and outcomes reported in the trial reports. We imputed mean and standard deviation when these were not available. This could have introduced bias. However, no evidence suggested such a bias, as exclusion of these trials did not alter the results significantly. It must be noted that the alternative to this imputation is exclusion of such trials or use of a table to report study results; selection of this option would have resulted in even greater bias and difficulty in interpreting data.

Agreements and disagreements with other studies or reviews This is the first systematic review for non-pregnant and non-lactating anaemic adults without chronic kidney disease. We agree with the trial authors who did not recommend routine intravenous iron. We agree with Lee et al, who suggest that improvement in haemoglobin with intravenous iron versus oral iron is of uncertain clinical significance in people with inflammatory bowel disease (Lee 2012). We do not agree with the suggestion of an important role for intravenous iron supplementation in people with cancer, as provided by Baribeault et al (Baribeault 2011). More recently, a systematic review was published that included all trials in which intravenous iron was compared with oral iron or no iron therapy, irrespective of the clinical setting (Litton 2013). Our findings are broadly similar to the findings of that review, which indicated that intravenous iron increased haemoglobin levels and decreased transfusion requirements. That systematic review reported increased infective complications with intravenous iron. Our review found no significant differences among serious adverse events. However, confidence intervals were wide; therefore the results that we iden-

tified might have been due to lack of evidence of effect rather than to lack of effect. We disagree with the authors of the other systematic review that intravenous iron might have broad applicability for many patients in hospital, among whom anaemia is common (Litton 2013), but we agree with the editorial that accompanied this article, which suggests that use of intravenous iron should not be adopted widely until further evaluation (McIntyre 2013).

AUTHORS’ CONCLUSIONS Implications for practice • On the basis of very low-quality evidence, we have determined that oral iron might decrease the proportion of people who require blood transfusion, but no evidence suggests that it decreases mortality. Oral iron might be useful in adults who can tolerate the adverse events, which are usually mild. • Very low-quality evidence suggests that intravenous iron results in a modest increase in haemoglobin levels compared with oral iron or inactive control with no evidence of clinical benefit. • No evidence suggests any advantage of one iron preparation or regimen over another.

Implications for research More randomised controlled trials at low risk of bias that are powered to measure clinically useful outcomes such as mortality, quality of life and blood transfusion requirements are needed.

ACKNOWLEDGEMENTS The Cochrane Injuries Group. Peer reviewers.

REFERENCES

References to studies included in this review Abrahamsen 1965 {published data only} Abrahamsen AF. The effect of orally and parenterally administered iron in posthaemorrhagic anaemia. Acta Medica Scandinavica 1965;177(4):503–7. Anker 2009 {published data only} Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al.Ferric carboxymaltose assessment in patients with Iron deficiency and chronic heart failure with and without anemia (FAIR-HF): a randomized,

double-blind, placebo-controlled, international multicenter phase III study. Circulation 2010;120(21):2156. ∗ Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al.Ferric carboxymaltose in patients with heart failure and iron deficiency. New England Journal of Medicine 2009;361(25):2436–48. Comin-Colet J, Lainscak M, Dickstein K, Filippatos G, Johnson P, Luscher TF, et al.Influence of intravenous ferric carboxymaltose on health-related quality of life measures in patients with chronic heart failure and iron deficiency: an analysis from the FAIR-HF study. European Journal of Heart


25

Failure Supplements 2010;9:S120. Comin-Colet J, Lainscak M, Dickstein K, Filippatos G, Johnson P, Luscher TF, et al.Intravenous ferric carboxymaltose improves health-related quality of life in patients with chronic heart failure and iron deficiency irrespective of renal function and anaemia status: an analysis from the FAIR-HF study. NDT Plus 2010;3(3 Suppl 3): iii217. Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, Luscher TF, et al.The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF study. European Heart Journal 2012; Vol. Epub ahead of print. Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, Luscher TF, et al.The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF study. European Heart Journal 2013;34(1): 30–8. Filippatos G, Farmakis D, Colet JC, Dickstein K, Luscher TF, Willenheimer R, et al.Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial. European Journal of Heart Failure 2013; Vol. Epub ahead of print. Van Craenenbroeck EM, Conraads VM, Greenlaw N, Gaudesius G, Mori C, Ponikowski P, et al.The effect of intravenous ferric carboxymaltose on red cell distribution width: a subanalysis of the FAIR-HF study. European Journal of Heart Failure 2013;15(7):756–62. Auerbach 2010 {published data only} Auerbach M, Silberstein PT, Webb RT, Averyanova S, Ciuleanu TE, Cam L, et al.Darbepoetin alfa (DA) 500MCG or 300MCG once every three weeks (Q3W) with or without iron in patients (PTS) with chemotherapy-induced anemia (CIA). Annals of Oncology 2008;19(S8):viii3. ∗ Auerbach M, Silberstein PT, Webb RT, Averyanova S, Ciuleanu TE, Shao J, et al.Darbepoetin alfa 300 or 500 µg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. American Journal of Hematology 2010;85(9):655–63. Bastit 2008 {published data only} Altintas S, Bastit L, Vandebroek A, Mossman T, Suto T. Analysis of quality of life responses by efficacy response status in cancer patients with chemotherapy-induced anaemia who received darbopoetin alfa 500 mcg every 3 weeks and IV iron [abstract]. Haematologica 2007;97(Suppl 1):286–7. ∗ Bastit L, Vandebroek A, Altintas S, Gaede B, Pinter T, Suto TS, 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. Journal of Clinical Oncology 2008;26(10):1611–8. Lerchenmueller C, Husseini F, Gaede B, Mossman T, Suto T, Vanderbroek A. Intravenous (IV) iron supplementation

in patients with chemotherapy-induced anemia (CIA) receiving darbepoetin alfa every 3 weeks (Q3W): iron parameters in a randomized controlled trial. Blood 2006; 108(11):Abstract 1552. Pinter T, Mossman T, Suto T, Vansteenkiste J. Effects of intravenous (IV) iron supplementation on responses to every-3-week (Q3W) darbepoetin alfa (DA) by baseline hemoglobin in patients (pts) with chemotherapy-induced anemia (CIA) [abstract]. Journal of Clinical Oncology 2007; 25(18S Part I):519. Vandebroek A, Altintas S, Gaede B, Smith K, Yao B, Schupp M. Darbepoetin alfa administered every 3 weeks with or without parenteral iron in anaemic patients with nonmyeloid malignancies receiving chemotherapy: interim results from a randomised open-label study. Haematologica 2006;91(Suppl 1):12. Vandebroek A, Gaede B, Altintas S, Smith K, Yao B, Schupp M, et al.A randomized open-label study of darbepoetin alfa administered every 3 weeks with or without parenteral iron in anemic subjects with nonmyeloid malignancies receiving chemotherapy. Journal of Clinical Oncology 2006;24(18S Part I):496. Vandebroek A, Gaede B, Altintas S, Smith K, Yao B, Schupp M, et al.A randomized open-label study of darbepoetin alfa administered every 3 weeks with or without parenteral iron in anemic subjects with nonmyeloid malignancies receiving chemotherapy. Journal of Supportive Oncology 2007;5(4 Suppl 2):24–6. Beck-da-Silva 2013 {published data only} ∗ Beck-da-Silva L, Piardi D, Soder S, Rohde LE, PereiraBarretto AC, de Albuquerque D, et al.IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. International Journal of Cardiology 2013; Vol. Epub ahead of print. Beck-da-Silva L, Rohde LE, Pereira-Barretto AC, de Albuquerque D, Bocchi E, Vilas-Boas F, et al.Rationale and design of the IRON-HF study: a randomized trial to assess the effects of iron supplementation in heart failure patients with anemia. Journal of Cardiac Failure 2007;13(1):14–7. Dangsuwan 2010 {published data only} Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecologic Oncology 2010;116(3): 522–5. Edwards 2009 {published data only} ∗ Edwards TJ, Noble EJ, Durran A, Mellor N, Hosie KB. Randomized clinical trial of preoperative intravenous iron sucrose to reduce blood transfusion in anaemic patients after colorectal cancer surgery. The British Journal of Surgery 2009;96(10):1122–8. Noble E, Edwards T, Durran A, Mellor N, Hosie KB. A prospective blinded placebo controlled randomised trial of intravenous iron supplementation in patients undergoing colorectal cancer surgery. Colorectal Disease 2009;11(Suppl S1):31.


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Evstatiev 2011 {published data only} Evstatiev R, Marteau P, Iqbal T, Khalif I, Gudehus M, Gasche C. Intravenously administered ferric carboxymaltose and iron sucrose significantly improve quality of life in patients with IBD-associated iron deficiency anaemia. Journal of Crohn’s and Colitis 2011;5(1):S91. ∗ Evstatiev R, Marteau P, Iqbal T, Khalif IL, Stein J, Bokemeyer B, 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. Iqbal T, Evstatiev R, Chopey K, Harjunpaa J, Gasche C. Significant benefit of ferric carboxymaltose in IBDassociated iron deficiency anaemia is independent of patient baseline characteristics. Journal of Crohn’s and Colitis 2011; 5(1):S96–7. Hedenus 2007 {published data only} ∗ Hedenus M, Birgegard G, Nasman P, Ahlberg L, Karlsson T, Lauri B, 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. Hedenus M, Birgegard G, Nasman P, Ahlberg L, Karlsson T, Lauri B, et al.Erratum: 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) vol 21 (627-32) 10.1038/sj.leu.2404562). Leukemia 2008;22(2):462. Hedenus M, Birgegard G, Näsman P, Ahlberg L, Karlsson T, Lauri B, et al.Adjuvant intravenous iron therapy potentiates epoetin beta treatment in anemic, non iron-depleted patients with lymphoproliferative disorders: results of the NIFE study. Hematologica 2006;91(Suppl 1):365. Hetzel 2012 {published data only} Hetzel D, Strauss W, Bernard K, Li J, Allen L. IV iron treatment of iron deficiency anaemia with ferumoxytol in patients with gastrointestinal disorders unable to take oral iron: a randomized controlled trial versus iron sucrose. Journal of Crohn’s and Colitis 2013;7(Suppl 1):S204. ∗ Hetzel D, Urboniene A, Bernard K, Strauss W, Cressman M, Li Z, et al.Potential new treatment option for iron deficiency anemia patients with a history of unsatisfactory oral iron therapy: results of a phase III, randomized, openlabel, active-controlled trial of ferumoxytol. Blood 2012; 120(21):2009. Karkouti 2006 {published data only} Karkouti K, McCluskey SA, Ghannam M, Salpeter MJ, Quirt I, Yau TM. Intravenous iron and recombinant erythropoietin for the treatment of postoperative anemia. Canadian Journal of Anaesthesia 2006;53(1):11–9. Lidder 2007 {published data only} Lidder PG, Hosie KB, Marsden M. A double blind prospective randomized controlled trial of iron supplementation in anaemic patients scheduled for

colorectal cancer surgery. Colorectal Disease 2004;6(Suppl 1):52–3. ∗ Lidder PG, Sanders G, Whitehead E, Douie WJ, Mellor N, Lewis SJ, et al.Pre-operative oral iron supplementation reduces blood transfusion in colorectal surgery: a prospective, randomised, controlled trial. Annals of the Royal College of Surgeons of England 2007;89(4):418–21. Lindgren 2009 {published data only} Lindgren S, Wikman O, Befrits R, Blom H, Eriksson A, Granno C, 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. Scandanavian Journal of Gastroenterology 2009;44(7):838–45. Maccio 2010 {published data only} Maccio A, Madeddu C, Gramignano G, Mulas C, Sanna E, Mantovani G. Efficacy and safety of oral lactoferrin supplementation associated with rHuEPObeta for the treatment of anemia in advanced cancer patients submitted to chemotherapy. Journal of Clinical Oncology 2010;28(15 Suppl 1):2010. ∗ Maccio A, Madeddu C, Gramignano G, Mulas C, Sanna E, Mantovani G. 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. Oncologist 2010;15(8):894–902. Madi-Jebara 2004 {published data only} Madi-Jebara SN, Sleilaty GS, Achouh PE, Yazigi AG, Haddad FA, Hayek GM, et al.Postoperative intravenous iron used alone or in combination with low-dose erythropoietin is not effective for correction of anemia after cardiac surgery. Journal of Cardiothoracic and Vascular Anesthesia 2004;18 (1):59–63. Parker 2010 {published data only} Parker MJ. Iron supplementation for anemia after hip fracture surgery: a randomized trial of 300 patients. The Journal of Bone and Joint Surgery. American Volume 2010;92 (2):265–9. Pieracci 2009 {published data only} Pieracci FM, Henderson P, Rodney JR, Holena DN, Genisca A, Ip I, et al.Randomized, double-blind, placebocontrolled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness. Surgical Infections 2009;10(1):9–19. Steensma 2010 {published data only} Steensma DP, Dakhil SR, Dalton R, Kahanic SP, Kugler JW, Stella PJ, et al.A 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: a study of the Mayo Clinic Cancer Research Consortium (MCCRC). Blood 2009;114(22):Abstract 630. ∗ Steensma DP, Sloan JA, Dakhil SR, Dalton R, Kahanic SP, Prager DJ, et al.Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on


27

the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia. Journal of Clinical Oncology 2010;29(1):97–105. Sutton 2004 {published data only} Sutton PM, Cresswell T, Livesey JP, Speed K, Bagga T. Treatment of anaemia after joint replacement: a doubleblind, randomised, controlled trial of ferrous sulphate versus placebo. The Journal of Bone and Joint Surgery. British Volume 2004;86(1):31–3. Vadhan-Raj 2013 {published data only} Dickerhoof R, DeBusk K, Bernard K, Strauss W, Allen LF, Acaster S. Measuring fatigue in iron deficiency anemia patients: a psychometric validation study. Value in Health 2013;16(3):A36. Raj SV, Cressman M, Ford D, Strauss W, Poss G, Bernard K, et al.Ferumoxytol treatment results in robust hemoglobin increases in iron deficiency anemia patients with a history of unsatisfactory oral iron therapy in a phase III, randomized, placebo-controlled trial. Blood 2012;120(21):2098. Raj SV, Hsieh A, Strauss W, Stevenson M, Bernard K, Allen LF. Ferumoxytol treatment demonstrates significant improvements in fatigue and health-related quality of life in iron deficiency anemia patients with a history of unsatisfactory oral iron therapy. Blood 2012;120(21):478. ∗ Vadhan-Raj S, Strauss W, Ford D, Bernard K, Boccia R, Li J, et al.Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron. American Journal of Hematology 2013; Vol. Epub ahead of print. Van Wyck 2009 {published data only} Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion 2009;49(12):2719–28.

References to studies excluded from this review Anker 2006 {published data only} Anker SD, Okonko DO, Grzeslo A, Witkowski T, Missouris CG, Banasiak W, et al.Intravenous iron sucrose in anemic and non-anemic iron deficient patients with CHF: a randomized, controlled, observer-blinded intervention study (FERRIC-HF). Journal of Cardiac Failure 2006;12 (8):S179.

Aronstam 1982 {published data only} Aronstam A, Aston DL. A comparative trial of a controlledrelease iron tablet preparation (’Ferrocontin’ Continus) and ferrous fumarate tablets. Pharmatherapeutica 1982;3(4): 263–7. Auerbach 2007 {published data only} Auerbach M, Henry DH. Increased importance of intravenous iron in chemotherapy-induced anemia. Journal of Clinical Oncology 2007;25(15):2145–6. Auerbach 2011 {published data only} Auerbach M, Pappadakis JA, Bahrain H, Auerbach SA, Ballard H, Dahl NV. Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia. American Journal of Hematology 2011;86(10): 860–2. Barish 2012 {published data only} Barish CF, Koch T, Butcher A, Morris D, Bregman DB. Safety and efficacy of intravenous ferric carboxymaltose (750 mg) in the treatment of iron deficiency anemia: two randomized, controlled trials. Anemia 2012;2012:172104. Barrison 1981 {published data only} Barrison IG, Roberts PD, Kane SP. Oral or parenteral iron treatment in chronic ulcerative colitis?. British Medical Journal 1981;282(6275):1514. Beris 2006 {published data only} Beris P, Verholen F, Sadowski M, Noger M, Hoffmeyer P. Correction of anemia of the post-operative period after orthopedic surgery by oral versus intravenous iron versus intravenous iron epo: a prospective randomized trial. Haematologica 2006;91(Suppl 1):6. Bermejo 2009 {published data only} Bermejo San Jose F. [Is intravenous iron really useful in inflammatory bowel disease? Would oral iron not be simpler and cheaper?]. Gastroenterologia y Hepatologia 2009;32(1): 63–4. Bernabeu-Wittel 2012 {published data only} Bernabeu-Wittel M, Aparicio R, Romero M, MurciaZaragoza J, Monte-Secades R, Rosso C, et al.Ferric carboxymaltose with or without erythropoietin for the prevention of red-cell transfusions in the perioperative period of osteoporotic hip fractures: a randomized controlled trial. The PAHFRAC-01 project. BMC Musculoskeletal Disorders 2012;13:27 (1 to 8).

Anker 2009a {published data only} Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al.Rationale and design of Ferinject((R)) Assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia. European Journal of Heart Failure 2009;11(11):1084–91.

Bisbe 2011 {published data only} Bisbe E, Garcia-Erce JA, Diez-Lobo AI, Munoz M. A multicentre comparative study on the efficacy of intravenous ferric carboxymaltose and iron sucrose for correcting preoperative anaemia in patients undergoing major elective surgery. British Journal of Anaesthesia 2011;107(3):477–8.

Anonymous 1966 {published data only} Anonymous. The therapeutic effectiveness of various compounds containing iron. Nutrition Reviews 1966;24(8): 232–5.

Black 1981 {published data only} Black GS. A comparison of two iron tablet preparations in the treatment of iron deficiency anaemia. Journal of International Medical Research 1981;9(4):295–6.


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Bulvik 1997 {published data only} Bulvik S, Karalnick S, Leibovitz G, Benist A, Niven M. Intravenous iron gluconate or iron saccharate for patients with iron deficiency anemia with malabsorption or oral iron intolerance. Blood 1997;90(10 Suppl 1 Pt 2):11b. Crosby 1994 {published data only} Crosby L, Palarski VA, Cottington E, Cmolik B. Iron supplementation for acute blood loss anemia after coronary artery bypass surgery: a randomized, placebo-controlled study. Heart & Lung 1994;23(6):493–9. Cuenca 2008 {published data only} Cuenca J, Garcia-Erce JA, Munoz M. Efficacy of intravenous iron sucrose administration for correcting preoperative anemia in patients scheduled for major orthopedic surgery. Anesthesiology 2008;109(1):151–2. Desai 1968 {published data only} Desai HG, Mehta BC, Borkar AV, Jeejeebhoy KN. Effect of intravenous iron therapy on gastric acid secretion in irondeficiency anaemia. Gut 1968;9(1):91–5. Earley 2009 {published data only} Earley CJ, Horska A, Mohamed MA, Barker PB, Beard JL, Allen RP. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Medicine 2009;10(2):206–11. Evers 1977 {published data only} Evers JEM. Iron-poly(sorbitol-gluconic acid) complex and iron-dextran in the treatment of severe iron deficiency anaemia. Scandinavian Journal of Haematology 1977;19 (Suppl 32):279–85. Evstatiev 2013 {published data only} Evstatiev R, Alexeeva O, Bokemeyer B, Chopey I, Felder M, Gudehus M, et al.Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2013;11 (3):269–77. Fitzgerald 2008 {published data only} Fitzgerald JE, Simpson JA, Acheson AG. The use of intravenous iron in patients with cancer related anaemia: don’t overlook iron deficiency anaemia in colorectal cancer. British Journal of Haematology 2008;143(5):754. Froessler 2010 {published data only} Froessler B, Papendorf D. Intravenous iron sucrose-an effective and attractive modality for perioperative anaemia management. Anaesthesia and Intensive Care 2010;38(5): 960–2. Garrido-Martin 2012 {published data only} Garrido-Martin P, Nassar-Mansur MI, De La Llana-Ducros R, Virgos-Aller TM, Fortunez PMR, Avalos-Pinto 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. Interactive CardioVascular and Thoracic Surgery 2012;15(6):1013–8.

Gasche 1995 {published data only} Gasche C, Dejaco C, Waldhor T, Reinisch W, Tillinger W, Vogelsang H, et al.[Double-blind, placebo-controlled study of erythropoietin and iron saccharate in the treatment of anaemia in Crohn’s disease]. Zeitschrift fur Gastroenterologie 1995;33(5):320. Gedik 1995 {published data only} Gedik Y, Erduran E, Mocan H, Aynaci FM, Okten A. The efficacy of ferrous sulfate and ferric polymaltose in therapy of iron deficiency anemia. Annals of Medical Sciences 1995;4 (2):143–4. Grote 2009 {published data only} Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Movement Disorders 2009;24(10): 1445–52. Harris 2009 {published data only} Harris S, Tepper D, Ip R. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiencyferric-HF: a randomized, controlled, observer-blinded trial. Congestive Heart Failure 2009;15(4):208. Hussain 2013 {published data only} Hussain I, Bhoyroo J, Butcher A, Koch TA, He A, Bregman DB. Direct comparison of the safety and efficacy of ferric carboxymaltose versus iron dextran in patients with iron deficiency anemia. Anemia 2013;2013:169107. Kaltwasser 1987 {published data only} Kaltwasser JP, Ockelmann R, Schalk KP. Oral iron therapy: preparations with rapid or delayed iron liberation?. Medizinische Klinik 1987;82(21):730–5. Kaltwasser 1989 {published data only} Kaltwasser JP, Schwarz-Van d SW. Oral iron treatment: bioavailability and therapeutic efficacy of ferrous iron as effervescent tablets in posthaemorrhagic iron-deficiency anaemia. Deutsche Medizinische Wochenschrift 1989;114 (31-32):1188–95. Kulnigg 2009 {published data only} Kulnigg S, Teischinger L, Dejaco C, Waldhor T, Gasche C. Rapid recurrence of IBD-associated anemia and iron deficiency after intravenous iron sucrose and erythropoietin treatment. American Journal of Gastroenterology 2009;104 (6):1460–7. Kulnigg-Dabsch 2012 {published data only} Kulnigg-Dabsch S, Evstatiev R, Dejaco C, Gasche C. Effect of iron therapy on platelet counts in patients with inflammatory bowel disease-associated anemia. PLoS ONE 2012;7(4):e34520. Lewinski 1973 {published data only} Lewinski U, van der Lijn E, Djaldetti M. [Intravenous iron-dextran versus peroral iron and blood transfusion for anemia]. Harefuah 1973;85(4):167–9. Liguori 1993 {published data only} Liguori L. Iron protein succinylate in the treatment of iron deficiency: controlled, double-blind, multicenter clinical


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trial on over 1,000 patients. International journal of Clinical Pharmacology, Therapy, and Toxicology 1993;31(3):103–23. Lipsic 2010 {published data only} Lipsic E, van der Meer P. Erythropoietin, iron, or both in heart failure: FAIR-HF in perspective. European Journal of Heart Failure 2010;12(2):104–5. Littlewood 2012 {published data only} Littlewood TJ. Intravenous or oral iron?. American Journal of Hematology 2012;87(2):134–5. Liu 2004 {published data only} Liu TC, Lin SF, Chang CS, Yang WC, Chen TP. Comparison of a combination ferrous fumarate product and a polysaccharide iron complex as oral treatments of iron deficiency anemia: a Taiwanese study. International Journal of Hematology 2004;80(5):416–20. Mundy 2005 {published data only} Mundy GM, Birtwistle SJ, Power RA. The effect of iron supplementation on the level of haemoglobin after lower limb arthroplasty. The Journal of Bone and Joint Surgery. British Volume 2005;87(2):213–7. Munoz 2011 {published data only} Munoz M, Naveira E, Seara J, Cordero J, Marcos F, Bisbe E. Postoperative intravenous iron after lower limb arthroplasty: a comparative study of different doses on transfusion requirements. European Journal of Anaesthesiology 2011;28: 90. Munoz 2011a {published data only} Munoz M, Naveira E, Seara J, Cordero J, Martos F. Postoperative iron after lower limb arthroplasty: a comparative study of the effects of 300 vs. 600 mg IV iron administration on transfusion requirements. Transfusion Alternatives in Transfusion Medicine 2011;12(1):34–5. Munoz 2012 {published data only} Munoz M, Naveira E, Seara J, Cordero J. Effects of postoperative intravenous iron on transfusion requirements after lower limb arthroplasty. British Journal of Anaesthesia 2012;108(3):532–4. Murgel 1969 {published data only} Murgel GA. Therapy of hypochromic anemia using ferrous sulfate (comparative study of reinforced sustained-release pills and conventional pills). Revista Brasileira de Medicina 1969;26(6):375–9. Najean 1995 {published data only} Najean Y, Acuto G, Scotti A. Multicentre double-blind clinical trial of iron protein succinylate in comparison with iron sulfate in the treatment of iron deficiency anaemia. Clinical Drug Investigation 1995;10(4):198–207. Onken 2013 {published data only} Bregman DB, Morris D, Koch TA, He A, Goodnough LT. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. American Journal of Hematology 2013;88(2):97–101. ∗ Onken JE, Bregman DB, Harrington RA, Morris D, Acs P, Akright B, et al.A multicenter, randomized, activecontrolled study to investigate the efficacy and safety of

intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion 2013; Vol. Epub ahead of print. Ravanbod 2013 {published data only} Ravanbod M, Asadipooya K, Kalantarhormozi M, Nabipour I, Omrani GR. Treatment of iron-deficiency anemia in patients with subclinical hypothyroidism. American Journal of Medicine 2013;126(5):420–4. Raya 2010 {published data only} Raya J, Garrido P, Pecos P, Martinez R, Nassar I, De La Llana R, et al.Analysis of two different schemes of iron treatment to improve postoperative anemia in cardiac surgery: a randomized double-disguised, triple-blind study. Haematologica 2010;95(Suppl 2):706. Rondinelli 2013 {published data only} Rondinelli MB, Inghilleri G, Pavesi M, Di Bartolomei A, Pagnotta R, Terlizzi F, et al.Efficacy of ferrous bisglycinate for the management of patient undergoing pre-operative blood donation or with pre-operative anaemia in orthopedic surgery: a prospective study. Transfusion Medicine 2013;23 (s1):36. Schatz 2013 {published data only} Schatz U, Arneth B, Siegert G, Siegels D, Fischer S, Julius U, et al.Iron deficiency and its management in patients undergoing lipoprotein apheresis. Comparison of two parenteral iron formulations. Atherosclerosis Supplements 2013;14(1):115–22. Serrano-Trenas 2011 {published data only} Serrano-Trenas JA, Ugalde PF, Cabello LM, Chofles LC, Lazaro PS, Benitez PC. Role of perioperative intravenous iron therapy in elderly hip fracture patients: a singlecenter randomized controlled trial. Transfusion 2011;51(1): 97–104. Singh 2007 {published data only} Singh A, Hertel J, Bernardo M, Baptista J, Kausz A, Brenner L, et al.A double-blind, placebo-controlled, randomized phase III study of the safety of ferumoxytol as a new intravenous iron replacement therapy. American Journal of Kidney Diseases 2007;49(4):A32. Strauss 2013 {published data only} Strauss W, Bernard K, Li Z, Allen L. Safety and efficacy of ferumoxytol vs. iron sucrose in the treatment of iron deficiency anemia (IDA) in patients with normal and abnormal renal function. Nephrology Dialysis Transplantation 2013;28(Suppl 1):i9. Wang 2003 {published data only} Wang L, Li G, Liao C, Wang F. The effects of oral vs venous iron supplement in treatment of iron deficiency of maintained patients with anemia [Abstract No. PUB324]. Journal of the American Society of Nephrology 2003;14(Suppl S):842a. Weatherall 2004 {published data only} Weatherall M, Maling TJ. Oral iron therapy for anaemia after orthopaedic surgery: randomized clinical trial. ANZ Journal of Surgery 2004;74(12):1049–51.


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Zauber 1992 {published data only} Zauber NP, Zauber AG, Gordon FJ, Tillis AC, Leeds HC, Berman E, et al.Iron supplementation after femoral head replacement for patients with normal iron stores. JAMA 1992;267(4):525–7.

Chen 2002 {published data only} Chen BB, Lin GW, Wu W, Chen Y, Wang JE, Wang YL. Comparitive study on three iron preparations for treatment of iron deficiency anemia: a randomized-controlled trial. Shanghai Medical Journal 2002;25(3):154–7.

References to studies awaiting assessment

Devasthali 1991 {published data only} Devasthali SD, Gordeuk VR, Brittenham GM, Bravo JR, Hughes MA, Keating LJ. Bioavailability of carbonyl iron: a randomized, double-blind study. European Journal of Haematology 1991;46(5):272–8.

Adsul 2005 {published data only} Adsul BB, Desai A, Gawde A, Baliga V. Comparative assessment of the bioavailability, efficacy and safety of a modified-release (MR) carbonyl iron tablet and oral conventional iron preparation in adult Indian patients with nutritional iron deficiency anaemia. Journal of the Indian Medical Association 2005;103(6):338–42. Anthony 2011 {published data only} ∗ Anthony LB, Gabrail NY, Ghazal H, Woytowitz DV, Flam MS, Drelichman A, et al.IV iron sucrose for cancer and/ or chemotherapy-induced anemia in patients treated with erythropoiesis stimulating agents. Community Oncology 2011;8(6):270–8. Bellet RE, Ghazal H, Flam M, Drelichman A, Gabrail N, Woytowitz D, et al.A phase III randomized controlled study comparing iron sucrose intravenously (IV) to no iron treatment of anemia in cancer patients undergoing chemotherapy and erythropoietin stimulating agent (ESA) therapy [Abstract No. 9109]. Journal of Clinical Oncology 2007;25(18S Part I):519. Auerbach 2004 {published data only} ∗ Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, et al.Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, openlabel, randomized trial. Journal of Clinical Oncology 2004; 22(7):1301–7. Auerbach M, Barker L, Bahrain H, Trout R, McIlwain M, Ballard H. Intravenous iron (IV Fe) optimizes the response to erythropoietin (EPO) in patients with anemia of cancer and cancer chemotherapy: results of a multicenter, openlabel, randomized trial. Blood 2001;98(11):799A. Ballard H, Rana J, Ackerman A, Merino R, Rosenoff S, Kastritsis C, et al.Total dose infusion (TDI) of iron dextran (ID) optimizes erythropoietin (EPO) responsiveness in the anemia of cancer (CA) [abstract]. Proceedings of the American Society of Clinical Oncology 1999;18:581a. Bisbe 2012 {published data only} Bisbe E. Intravenous iron to treat post-operative anaemia. Transfusion Medicine 2013;23(s1):13–4. Bisbe E. Intravenous iron to treat postoperative anaemia. Vox Sanguinis 2013;105(Suppl 1):50. ∗ Bisbe E, Molto L, Arroyo R, Santiveri X, Munoz M. The efficacy of intravenous iron for treating postoperative anemia and hastening functional recovery in patients undergoing total knee arthroplasty: preliminary results from a randomized controlled trial. Transfusion Alternatives in Transfusion Medicine 2012;12(2):29–30.

Erichsen 2005 {published data only} Erichsen K, Ulvik RJ, Grimstad T, Berstad A, Berge RK, Hausken T. Effects of ferrous sulphate and non-ionic ironpolymaltose complex on markers of oxidative tissue damage in patients with inflammatory bowel disease. Alimentary Pharmacology & Therapeutics 2005;22(9):831–8. ∗ Erichsen K, Ulvik RJ, Nysaeter G, Johansen J, Ostborg J, Berstad A, et al.Oral ferrous fumarate or intravenous iron sucrose for patients with inflammatory bowel disease. Scandinavian Journal of Gastroenterology 2005;40(9): 1058–65. Ferrari 2012 {published data only} Ferrari P, Nicolini A, Manca ML, Rossi G, Anselmi L, Conte M, et al.Treatment of mild non-chemotherapy-induced iron deficiency anemia in cancer patients: comparison between oral ferrous bisglycinate chelate and ferrous sulfate. Biomedicine and Pharmacotherapy 2012; Vol. Epub ahead of print. Giordano 2011 {published data only} Giordano G, Mondello P, Tambaro R, De Maria M, D’Amico F, Sticca G, et al.Intravenous iron support vs oral liposomal iron support in patients with refractory anemia treated with Epo alpha. Monocentric prospective study. Leukemia Research 2011;35:S137. Gordeuk 1987 {published data only} Gordeuk VR, Brittenham GM, Hughes M, Keating LJ, Opplt JJ. High-dose carbonyl iron for iron deficiency anemia: a randomized double-blind trial. The American Journal of Clinical Nutrition 1987;46(6):1029–34. Henry 2007 {published data only} Henry DH, Dahl NV. Does quality of life improvement precede anemia correction in patients with chemotherapyinduced anemia treated with intravenous iron? [abstract]. Journal of Clinical Oncology 2007;25(18S Part I):513. Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR. Intravenous ferric gluconate (FG) for increasing response to epoetin (EPO) in patients with anemia of cancer chemotherapy: results of a multicenter, randomized trial. Blood 2004;104(11 Part 2):10b. ∗ Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 2007;12(2):231–42.


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Izuel-Rami 2006 {published data only} Izuel-Rami M, Garcia-Erce JA, Cuenca J, Gomez-Barrera M, Villar I, Rabanaque MJ. Recovery from postoperative anaemia after hip fracture replacement surgery. Is there a role for erythropoietin and intravenous iron?. Transfusion Alternatives in Transfusion Medicine 2006;8(1 Suppl):81. Jacobs 2000 {published data only} Jacobs P, Wood L, Bird AR. Erythrocytes: better tolerance of iron polymaltose complex compared with ferrous sulphate in the treatment of anaemia. Hematology 2000;5(1):77–83. Jakobsen 2013 {published data only} Jakobsen D, Wiesenthal M, Hartmann F, Dignass A, WeberMangal S, Stein J. Safety and efficacy of bolus administered ferric carboxymaltose (500 mg) in the treatment of iron deficiency anaemia in IBD patients. Journal of Crohn’s and Colitis 2013;7(Suppl 1):S162. Kanakaraddi 1973 {published data only} Kanakaraddi VP, Hoskatti CG, Nadig VS, Patil CK, Maiya M. Comparative therapeutic study of T.D.I. and I.M. injections of iron dextran complex in anaemia. Journal of Association of Physicians of India 1973;21(10):849–53. Kang 2006 {published data only} Kang SB, Kim SC, Kim YT. Phase IV randomized study on safety and usefulness of parenteral iron (iron sucrose, venoferrum C) in the management of preoperative anemia in patients with menorrhagia: preliminary data. XVIII FIGO World Congress of Gynecology and Obstetrics 2006;2: 89. Kim 2007 {published data only} Kim YT, Kim SW, Yoon BS, Cho HJ, Nahm EJ, Kim SH, et al.Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy. Gynecologic Oncology 2007;105(1):199–204. Kim 2009 {published data only} Kim YH, Chung HH, Kang SB, Kim SC, Kim YT. 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. Acta Haematologica 2009;121(1):37–41. Kulnigg 2008 {published data only} Kulnigg S, Rumyantsev V, Stoinov S, Simanenkov V, Levchenko E, Karnafel W, et al.A novel intravenous iron formulation for treatment of anemia in IBD: the Ferinject randomized, controlled trial. Gastroenterology 2007;132(4 Suppl 2):A501–2. Kulnigg S, Rumyantsev V, Stoinov S, Simanenkov V, Levchenko E, Karnafel W, et al.A novel intravenous iron formulation for treatment of anemia in IBD: the Ferinject randomized, controlled trial. Zeitschrift fur Gastroenterologie 2007;44(A2):645–6. ∗ Kulnigg S, Stoinov S, Simanenkov V, Dudar LV, Karnafel W, Garcia LC, et al.A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized

controlled trial. American Journal of Gastroenterology 2008; 103(5):1182–92. Langstaff 1993 {published data only} Langstaff RJ, Geisser P, Heil WG, Bowdler JM. Treatment of iron-deficiency anaemia: a lower incidence of adverse effects with Ferrum Hausmann than ferrous sulphate. British Journal of Clinical Research 1993;4:191–8. Li 2005 {published data only} Li XX, Chen XL, Zhang MH, Wang YH, Da WM, Li JY. [A randomized controlled and multicenter clinical study of ferrous L-threonate in treatment of iron deficiency anemia]. Zhonghua Nei Ke Aa Zhi [Chinese Journal of Internal Medicine] 2005;44(11):844–7. Michalopoulou 2009 {published data only} Michalopoulou H, Vaitsis J, Massias S, Stamatis P. Effect of correction of anemia in severe congestive heart failure. Critical Care 2009;13:S168. Mimura 2008 {published data only} Mimura EC, Bregano JW, Dichi JB, Gregorio EP, Dichi I. Comparison of ferrous sulfate and ferrous glycinate chelate for the treatment of iron deficiency anemia in gastrectomized patients. Nutrition 2008;24(7-8):663–8. NCT00199277 {published data only} Marti PP. Iron therapy in colo-rectal neoplasm and iron deficiency anemia: intravenous iron sucrose versus oral ferrous sulphate. http://ClinicalTrials.gov/show/ NCT00199277 2005:Accessed November 2014. NCT00236951 {published data only} Trokars M. Intravenous (IV) iron vs. no iron as the treatment of anemia in cancer patients undergoing chemotherapy and erythropoietin therapy. http:// ClinicalTrials.gov/show/NCT00236951 2010:Accessed November 2014. NCT00482716 {published data only} Agrawal SG. Epoetin alfa or epoetin beta with or without iron infusion in treating anemia in patients with cancer. http://ClinicalTrials.gov/show/NCT00482716 2009: Accessed November 2014. NCT00704028 {published data only} Tokars M. Safety and tolerability of ferric carboxymaltose (FCM) versus iron dextran in treating iron deficiency anemia. http://ClinicalTrials.gov/show/NCT00704028 2011:Accessed November 2014. NCT00706667 {published data only} Theusinger O. Intravenous ferric carboxymaltose (Ferinject ® ) with or without erythropoietin in patients undergoing orthopaedic surgery. http://ClinicalTrials.gov/show/ NCT00706667 2013:Accessed November 2014. NCT00810030 {published data only} Gasche C. Ferinject for correction of anaemia in IBD patients, FER-IBD-COR. http://ClinicalTrials.gov/show/ NCT00810030 2012:Accessed November 2014. NCT00978575 {published data only} Vilstrup H. Iron substitution after upper gastro-intestinal bleeding. http://ClinicalTrials.gov/show/NCT00978575 2013:Accessed November 2014.


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NCT00982007 {published data only} Tokars M. Efficacy and safety of intravenous ferric carboxymaltose (FCM) in patients with iron deficiency anemia (IDA). http://ClinicalTrials.gov/show/ NCT00982007 2013:Accessed November 2014. NCT01017614 {published data only} Pharmacosmos A/S. Iron oligosaccharide in inflammatory bowel disease subjects with iron deficiency anaemia. http:/ /ClinicalTrials.gov/show/NCT01017614 2012:Accessed November 2014. NCT01100879 {published data only} Eirini K, Cushway T. Ferric carboxymaltose for treatment of anaemia of cancer in subjects with multiple myeloma receiving chemotherapy. http://ClinicalTrials.gov/show/ NCT01100879 2011:Accessed November 2014. NCT01101399 {published data only} Karlsson T, McNamara M. Ferric carboxymaltose in subjects with functional iron deficiency undergoing chemotherapy. http://ClinicalTrials.gov/show/NCT01101399 2012: Accessed November 2014. NCT01114139 {published data only} AMAG Pharmaceuticals, Inc. A trial of ferumoxytol for the treatment of iron deficiency anemia. http:// ClinicalTrials.gov/show/NCT01114139 2013:Accessed November 2014. NCT01114204 {published data only} AMAG Pharmaceuticals, Inc. A trial comparing ferumoxytol with iron sucrose for the treatment of iron deficiency anemia. http://ClinicalTrials.gov/show/ NCT01114204 2013:Accessed November 2014. NCT01145638 {published data only} Thomsen LL. A study of intravenous iron isomaltoside 1000 (Monoferâ® ) as monotherapy (without erythropoiesis stimulating agents) in comparison with oral iron sulfate in subjects with non-myeloid malignancies associated with chemotherapy induced anaemia (CIA). http:// ClinicalTrials.gov/show/NCT01145638 . Accessed November 2014. NCT01160198 {published data only} GSK Clinical Trials. A study to demonstrate the efficacy and tolerability of ferrous bisglycinate chelate in iron deficiency anaemia and to compare these with those of ferrous ascorbate. http://ClinicalTrials.gov/show/NCT01160198 2012:Accessed November 2014. NCT01180894 {published data only} Pieracci FM, Moore EE. IV iron for the anemia of traumatic critical illness. http://ClinicalTrials.gov/show/ NCT01180894 2012:Accessed November 2014. NCT01307007 {published data only} Tocars M. Hypophosphatemia with intravenous ferric carboxymaltose versus iron dextran in women with iron deficiency secondary to heavy uterine bleeding. http:// ClinicalTrials.gov/show/NCT01307007 2013:Accessed November 2014. NCT01309659 {published data only} Price E, Schrier S, Artiz A. Trial to evaluate the efficacy of intravenous iron in older adults with unexplained anemia.

http://ClinicalTrials.gov/show/NCT01309659 2012: Accessed November 2014. NCT01340872 {published data only} Harper C, Emery L. Safety and efficacy study of oral ferric iron to treat iron deficiency anaemia in quiescent ulcerative colitis (AEGIS-1). http://ClinicalTrials.gov/ show/NCT01340872 2011:Accessed November 2014. NCT01352221 {published data only} Harper C, Emery L. Safety and efficacy study of oral ferric iron to treat iron deficiency anaemia in quiescent Crohn’s disease (AEGIS-2). http://ClinicalTrials.gov/show/ NCT01352221 2011:Accessed November 2014. NCT01425463 {published data only} UCB, Inc. A double-blind, double-dummy, parallel, active-controlled, randomized and multi-center trial to investigate efficacy and safety in subjects with iron deficiency anemia for ferrous (II) glycine sulphate complex versus polyferose capsules therapy. http://ClinicalTrials.gov/show/ NCT01425463 2013:Accessed November 2014. NCT01428843 {published data only} Savoye G, Colombel JF. Comparison of ferrisat vs placebo in anemia associated to inflammatory bowel disease during anti-TNF therapy. http://ClinicalTrials.gov/show/ NCT01428843 2012:Accessed November 2014. NCT01690585 {published data only} Blot J. Efficacy of parenteral iron supplementation after gastrointestinal bleeding in subjects over 65. http:// ClinicalTrials.gov/show/NCT01690585 2013:Accessed November 2014. NCT01701310 {published data only} Keeler B, Ahceson AG. IVICA: intravenous iron in colorectal cancer associated anaemia. http://ClinicalTrials.gov/show/ NCT01701310 2013:Accessed November 2014. NCT01725789 {published data only} Kim YW. Ferinject® assessment in gastrectomy patients with acute isovolemic anemia (FAIRY). http://ClinicalTrials.gov/ show/NCT01725789 2013:Accessed November 2014. NCT01733979 {published data only} Chae SW. Efficacy and safety of heme-iron polypeptide on improvement of anemia. http://ClinicalTrials.gov/show/ NCT01733979 2012:Accessed November 2014. NCT01837082 {published data only} Karakas M. Iron in congestive heart failure. http:// ClinicalTrials.gov/show/NCT01837082 2013:Accessed November 2014. NCT01857011 {published data only} Montano-Pedroso JC. Iron supplementation for acute anemia after postbariatric abdominoplasty. http:// ClinicalTrials.gov/show/NCT01857011 2013:Accessed November 2014. NCT01927328 {published data only} Keeler B, Acheson AG. Iron replacement in oesophagogastric neoplasia. http://ClinicalTrials.gov/show/NCT01927328 2013:Accessed November 2014. NCT01950247 {published data only} Koch T, Trokars M. Trial to evaluate the utility of serum hepcidin levels to predict response to oral or iv iron and


33

to compare safety, effect on quality of life, and resource utilization of injectafer vs. intravenous standard of care for the treatment of iron deficiency anemia (IDA) in an infusion center setting. http://ClinicalTrials.gov/show/ NCT01950247 2013:Accessed November 2014. Okonko 2008 {published data only} Okonko D, Greszlo A, Witkowski T, Mandal A, Slater R, Roughton M, et al.Effect of intravenous iron sucrose on exercise tolerance in anaemic and nonanaemic patients with symptomatic chronic heart failure and iron deficiency (ferric-HF): a randomised, controlled, observer-blinded trial. Heart 2007;93(Suppl 1):A41. Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Foldes G, et al.Effect of intravenous iron sucrose on exercise tolerance in anemic and non-anemic patients with symptomatic chronic heart failure and iron deficiency: a randomised, controlled, observer-blinded trial (FERRICHF). Circulation 2006;114(18 Suppl S):407. ∗ Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, 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. Journal of the American College of Cardiology 2008;51 (2):103–12. Okonko DO, Grzeslo A, Witkowski T, Missouris CG, Banasiak W, Poole-Wilson PA, et al.Effect of intravenous iron sucrose on exercise tolerance in anaemic and nonanaemic iron deficient patients with chronic heart failure: a randomised, controlled, observer-blinded trial (FERRICHF). European Heart Journal 2006;27(Suppl 1):167. Olijhoek 2001 {published data only} Olijhoek G, Megens JGN, Musto P, Nogarin L, GassmannMayer C, Vercammen E, 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. Oliver 2010 {published data only} Oliver A, Sierra P, Noe L, Monllau V, Ortiz JC. Efficacy of post-operative intravenous iron in elective major urological surgery. Transfusion Alternatives in Transfusion Medicine 2010;11(Suppl S2):33. Pedrazzoli 1988 {published data only} Pedrazzoli P, Scotti A, Farina D. Comparison trial of iron succinylprotein complex or iron gluconate complex in the treatment of iron deficiency anemia. Clinical Therapeutics 1988;10(4):414–20. Pedrazzoli 2008 {published data only} ∗ Pedrazzoli P, Farris A, Del Prete S, Del Gaizo F, Ferrari D, Bianchessi C, et al.Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. Journal of Clinical Oncology 2008;26(10):1619–25. Siena S, Farris A, Del Prete S, Del Gaizo F, Ferrari D, Bianchessi C, et al.Randomized trial of intravenous iron supplementation in patients with chemotherapy-related

anemia without iron deficiency treated with darbepoetin alfa. Annals of Oncology 2007;18(Suppl 11):87–8. Prasad 2009 {published data only} Prasad N, Rajamani V, Hullin D, Murray JM. Postoperative anaemia in femoral neck fracture patients: does it need treatment? A single blinded prospective randomised controlled trial. Injury 2009;40(10):1073–6. Prassler 1998 {published data only} Prassler R, Deppe H, Huchzermeyer H. Value of iron supplementation in gastrointestinal bleeding. Leber Magen Darm 1998;28(1):21–3. Roe 1968 {published data only} Roe PF. The effect of varying concentrations of intravenous iron dextran (Imferon) on the complication rate. East African Medical Journal 1968;45(11):713–9. Schroder 2005 {published data only} ∗ Schroder O, Mickisch O, Seidler U, De Weerth A, Dignass AU, Herfarth H, 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. American Journal of Gastroenterology 2005;100(11): 2503–9. Schroder O, Mickisch O, Seidler U, de Weerth A, Dignass AU, Herfarth H, et al.A randomised multi-centre study on the application of intravenous iron sucrose versus oral iron sulphate in the therapy of iron deficient anaemia in patients with chronic irritable bowel disease. Zeitschrift fur Gastroenterologie 2005;43(8):915. Seid 2006 {published data only} Seid MH, Mangione A, Valaoras TG, Anthony LB, Barish CF. Safety profile of iron carboxymaltose, a new high dose intravenous iron in patients with iron deficiency anemia. Blood 2006;108(11 Part 2):8. Velhal 1991 {published data only} Velhal GD, Bichile SK, Pai NP, Tilwe S. Effectivness of oral versus parenteral iron therapy study conducted at urban health centre. Indian Journal of Community Medicine 1991; 16(4):157–60.

References to ongoing studies NCT01692418 {published data only} Richards T. Preoperative intravenous iron to treat anaemia in major surgery. http://ClinicalTrials.gov/show/ NCT01692418 2012.

Additional references Albaramki 2012 Albaramki J, Hodson EM, Craig JC. Parenteral versus oral iron therapy for adults and children with chronic kidney disease. Cochrane Database of Systematic Reviews 2012, Issue 1. [DOI: 10.1002/14651858.CD007857.pub2] Bailie 2012 Bailie GR. Comparison of rates of reported adverse events associated with i.v. iron products in the United States.


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Foubert 2006 Foubert J. Cancer-related anaemia and fatigue: assessment and treatment. Nursing Standard 2006;20(36):50–7.

Balarajan 2011 Balarajan Y, Ramakrishnan U, Ozaltin E, Shankar AH, Subramanian SV. Anaemia in low-income and middleincome countries. Lancet 2011;378(9809):2123–35.

Ghali 2009 Ghali JK. Anemia and heart failure. Current Opinion in Cardiology 2009;24(2):172–8.

Baribeault 2011 Baribeault D, Auerbach M. Iron replacement therapy in cancer-related anemia. American Journal of Health-System Pharmacy 2011;68(10 Suppl 1):S4–14.

Goddard 2011 Goddard AF, James MW, McIntyre AS, Scott BB. Guidelines for the management of iron deficiency anaemia. Gut 2011 May 11 [Epub ahead of print].

Beattie 2009 Beattie WS, Karkouti K, Wijeysundera DN, Tait G. Risk associated with preoperative anemia in noncardiac surgery: a single-center cohort study. Anesthesiology 2009;110(3): 574–81.

Goonewardene 2012 Goonewardene M, Shehata M, Hamad A. Anaemia in pregnancy. Best Practice & Research. Clinical Obstetrics & Gynaecology 2012;26(1):3–24.

Danielson 2004 Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. Journal of the American Society of Nephrology 2004;15(Suppl 2):S93–8. Davis 2012 Davis SL, Littlewood TJ. The investigation and treatment of secondary anaemia. Blood Reviews 2012;26(2):65–71. Deeks 2011 Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-analyses In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochranehandbook.org. DeMets 1987 DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987; 6(3):341–50. DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177–88. Dodd 2004 Dodd JM, Dare MR, Middleton P. Treatment for women with postpartum iron deficiency anaemia. Cochrane Database of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/14651858.CD004222.pub2] Dunne 2002 Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. Journal of Surgical Research 2002;102(2):237–44. Egger 1997 Egger M, Davey SG, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ (Clinical Research Ed) 1997;315(7109):629–34. Fireman 2004 Fireman Z, Kopelman Y. The role of video capsule endoscopy in the evaluation of iron deficiency anaemia. Digestive and Liver Disease 2004;36(2):97–102.

Gurusamy 2009 Gurusamy KS, Gluud C, Nikolova D, Davidson BR. Assessment of risk of bias in randomized clinical trials in surgery. The British Journal of Surgery 2009;96(4):342–9. Higgins 2002 Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539–58. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Colloboration, 2011. www.cochrane-handbook.org. Higgins 2011a Higgins JPT, Deeks JJ. Chapter 7: Selecting studies and collecting data In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org. Higgins 2011b Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org. Hyder 2002 Hyder SM, Persson LA, Chowdhury AM, Ekstrom EC. Do side-effects reduce compliance to iron supplementation? A study of daily- and weekly-dose regimens in pregnancy. Journal of Health, Population, and Nutrition 2002;20(2): 175–9. ICH-GCP 1996 International Conference on Harmonisation of Technical Requiements for Registration of Pharmaceuticals for Human Use. Code of Federal Regulation & ICH Guidelines. Media: Parexel Barnett, 1996. Jain 2012 Jain N, Jain VM. Prevalence of anemia in school children. Medical Practice and Review 2012;3(1):1–4. Kjaergard 2001 Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and


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small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135(11):982–9. Lee 2012 Lee TW, Kolber MR, Fedorak RN, van Zanten SV. Iron replacement therapy in inflammatory bowel disease patients with iron deficiency anemia: a systematic review and metaanalysis. J Crohn’s Colitis 2012;6(3):267–75. Leichtle 2011 Leichtle SW, Mouawad NJ, Lampman R, Singal B, Cleary RK. Does preoperative anemia adversely affect colon and rectal surgery outcomes?. Journal of the American College of Surgeons 2011;212(2):187–94. Litton 2013 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 (Clinical Research ed) 2013; 347:f4822. Liu 2012 Liu K, Kaffes AJ. Iron deficiency anaemia: a review of diagnosis, investigation and management. European Journal of Gastroenterology & Hepatology 2012;24(2):109–16.

Newell 1992 Newell DJ. Intention-to-treat analysis: implications for quantitative and qualitative research. International Journal of Epidemiology 1992;21(5):837–41. NLM Anemia U.S. National Library of Medicine. Anemia. http:// www.ncbi.nlm.nih.gov/mesh/68000740 (accessed 19 July 2011). Parmar 1998 Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24): 2815–34. Reveiz 2011 Reveiz L, Gyte GML, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: 10.1002/14651858.CD003094.pub3] RevMan 2012 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Lundh 2012 Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.MR000033.pub2]

Santiago 2012 Santiago P. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview. TheScientificWorldJournal 2012;2012:846824.

Macaskill 2001 Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Statistics in Medicine 2001;20(4):641–54.

Scholz 1997 Scholz BD, Gross R, Schultink W, Sastroamidjojo S. Anaemia is associated with reduced productivity of women workers even in less-physically-strenuous tasks. British Journal of Nutrition 1997;77(1):47–57.

McIntyre 2013 McIntyre LA, Tinmouth A, Fergusson D. Intravenous iron therapy for treatment of anaemia. BMJ (Clinical Research ed) 2013;347:f5378. Moher 1998 Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al.Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? . Lancet 1998;352(9128):609–13. Musallam 2011 Musallam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, et al.Preoperative anemia and postoperative outcomes in noncardiac surgery. Lancet 2011; 378(9800):1396–407. NCBI-Hematocrit NCBI. Hematocrit. http://www.ncbi.nlm.nih.gov/mesh/ 68006400 (accessed 19 July 2011). NCBI-Hemoglobins NCBI. Hemoglobins. http://www.ncbi.nlm.nih.gov/mesh/ 68006454 (accessed 19 July 2011). NCBI-Iron NCBI. Iron. http://www.ncbi.nlm.nih.gov/mesh/ 68007501 (accessed 19 July 2011).

Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408–12. Schünemann 2011 Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al.Chapter 12: Interpreting results and drawing conclusions. Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviewsof Interventions Version 5.1.0 [updated March 2011].The Cochrane Collaboration, 2011. www.cochrane-handbook.org. Silverstein 2004 Silverstein SB, Rodgers GM. Parenteral iron therapy options. American Journal of Hematology 2004;76(1):74–8. Sterne 2011 Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochranehandbook.org.


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Tierney 2007 Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. von Haehling 2010 von Haehling S, Schefold JC, Hodoscek LM, Doehner W, Mannaa M, Anker SD, et al.Anaemia is an independent predictor of death in patients hospitalized for acute heart failure. Clinical Research in Cardiology 2010;99(2):107–13. Waldmann 2004 Waldmann A, Koschizke JW, Leitzmann C, Hahn A. Dietary iron intake and iron status of German female vegans: results of the German vegan study. Annals of Nutrition & Metabolism 2004;48(2):103–8.

NHD˙01˙13/en/ 2001:WHO/NHD/01.3 (accessed 19 August 2011). WHO 2008 World Health Organization. Worldwide prevalence of anaemia 1993-2005. http://www.who.int/vmnis/ publications/anaemia˙prevalence/en/index.html. (accessed 19 August 2011). Wood 2008 Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al.Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ (Clinical Research ed) 2008;336:601–5.

Weiss 2005 Weiss G, Goodnough LT. Anemia of chronic disease. The New England Journal of Medicine 2005;352(10):1011–23.

Yadav 2011 Yadav D, Chandra J. Iron deficiency: beyond anemia. Indian Journal of Pediatrics 2011;78(1):65–72.

WHO 2001 World Health Organization, United Nations University, UNICEF. Iron deficiency anaemia. Assessment, prevention, and control. A guide for managers. http://www.who.int/ reproductivehealth/publications/maternal˙perinatal˙health/

Zeng 2009 Zeng X, Wu T. Iron supplementation for iron deficiency anemia in children. Cochrane Database of Systematic Reviews 2007, Issue 2. [DOI: 10.1002/14651858.CD006465] ∗ Indicates the major publication for the study


37

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Abrahamsen 1965 Methods

Randomised clinical trial

Participants

Country: Norway Sample size: 30 Postrandomisation dropout(s): 0 (0%) Revised sample size: 30 Females: not stated Mean age: not stated Inclusion criteria: • Patients with acute or chronic gastrointestinal bleeding with haemoglobin < 10 g/ dL • Serum iron < 50 mcg/dL Exclusion criteria: • Chronic infection • Renal disease • Cancer • Previous gastrectomy

Interventions

Participants were randomly assigned to the following groups: Group 1: intramuscular iron (n = 10) Further details: iron sorbitol citric acid complex 100 mg/d until calculated dose was reached Group 2: oral iron (n = 10) Further details: ferrous fumarate 300 mg in divided doses Group 3: control (n = 10) Further details: no intervention

Outcomes

Outcomes reported were mortality, haemoglobin levels and serious adverse events Time of measurements: 3 weeks from start of treatment

Notes

Attempts were made to contact study authors in August 2012. They replied in September 2012

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Thirty envelopes were used. In ten were written oral iron, in ten parenteral iron, and in ten no iron. The envelopes were mixed, and one envelope was opened for each patient” (study author replies)

Allocation concealment (selection bias)

Quote: “Thirty envelopes were used. In ten were written oral iron, in ten parenteral iron, and in ten no iron. The

Low risk


38

Abrahamsen 1965

(Continued)

envelopes were mixed, and one envelope was opened for each patient” (study author replies) Blinding of participants and personnel High risk (performance bias) All outcomes

Quote: “The patient and persons who administrated the treatment were informed. The laboratory results were opened at the end of the study” (study author replies)

Blinding of outcome assessment (detection High risk bias) All outcomes

Quote: “The patient and persons who administrated the treatment were informed. The laboratory results were opened at the end of the study” (study author replies)

Incomplete outcome data (attrition bias) All outcomes

Low risk

Comment: No postrandomisation dropouts were reported

Selective reporting (reporting bias)

Low risk

Comment: All important clinical outcomes were reported

Source of funding bias

Low risk

Quote: “Not funded” (study author replies)

Anker 2009 Methods


Participants

Country: multi-centric (Europe) Sample size: 158 Postrandomisation dropout(s): 0 (0%) Revised sample size: 158 Females: not stated Mean age: not stated Inclusion criteria: • Ambulatory patients who had chronic heart failure • Hb between 9.5 and 13.5 g/dL • Iron deficiency Exclusion criteria: • Uncontrolled hypertension • Other clinically significant heart disease or inflammation, or clinically significantly impaired liver or renal function

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 110) Further details: ferric carboxymaltose 200 mg IV weekly until iron repletion was achieved followed by a maintenance 4-weekly dose Group 2: control (n = 48) Further details: normal saline placebo

Outcomes

Outcomes reported were mortality, proportion of patients requiring blood transfusion, haemoglobin levels, quality of life measurements and serious adverse events (in the subgroup of anaemic participants) Time of measurement: 24 weeks from start of treatment


39

Anker 2009

(Continued)

Notes

Attempts were made to contact the study author in August 2012. They provided additional information

Risk of bias Bias




Quote: “Randomization was performed by IVRS (Interactive Voice Response System), stratified by region in a 2:1 ratio (FCM:placebo). Blocks of 6 (4FCM, 2 placebo) were generated per sites” Comment: The IVRS utilises a dynamic randomisation system with an adaptive minimisation technique for prespecified stratification variables (study author replies)


Low risk

Quote: “Using a central interactive voice-response system, we randomly assigned eligible patients, in a 2:1 ratio, to receive either ferric carboxymaltose (provided by Vifor Pharma) or placebo (normal saline)”

Blinding of participants and personnel Low risk (performance bias) All outcomes


Blinding of outcome assessment (detection Low risk bias) All outcomes



Low risk

Comment: No anaemic patients were excluded from the trial (study author replies)


Low risk

Comment: All important outcomes were reported


High risk

Quote: “Sponsored by Vifor Pharma”

Auerbach 2010 Methods


Participants

Country: multi-centric (worldwide) Sample size: 243 Postrandomisation dropout(s): 5 (2.1%) Revised sample size: 238 Females: 158 (66.4%) Mean age: 63 years Inclusion criteria:


40

Auerbach 2010

(Continued)

• ≥ 18 years of age • Active non-myeloid malignancies • Anemia (screening haemoglobin ≤ 10 g/dL) related to cancer and chemotherapy • ≥ 8 additional weeks of planned chemotherapy • Adequate renal and liver function • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Exclusion criteria: • Absolute iron de ciency • Known sensitivity to iron • History of a haematological disorder that could cause anaemia (other than a nonmyeloid malignancy) • Unstable or uncontrolled cardiac disease • History of deep vein thrombosis within 6 months before screening • RBC transfusions or erythropoietic therapy or myeloablative radiation therapy within 28 days before randomisation and/or screening Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 116) Further details: IV iron (further details not available) 400 mcg thrice weekly until ferritin level exceeded 1000 ng/mL (and reinstated if ferritin level dropped to 800 ng/mL) Group 2: control (n = 122) Further details: no intervention (oral iron was allowed)

Outcomes

Outcomes reported were mortality, blood transfusion requirements, change in Hb and serious adverse events Time of measurement: end of treatment

Notes

Reason for postrandomisation dropout(s): did not receive drug Attempts were made to contact study authors in August 2012

Risk of bias Bias



Random sequence generation (selection Unclear risk bias)

Comment: This information was not available


Quote: “A randomization list was created and maintained by an independent randomization group at the study sponsor using permuted blocks”

Low risk

Blinding of participants and personnel High risk (performance bias) All outcomes

Quote: “The study was blinded to the dose of darbepoetin alfa administered and open-label for IV iron administration”

Blinding of outcome assessment (detection Unclear risk bias) All outcomes



41

Auerbach 2010

(Continued)


High risk

Comment: Postrandomisation dropouts were reported


Low risk

Comment: Important outcomes were reported


Unclear risk


Bastit 2008 Methods


Participants

Country: international multi-centric trial in Europe Sample size: 398 Postrandomisation dropout(s): 2 (0.5%) Revised sample size: 396 Females: 240 (60.6%) Mean age: 61 years Inclusion criteria: • Patients with non-myeloid malignancy with anaemia (Hb < 11 g/dL) • At least 18 years of age • Eastern Cooperative Oncology Group performance status score of 0 to 2 • Adequate renal and liver function • At least 8 weeks of cytotoxic chemotherapy planned Exclusion criteria: • Patients with chronic myeloid leukaemia, acute myeloid or lymphocytic leukaemia, hairy cell leukaemia, Burkitt’s lymphoma or lymphoblastic lymphoma • History of thromboembolism or primary haematological disorder (other than malignancy) that could cause anaemia • Iron deficiency (transferrin saturation < 15% and serum ferritin < 10 ng/mL) • Serum ferritin > 800 ng/mL • Received an RBC transfusion within 14 days or any ESA within 4 weeks preceding randomisation

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 200) Further details: intravenous sodium ferric gluconate or iron sucrose 200 mg every 3 weeks as single dose or 2 doses Group 2: control (n = 196) Further details: oral iron or no intervention according to standard practice

Outcomes

Outcomes reported were mortality, blood transfusion requirements, quality of life and serious adverse events Time of measurements: not stated

Notes

Reason for postrandomisation dropout(s): did not receive darbopoetin Attempts were made to contact study authors in August 2012

Risk of bias Iron therapy in anaemic adults without chronic kidney disease (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

42

Bastit 2008

(Continued)

Bias






Quote: “Randomization, assigned using an interactive voice response system, was stratified by tumor type…”

Low risk

Blinding of participants and personnel Unclear risk (performance bias) All outcomes





High risk



Low risk

Comment: Important clinical outcomes were reported


Unclear risk


Beck-da-Silva 2013 Methods


Participants

Country: Brazil Number randomly assigned: 23 Postrandomisation dropouts: 0 (0%) Revised sample size: 23 Average age: 66 years Females: 7 (30.4%) Inclusion criteria: • 18 years of age or older • Clinical diagnosis of heart failure for at least 3 months before study entry • New York Heart Association (NYHA) functional class II to IV, able to perform ergospirometry • Documentation of left ventricular eject fraction < 40% within past 6 months • Adequate baseline therapy for heart failure based on patient’s functional class (βblockers, ACE inhibitors irrespective of functional class except if contraindications, digoxin, spironolactone if NYHA class III or IV) • Stable baseline heart failure therapy with same doses of medications and no intent to increase doses for the following 3 months • Haemoglobin ≤ 12 g/dL and ≥ 9 g/dL • Transferrin saturation < 20% and ferritin < 500 µg/L • Ability to provide written informed consent Exclusion criteria:


43

Beck-da-Silva 2013

(Continued)

• Any clinically overt bleeding: gastrointestinal bleeding, hypermenorrhoea, history of peptic ulcer without evidence of healing or in ammatory intestinal disease • Uncorrected hypothyroidism • Other in ammatory, neoplastic or infectious disease • Serum creatinine > 1.5 mg/dL • Previous intolerance to oral elemental iron compounds • Heart failure due to alcoholic cardiomyopathy, current regular drinker of alcoholic beverages or heart failure due to peripartum cardiomyopathy • Recent admission for decompensated heart failure (past month) • Recent myocardial revascularisation procedures (past 3 months) • Recent acute coronary syndrome, stroke or transient ischaemic attack (past 3 months) • Active or metastatic neoplastic disease with life expectancy of less than 1 year • Patients on heart transplantation list • Patients who had participated in any other clinical trial or study within the past month • Pregnant or lactating women • Premenopausal women who are not using an effective method of contraception • Patients using prohibited medications or who have not yet accomplished the washout period • Patients currently participating in cardiovascular rehabilitation programmes • Patients with pacemakers, implanted de brillators or cardiac resynchronisation therapy Interventions

Participants were randomly assigned to 2 groups: Group 1: IV iron (n = 10) Further details: iron sucrose 200 mg intravenously, once a week, in 30 minute infusions, for 5 weeks and placebo of oral presentation, 3 times a day, for 8 weeks Group 2: oral iron (n = 7) Further details: ferrous sulphate 200 mg, orally, 3 times a day, for 8 weeks and placebo of IV presentation once a week, for 5 weeks Group 3: control (n = 6) Further details: placebo

Outcomes

Outcomes reported were mortality, serious adverse events and haemoglobin

Notes

Time of measurement: 13 weeks from start of treatment Attempts were made to contact study authors in September 2013. They provided additional replies

Risk of bias Bias



Support for judgement Quote: “The randomization system will be based on a computerized table of random numbers and performed in blocks of 3 per participating center”


44

Beck-da-Silva 2013

(Continued)


Low risk

Quote: “Each of the 8 participating centers will randomize patients by telephone contact with the randomization center at Hospital de Cl nicas de Porto Alegre”


Quote: “Patients were randomized in a double-blind method to receive…Each participating center will elect a third-party blind individual (usually a registered nurse) who will open the allocated medication box, prepare iron sucrose infusions or saline, and administer the preparations to patients using opaque devices. Both patient and attending physicians or nurses will be blind to allocated therapy. Oral medications and oral placebo will be identical in all aspects”


Quote: “Patients were randomized in a double-blind method to receive…Each participating center will elect a third-party blind individual (usually a registered nurse) who will open the allocated medication box, prepare iron sucrose infusions or saline, and administer the preparations to patients using opaque devices. Both patient and attending physicians or nurses will be blind to allocated therapy. Oral medications and oral placebo will be identical in all aspects”


Low risk



Low risk

Comment: Mortality and serious adverse events were reported


High risk

Quote: “The sponsors provided the intravenous iron formulation, the placebo formulations for oral and intravenous administration as well as most of the study costs”

Dangsuwan 2010 Methods


Participants

Country: Thailand Sample size: 44 Postrandomisation dropout(s): 0 (0%) Revised sample size: 44 Females: 44 (100%) Mean age: 51 years Inclusion criteria: • Patients with ovarian cancer, endometrial cancer or synchronous ovarian and endometrial cancer receiving rst-line platinum-based chemotherapy after primary surgery • Haemoglobin level below 10 g/dL • Aged 20 to 65 years


45

Dangsuwan 2010

(Continued)

• Normal liver and kidney function • No prior radiotherapy, had at least 1 remaining cycle of chemotherapy Exclusion criteria: • Patients with iron hypersensitivity • Risk of iron overload such as chronic renal failure or thalassaemia major • Progressive disease • Bone marrow metastasis • Inability to monitor weekly complete blood counts Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 22) Further details: iron sucrose 200 mg over 30 minutes intravenous weekly Group 2: oral iron (n = 22) Further details: ferrous (preparation not known) 200 mg thrice daily

Outcomes

Outcomes reported were mortality, blood transfusion requirements, quality of life, haemoglobin levels and serious adverse events Time of measurements: not stated

Notes

Attempts were made to contact study authors in August 2012. They replied promptly

Risk of bias Bias




Quote: “Randomization was done using a random table”


Quote: “Only the first investigation knew the allocation number”; “We had the other persons enrol the patients. But the first author run the allocation number according to the stratification” (study author replies)

Low risk


Quote: “Patient and drug administrator were not blinded, however the outcome assessors was blinded” (study author replies)


Quote: “Patient and drug administrator were not blinded, however the outcome assessors was blinded” (study author replies)


Low risk

Quote: “There were no post-randomisation drop-outs” (study author replies)


Low risk



Low risk

Quote: “We did not have source of funding. However, the company (DKSH Limited, Bangkok, Thailand) supported


46

Dangsuwan 2010

(Continued)

Venofer. But the company did not involve in research protocol and manuscript writing” (study author replies)

Edwards 2009 Methods

Randomised controlled trial

Participants

Country: UK Sample size: 18 Postrandomisation dropout(s): not stated Revised sample size: 18 Females: not stated Mean age: not stated Inclusion criteria: • Patients scheduled to undergo bowel resection for suspected colorectal cancer Exclusion criteria: • Younger than 18 years • Existing (or had been taking) oral iron supplementation within 6 weeks of the day they were approached • Received a blood transfusion within that same period • If date of scheduled surgery fell within 15 days of date of recruitment

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 9) Further details: 300 mg iron sucrose made up to 250 mL with 0.9% saline 2 infusions separated by at least 24 hours completed within a minimum of 14 days before undergoing elective surgery Group 2: control (n = 9) Further details: equal volume of normal saline placebo

Outcomes

Outcomes reported were blood transfusion requirements and haemoglobin levels Time of measurements: blood transfusion requirements postoperatively and haemoglobin levels preoperatively

Notes

This study included anaemic and non-anaemic participants. Only anaemic participants were included in this review Attempts were made to contact study authors in August 2012

Risk of bias Bias



Support for judgement Quote: “Participants were allocated to either the treatment (iron) group or a placebo group, based on a computer-generated randomization sequence provided by the Research and Development Support Unit”


47

Edwards 2009

(Continued)


Low risk

Quote: “Allocation codes were sealed in sequentially numbered opaque envelopes which were secured within a locked store room in a dedicated research unit (this was remote from the clinical areas of the hospital where participants were to undergo outpatient, ward and operative treatment). Only after recruitment was an envelope opened by the investigator administering the infusion, following the inscribed strict numerical order and for the relevant subset appropriate to the Hb status of the participant”


Quote: “Although the investigator administering the infusion was not blinded to the treatment group, this was concealed from the patient by using an opaque sheath to cover the drug giving set. The chief investigator and clinicians involved in perioperative care also remained blinded to the treatment group for the duration of the trial”


Quote: “The chief investigator and clinicians involved in perioperative care also remained blinded to the treatment group for the duration of the trial”


Unclear risk

Comment: 2 postrandomisation dropouts were reported. Whether these participants were anaemic was not clear


High risk

Comment: Important clinical outcomes were not reported


High risk

Comment: The review authors thank Syner-Med Pharmaceutical Products Limited for providing Venofer and for funding the blood tests

Evstatiev 2011 Methods


Participants

Country: multi-centric (Europe) Sample size: 485 Postrandomisation dropout(s): 2 (0.4%) Revised sample size: 483 Females: 284 (58.8%) Mean age: 39 years Inclusion criteria: • Patients with iron deficiency anaemia (Hb 7 to 12 g/dL in females and 7 to 13 g/ dL in males) • Mild to moderate inflammatory bowel disease • Normal levels of vitamin B-12 and folic acid


48

Evstatiev 2011

(Continued)

• 18 years of age or older • Females of childbearing potential had to have a negative urine pregnancy test at screening and had to use an acceptable method of birth control during the study and for up to 1 month after the last dose of the study drug Exclusion criteria: • Patients with intravenous or oral iron treatment or blood transfusions within 4 weeks before screening • History of erythropoietin treatment • Chronic alcohol abuse; chronic liver disease or increase in transaminases more than 3 times above the normal upper range limit • Presence of portal hypertension with oesophageal varices • Known hypersensitivity to study drug • History of acquired iron overload • Myelodysplastic syndrome • Pregnancy or lactation • Known active infection • Clinically significant overt bleeding • Active malignancy or chronic renal failure • Surgery with relevant blood loss (Hb decrease < 2 g/dL) in the 3 months before screening or planned surgery within following 3 months • Known human immunodeficiency virus; hepatitis B or hepatitis C virus infection • Significant cardiovascular disease • Body weight < 35 kg • Participation in any other interventional study within 1 month before screening Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 244) Further details: IV ferric carboxymaltose in single dose (repeated twice if necessary) Group 2: preparation 2 (n = 239) Further details: IV iron sucrose twice weekly up to 11 infusions

Outcomes

Outcomes reported were serious adverse events and haemoglobin levels Time of measurement: 12 weeks from start of treatment

Notes

Reason for postrandomisation dropout(s): did not receive treatment Attempts were made to contact study authors in August 2012

Risk of bias Bias



Support for judgement Quote: “Patients were randomized 1:1 to each of the treatment arms according to a predefined, computer-generated list and stratified by gender and disease (CD/UC) as provided via sequentially numbered randomization envelopes by data management, PAREXEL International GmbH”


49

Evstatiev 2011

(Continued)


Low risk

Quote: “Patients were randomized 1:1 to each of the treatment arms according to a predefined, computer-generated list and stratified by gender and disease (CD/UC) as provided via sequentially numbered randomization envelopes by data management, PAREXEL International GmbH” Comment: Allocation concealment probably achieved


Quote: “Both participants and physicians were aware of which treatment was being administered”


Quote: “Both participants and physicians were aware of which treatment was being administered”


High risk



High risk

Comment: Important outcomes were not reported


High risk

Quote: “The authors thank all investigators at all study sites (see Appendix), the support in funding and conducting the study (Barbara von Eisenhart Rothe, responsible Medical Director; Janne Harjunpää, statistical analysis; Vifor Pharma, Switzerland), and medical writing support (Walter Fürst; SFL Regulatory Affairs & Scienti c Communication, Switzerland)”

Hedenus 2007 Methods


Participants

Country: Sweden Sample size: 67 Postrandomisation dropout(s): 0 (0%) Revised sample size: 67 Females: 42 (62.7%) Mean age: 76 years Inclusion criteria: • Adults with a diagnosis of clinically stable lymphoproliferative malignancy (indolent non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukaemia (CLL) or multiple myeloma (MM)) not requiring chemotherapy or blood transfusions • Hb level of 9 to 11 g/dL (measured on 2 occasions within 1 month and an interval of at least 2 weeks) • Demonstration of stainable iron in a bone marrow aspirate within 1 month before inclusion Exclusion criteria: • Patients with anaemia attributable to factors other than cancer (such as vitamin


50

Hedenus 2007

(Continued)

B12 or folate deficiency, haemolysis or active inflammatory or infectious disease) • Serum ferritin > 800 mg/L • Serum creatinine > 175 mmol/L • Serum bilirubin > 40 mmol/L • Eastern Cooperative Oncology Group performance status of > 2 • Prior antitumour therapy within 8 weeks before randomisation or expected within 16 weeks following inclusion • Prior epoetin treatment within 12 weeks of enrolment • Iron therapy within the previous 4 weeks • Uncontrolled hypertension or cardiac disease • Neurological or psychiatric disorders • Pregnancy Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 33) Further details: intravenous iron sucrose 100 mg per week for 6 weeks followed by 100 mg every alternative week for 8 weeks Group 2: control (n = 34) Further details: no intervention

Outcomes

Outcomes reported were mortality, blood transfusion requirements and haemoglobin levels Time of measurements: end of treatment

Notes

Attempts were made to contact study authors in August 2012

Risk of bias Bias




Quote: “A central randomization procedure was used (fax formular) and patients received numbers in a consecutive order according to a predetermined scheme and randomly allocated to either receive IV iron or no iron” (study author replies)


Quote: “A central randomization procedure was used (fax formular) and patients received numbers in a consecutive order according to a predetermined scheme and randomly allocated to either receive IV iron or no iron” (study author replies)

Low risk


Quote: “This was a prospective, open-label, randomized, multicenter study”


Quote: “This was a prospective, open-label, randomized, multicenter study”


51

Hedenus 2007

(Continued)


Low risk



Low risk



High risk

Comment: This work was supported by grants from Roche AB, Sweden, and the Research and Development Centre, Sundsvall Hospital, Sundsvall, Sweden

Hetzel 2012 Methods


Participants

Country: Australia Number randomly assigned: 605 Postrandomisation dropouts: 0 (0%) Revised sample size: 605 Average age: not stated Females: not stated Inclusion criteria: • Gastrointestinal patients with iron deficiency anaemia who cannot take oral iron

Interventions

Participants were randomly assigned to 2 groups: Group 1: IV iron (n = 406) Further details: ferrumoxytol 510 mg 2 doses 3 to 8 days apart Group 2: IV iron (n = 199) Further details: iron sucrose 200 mg 5 infusions over 14 days

Outcomes

Outcomes reported were mortality and serious adverse events

Notes

Time of measurement: 5 weeks after start of treatment Attempts were made to contact study authors in September 2013. They provided additional information

Risk of bias Bias




Quote: “The randomization scheme and codes were computer-generated” (study author replies)


Quote: “An interactive voice response system (IVRS) was used to assign unique randomization numbers for each subject. This is a telephone based system that was accessible at all times. Randomization numbers were not reused for any use” (study author replies)

Low risk


52

Hetzel 2012

(Continued)


Quote: “Open-label”


Quote: “Open-label”


Low risk



Low risk

Comment: Mortality and morbidity were reported


High risk

Comment: sponsored by AMAG Pharmaceuticals Inc

Karkouti 2006 Methods


Participants

Country: Canada Sample size: 26 Postrandomisation dropout(s): 5 (19.2%) Revised sample size: 21 Females: 5 (23.8%) Mean age: 62 years Inclusion criteria: • Adult patients (> 18 years old) undergoing open-heart surgery, total hip arthroplasty or spinal fusion with Hb between 7 and 9 g/dL on the morning of the first postoperative day (POD-1) Exclusion criteria: • Preoperative anaemia (Hb < 12 g/dL in women and < 14 g/dL in men) • Preoperative autologous blood donation • IV iron or erythropoietin therapy • Active infection • Pregnancy or lactation • Major co-morbidities (previous history of stroke, transient ischaemic attacks or seizures; significant respiratory disease (FEV1 < 50% predicted), renal disease (creatinine > 200 micromol/L) • Liver disease (hepatitis, cirrhosis) • Uncontrolled hypertension (systolic > 180, diastolic > 100 mmHg) • Any haematological disease (e.g. thromboembolic events, haemoglobinopathy, coagulopathy, haemolytic disease) • Patients with ongoing haemorrhage • Evidence of organ dysfunction on POD-1

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 11) Further details: iron sucrose 200 mg IV on 1st, 2nd and 3rd postoperative days for a


53

Karkouti 2006

(Continued)

total of 600 mg Group 2: control (n = 10) Further details: normal saline placebo Another group in which erythropoietin was added to iron was excluded from analysis Outcomes

Outcomes reported were blood transfusion requirements and haemoglobin levels Time of measurements: 42nd postoperative day

Notes

Study authors used arbitrary weights to adjust haemoglobin levels based on transfusion Reason for postrandomisation dropout(s): 4 withdrew, so the primary outcome could not be measured. In one, the primary outcome could not be measured Attempts were made to contact study authors in August 2012. They replied promptly

Risk of bias Bias




Quote: “In each stratum, patients were randomized in randomly permuted blocks of three patients according to a computer-generated table of random numbers”


Low risk

Quote: “The assignments were placed into opaque sequentially numbered envelopes with pharmacy”


Quote: “For all three groups the IV solution was draped with an opaque cover and the IV tubing was covered with a translucent tape. Patients in the vontrol group and the iron group received SC and IV injections of normal saline” Comment: Subcutaneous placebo was for blinding different groups to the combination treatment of iron and erythropoietin


Quote: “For all three groups the IV solution was draped with an opaque cover and the IV tubing was covered with a translucent tape. Patients in the vontrol group and the iron group received SC and IV injections of normal saline” Comment: Subcutaneous placebo was for blinding different groups to the combination treatment of iron and erythropoietin


High risk



Low risk



High risk

Quote: “K. Karkouti is supported in part by the Canadian Institutes of Health Research and the Canadian Blood Services. T.M. Yau is supported in part by the Canadian Insti-


54

Karkouti 2006

(Continued)

tutes of Health Research and the Heart and Stroke Foundation of Ontario. K. Karkouti and S.A. McCluskey have received research funding and speakers’ fees from Ortho Biotech” Lidder 2007 Methods


Participants

Country: UK Sample size: 20 Postrandomisation dropout(s): not stated Revised sample size: 20 Females: 9 (45%) Mean age: not stated Inclusion criteria: • Patients undergoing surgery for colorectal cancer (only anaemic patients were included in this review)

Interventions

Participants were randomly assigned to the following groups:C Group 1: oral iron (n = 6) Further details: 200 mg oral ferrous sulphate until surgery Group 2: control (n = 14) Further details: no intervention

Outcomes

Outcome reported was blood transfusion requirements Time of measurement: perioperative

Notes


Risk of bias Bias






Quote: “patients were randomised (by telephone to a distant centre) to…”

Low risk


Quote: “It was not possible to use a placebo and blind the patient, as oral iron alters stool colour”


Quote: “The clinical team (surgeons, nurses, anaesthetists) were blinded to treatment allocation. The collection of data was performed by a research fellow not involved in the direct care of the patient, and gathered from the clinical notes”


55

Lidder 2007

(Continued)


Unclear risk



High risk



Unclear risk


Lindgren 2009 Methods


Participants

Country: Sweden Sample size: 91 Postrandomisation dropout(s): not stated Revised sample size: 91 Females: 63 (69.2%) Mean age: 42 years Inclusion criteria: • Patients with inflammatory bowel disease with iron deficiency anaemia (haemoglobin (Hb) concentration < 11.5 g/dL with serum ferritin concentrations ≤ 30 mcg/dL and iron deficiency based on iron, transferrin and ferritin) • Age between 18 and 85 years Exclusion criteria: • Active relapsing stage of inflammatory bowel disease • Pregnant • Clinically significant haematological disease other than iron-deficiency anaemia or any other clinically significant disease/dysfunction that in the opinion of the investigator disqualified them from this study • Symptomatic intestinal strictures • Treated with oral or parenteral iron during previous month • Serum creatinine levels > 250 mmol/L • Deficiencies in cobalamin and/or folic acid • Contraindications for administration of iron sucrose or ferrous sulphate • If there were plans for significant surgery during the study period

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 45) Further details: iron sucrose 200 mg once a week or twice a week for 20 weeks to reach the cumulative dose Group 2: oral iron (n = 46) Further details: ferrous sulphate 200 mg twice a day for 20 weeks

Outcomes

Outcomes reported were haemoglobin levels and serious adverse events Time of measurements: end of treatment

Notes



56

Lindgren 2009

(Continued)

Bias




Quote: “Patients were allocated to any of the treatments over the Internet, by applying the minimization method to ensure a balance within the patient factors age, B-Hb and S-ferritin”


Quote: “Patients were allocated to any of the treatments over the Internet, by applying the minimization method to ensure a balance within the patient factors age, B-Hb and S-ferritin” Comment: In the absence of blinding, this may lead to bias

Low risk


Quote: “Venofer is a dark-brown, non-transparent, aqueous solution to be administered intravenously. There is no placebo solution available” Comment: Participants and healthcare providers not blinded


Comment: Although the trial states that observer blinding was performed, further details were not available


Unclear risk



High risk

Comment: Important clinical outcomes were not reported


High risk

Comment: The study was supported by Renapharma AB, Uppsala, Sweden

Maccio 2010 Methods


Participants

Country: Italy Sample size: 148 Postrandomisation dropout(s): 0 (0%) Revised sample size: 148 Females: 59 (39.9%) Mean age: 68 years Inclusion criteria: • Patients with advanced cancer with Hb level ≤ 10 g/dL • 18 years of age or older • Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤ 2 • No previous treatment • Receiving first-line chemotherapy while on study • Serum ferritin level ≥ 100 ng/mL but ≤ 800 mg/dL and/or transferrin saturation


57

Maccio 2010

(Continued)

> 15% • Life expectancy ≥ 6 months • Adequate renal and hepatic function Exclusion criteria: • Patients with anaemia attributable to factors other than cancer and chemotherapy (e.g. B12 or folate deficiency, haemolysis, gastrointestinal bleeding, myelodysplastic syndrome, bone marrow metastases) • Prior transfusion, ESA or IV iron therapy within 4 weeks of enrolment • Allergy or intolerance to iron and/or rHuEPO, active infection • Absolute iron deficiency • Pregnancy, breastfeeding, inadequate birth control measures • History of seizure disorders • Active cardiac disease, thromboembolic disease and uncontrolled hypertension Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 73) Further details: 125 mg of ferric gluconate IV once weekly Group 2: oral iron (n = 75) Further details: 200 mg of lactoferrin daily

Outcomes

Outcomes reported were haemoglobin levels Time of measurements: end of treatment

Notes


Risk of bias Bias




Quote: “Patients were randomized using a computer-generated list of random numbers elaborated by an external data manager” (study author replies)


Quote: “The allocation concealment incorporates the involvement of an external data manager, not a physician involved in patient management, who assigned the randomization sequence in order to protect the randomization sequence until allocation” (study author replies)

Low risk


Quote: “This was an open-label, randomized, controlled, prospective study comparing the efficacy and safety of rHuEPO combined with oral lactoferrin (Lattoglobina; Grunenthal- Formenti, Milan, Italy) or IV iron supplementation in advanced cancer patients with anemia undergoing chemotherapy”


Quote: “This was an open-label, randomized, controlled, prospective study comparing the efficacy and safety of rHuEPO combined with oral lactoferrin (Lattoglobina;


58

Maccio 2010

(Continued)

Grunenthal- Formenti, Milan, Italy) or IV iron supplementation in advanced cancer patients with anemia undergoing chemotherapy” Incomplete outcome data (attrition bias) All outcomes

Low risk



Low risk



Low risk

Quote: “This work was supported by the Associazione Sarda per la ricerca nell’Oncologia Ginecologica-ONLUS”; “No funding has been received from the drug manufacturer. The study was not sponsored nor funded by any manufacturers” (study author replies)

Madi-Jebara 2004 Methods


Participants

Country: Lebanon Sample size: 80 Postrandomisation dropout(s): 0 (0%) Revised sample size: 80 Females: not stated Mean age: not stated Inclusion criteria: • 120 American Society of Anesthesiologists (ASA) II or III patients, who underwent elective cardiac surgery using cardiopulmonary bypass and in whom postpump haemoglobin ranged between 7 and 10 g/dL Exclusion criteria: • Transfusion of allogeneic blood intraoperatively • Unstable haemodynamic status after surgery • Ejection fraction < 40% • Preoperative anaemia of any cause such as renal failure, hypothermic bypass • Contraindications for parenteral iron such as rheumatoid arthritis, history of allergic reactions to iron, haemosiderosis and liver disease

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 40) Further details: iron sucrose IV 200 mg/d starting on day 1 to reach total iron deficit Group 2: control (n = 40) Further details: placebo. Another group in which iron was used in combination with erythropoietin was excluded

Outcomes

Outcomes reported were mortality, blood transfusion requirements and haemoglobin levels Time of measurements: 30 days from start of treatment


59

Madi-Jebara 2004

(Continued)

Notes


Risk of bias Bias






Quote: “Drug manipulation and assignment were handled by the central pharmacy to assure double blinding”

Low risk

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

Comment: Although a placebo was used, further details of placebo such as colour were not available




Low risk

Comment: No postrandomisation dropouts for the main clinical outcomes were reported


Low risk



Unclear risk


Parker 2010 Methods


Participants

Country: UK Number randomly assigned: 300 Postrandomisation dropouts: 0 (0%) Revised sample size: 300 Average age: 82 years Females: 245 (81.7%) Inclusion criteria: • Postoperative haemoglobin level < 110 g/L within 5 days after hip fracture surgery Exclusion criteria: • Patient unwilling to give written informed consent or for whom the relative or next of kin was unavailable or declined to give assent • Postoperative haemoglobin level ≥ 110 g/L • Multiple trauma (defined as more than 2 other fractures or any other fracture requiring surgery other than simple manipulation) • Patient unable to take oral iron medication because of adverse effects • Patient taking iron therapy at time of admission • Haemoglobin level < 110 g/L at time of admission


60

Parker 2010

(Continued)

• Patient unable to attend routine follow-up at hip fracture clinic • Age < 60 years Interventions

Participants were randomly assigned to 2 groups Group 1: oral iron (n = 150) Further details: ferrous sulphate 200 mg twice daily orally for 28 days Group 2: control (n = 150) Further details: no intervention

Outcomes

Outcomes reported were mortality, serious adverse events and haemoglobin levels Time of measurement: mortality 1 year; adverse events and haemoglobin levels 6 weeks after hospital discharge

Notes

Attempts were made to contact study authors in November 2012. They replied promptly

Risk of bias Bias




Quote: “The envelopes for this study were prepared by me, sealed, mixed up and then numbered” (study author replies)


Quote: “Randomization was accomplished by opening a sealed opaque numbered envelope for each patient”

Low risk


Quote: “Potential weaknesses of the study include the lack of a placebo”


Quote: “Also, there was no blinding of the outcome assessors for the present study”


Low risk



Low risk



Low risk

Quote: “There was no external funding for this study” (study author replies)

Pieracci 2009 Methods


Participants

Country: USA Sample size: 200 Postrandomisation dropout(s): 0 (0%)


61

Pieracci 2009

(Continued)

Revised sample size: 200 Females: 103 (51.5%) Mean age: 57 years Inclusion criteria: • Admitted to the general surgical, burn or neurosurgical intensive care unit (ICU) • Age ≥ 18 years • Hb < 13 g/dL • < 72 hours from hospital admission • Current tolerance of enteral medications • Expected ICU length of stay ≥ 5 days Exclusion criteria: • Active bleeding • Chronic inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis) • End-stage renal disease (dialysis-dependent) • Haematological disorders (e.g. thalassaemia, sickle cell disease, myelodysplasia) • Macrocytic anaemia • Current use of erythropoietin • Pregnancy • Prohibition of RBC transfusions • Moribund state in which death was imminent • Enrolment in any other clinical trial Interventions

Participants were randomly assigned to the following groups: Group 1: oral iron (n = 97) Further details: enteral iron sulphate 325 mg thrice daily for 6 weeks or until discharge Group 2: control (n = 103) Further details: placebo

Outcomes

Outcomes reported were blood transfusion requirements Time of measurement: end of treatment

Notes


Risk of bias Bias






Low risk

Quote: “Randomization was accomplished by the investigational pharmacy (SB) using a block pattern stratified by ICU type”


Quote: “All involved parties with the exception of the investigational pharmacist were blinded to the identity of the study drug, including patients and their families, those administering the intervention, and those assessing


62

Pieracci 2009

(Continued)

the outcomes...” Blinding of outcome assessment (detection Low risk bias) All outcomes

Quote: “All involved parties with the exception of the investigational pharmacist were blinded to the identity of the study drug, including patients and their families, those administering the intervention, and those assessing the outcomes...”


Low risk



High risk



Unclear risk


Steensma 2010 Methods


Participants

Country: USA Sample size: 502 Postrandomisation dropout(s): 12 (2.4%) Revised sample size: 490 Females: 320 (65.3%) Mean age: 64 years Inclusion criteria: • 18 years of age or older • Receiving chemotherapy for a non-myeloid neoplasm • Hb < 11.0 g/dL • Ferritin > 20 ng/mL • Transferrin saturation < 60% • Zubrod performance score better than 2 Exclusion criteria: • Patients with history of thromboembolism within 1 year of enrolment • Genetic haemochromatosis • Recent surgery • Anaemia caused by myelodysplastic syndrome, nutritional deficiency or a nonneoplastic haematologic disorder such as thalassaemia • Received an ESA within 3 months or red cell transfusion within 14 days

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 164) Further details: sodium ferric gluconate complex in sucrose IV 187.5 mg over 90 minutes once every 3 weeks for 5 doses Group 2: oral iron (n = 163) Further details: ferrous sulphate oral 325 mg once daily Group 3: control (n = 163) Further details: oral placebo


63

Steensma 2010

(Continued)

Outcomes

Outcomes reported were mortality, blood transfusion requirements, quality of life and serious adverse events Time of measurements: 16 weeks from start of treatment

Notes

Reason for postrandomisation dropout(s): did not have haemoglobin measurements Attempts were made to contact study authors in August 2012. They replied promptly

Risk of bias Bias




Quote: “It was computer generated” (study author replies)


Quote: “Random assignment was done by calling the central randomization center by telephone”

Low risk


Quote: “Patients and investigators were blinded to assignment of oral iron or oral placebo, but, for practical reasons, assignment to IV iron versus an oral product was not blinded”


Quote: “Patients and investigators were blinded to assignment of oral iron or oral placebo, but, for practical reasons, assignment to IV iron versus an oral product was not blinded”


High risk



Low risk



Unclear risk

Quote: “Supported in part by Public Health Service Grant No. CA-124477 and grant from Amgen (Thousand Oaks, CA) to the Mayo Clinic Cancer Research Consortium”

Sutton 2004 Methods


Participants

Country: UK Number randomly assigned: 72 Postrandomisation dropouts: not stated Revised sample size: 72 Average age: 70 years Females: 30 (41.7%) Inclusion criteria:


64

Sutton 2004

(Continued)

• Anaemic patients (8 to 12 g/dL for men and 8 to 11 g/dL for women) at 5 to 7 days postoperatively after primary hip or knee arthroplasty Exclusion criteria: • Preoperative level of haemoglobin < 12 g/dL for men and < 11 g/dL for women • Not able to give informed consent • Were to be followed up elsewhere • Had rheumatoid arthritis • Were taking ciprofloxacin, tetracyclines, antacids or bisphosphonates • Already taking iron salts or vitamin supplements, which might include iron Interventions

Participants were randomly assigned to 2 groups: Group 1: oral iron (n = 35) Further details: ferrous sulphate 200 mg thrice daily orally for 6 weeks after surgery Group 2: control (n = 37) Further details: gelatine placebo

Outcomes

Outcomes reported were haemoglobin levels Time of measurement: end of treatment

Notes

Attempts were made to contact study authors in November 2012

Risk of bias Bias




Quote: “Those patients who entered into the study were randomly assigned by the hospital pharmacy into two groups using computer generated random numbers”


Low risk

Quote: “Those patients who entered into the study were randomly assigned by the hospital pharmacy into two groups using computer generated random numbers”


Quote: “One group received ferrous sulphate in 200 mg capsules and the second (37 patients) were given a gelatine placebo. Both groups were prescribed their capsules three times daily for six weeks after discharge from hospital. Both patients and investigators were blind to the treatment allocated until the end of the trial”


Quote: “One group received ferrous sulphate in 200 mg capsules and the second (37 patients) were given a gelatine placebo. Both groups were prescribed their capsules three times daily for six weeks after discharge from hospital. Both patients and investigators were blind to the treatment allocated until the end of the trial”



Unclear risk


65

Sutton 2004

(Continued)


Low risk



Low risk

Quote: “No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article”

Vadhan-Raj 2013 Methods


Participants

Country: worldwide Number randomly assigned: 812 Postrandomisation dropouts: 4 (0.5%) Revised sample size: 808 Average age: 45 years Females: 720 (89.1%) Inclusion criteria: • 18 years of age or older with a history of iron deficiency anaemia, defined as haemoglobin (Hgb) level < 10.0 g/dL and transferrin saturation (TSAT) < 20% • History of unsatisfactory oral iron therapy or those in whom oral iron could not be used Exclusion criteria: • History of allergy to iron • Hb level ≤ 7.0 g/dL • Serum ferritin > 600 ng/mL • Known causes of anaemia other than iron deficiency • Active infection • Haematological malignancies • On dialysis or had estimated glomerular filtration rate < 30 mL/min/1.73 m2 • Pregnant, intended to become pregnant or were breastfeeding • Patients who received another investigational agent or IV iron therapy within 4 weeks of screening, or who had received oral iron therapy or blood transfusion within 2 weeks before screening

Interventions

Participants were randomly assigned to 2 groups Group 1: IV iron (n = 608) Further details: ferumoxytol 510 mg IV weekly for 5 weeks Group 2: control (n = 200) Further details: placebo

Outcomes

Outcomes reported were mortality, morbidity, quality of life and haemoglobin levels

Notes

Time of measurement: 5 weeks after start of treatment Attempts were made to contact study authors in September 2013 Reasons for postrandomisation dropouts: adverse event (1); protocol violation (1); withdrew consent (2)


66

Vadhan-Raj 2013

(Continued)

Bias






Low risk

Quote: “Patients were randomized using an Interactive Voice Randomization System”


Quote: “Blinding was accomplished by having both ferumoxytol and normal saline administered in a shrouded manner by a unblinded Test Article Administrator, while both study participants and all other study staff including the investigator were blinded to what was administered”


Quote: “Blinding was accomplished by having both ferumoxytol and normal saline administered in a shrouded manner by a unblinded Test Article Administrator, while both study participants and all other study staff including the investigator were blinded to what was administered”


High risk



Low risk

Comment: Mortality and morbidity were reported


Unclear risk

Quote: “All data were analyzed by representatives of the clinical and biostatistical groups of AMAG Pharmaceuticals”

Van Wyck 2009 Methods


Participants

Country: USA, Mexico Sample size: 477 Postrandomisation dropout(s): 24 (5%) Revised sample size: 453 Females: 453 (100%) Mean age: 39 years Inclusion criteria: • Patients with anaemia, defined as haemoglobin ≤ 11.0 g/dL • 18 years of age or older • Heavy uterine bleeding • Use of adequate birth control • Serum transferrin saturation ≤ 25%, and serum ferritin level ≤ 100 ng/mL Exclusion criteria: • Red blood cell (RBC) transfusion or parenteral iron administration within prior 8 weeks or anticipated need for blood transfusion during study


67

Van Wyck 2009

(Continued)

• Existing disorders of erythropoiesis • Haemochromatosis • Initiation of hormonal therapy potentially affecting uterine bleeding during 8 weeks before study entry • Use of erythropoiesis-stimulating agents within prior 12 weeks • Postmenopausal patients without endometrial biopsy within prior 6 months • Malignancy • Endometrial hyperplasia with atypia • Alcohol or drug abuse • Myelosuppressive therapy • Evidence of chronic viral infection (hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus) • Serum transaminase level > 1.5 times upper limit of normal • Serum creatinine level > 2.0 mg/dL Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 228) Further details: ferric carboxymaltose 500 mg IV on study day 0, 7, 14 (as needed) to obtain calculated dose Group 2: oral iron (n = 225) Further details: ferrous sulphate 325 mg 3 times daily for 42 days

Outcomes

Outcomes reported were mortality, quality of life, haemoglobin levels and serious adverse events Time of measurements: 6 weeks from start of treatment

Notes

Reason for postrandomisation dropout(s): did not complete study or haemoglobin levels were not available Attempts were made to contact study authors in August 2012

Risk of bias Bias




Quote: “The randomization sequence for the VIT02/03 studies were generated by using Proc Plan in SAS Version 8 by the CRO we used for these trials”


Quote: “Treatment group and subject number were assigned by blocked randomization using an interactive voice response system”

Low risk


Quote: “This was an open-label, Phase 3, randomized, active control clinical trial with two parallel treatment groups”


Quote: “This was an open-label, Phase 3, randomized, active control clinical trial with two parallel treatment groups”


68

Van Wyck 2009

(Continued)


High risk



Low risk



Unclear risk

Quote: “Support for this study was provided by American Regent, Inc., the human drug division of Luitpold Pharmaceuticals, Shirley, NY”

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Anker 2006

No separate data for anaemic and non-anaemic participants

Anker 2009a

Protocol for a trial

Anonymous 1966

Not a randomised controlled trial

Aronstam 1982

Includes pregnant participants

Auerbach 2007


Auerbach 2011


Barish 2012

Significant proportion of participants had chronic kidney disease; no separate data were available for participants without chronic kidney disease

Barrison 1981

Not a randomised clinical trial

Beris 2006

No separate data for anaemic and non-anaemic patients

Bermejo 2009


Bernabeu-Wittel 2012

Protocol for a trial

Bisbe 2011


Black 1981

It was not clear whether this was a randomised controlled trial. As the study author does not work at the institution any longer and no forwarding details were provided, we were unable to contact the study author to ascertain whether this was a randomised controlled trial

Bulvik 1997


Crosby 1994



69

(Continued)

Cuenca 2008


Desai 1968


Earley 2009

Not in anaemic participants

Evers 1977

Includes pregnant and postpartum participants

Evstatiev 2013

Not in anaemic participants

Fitzgerald 2008


Froessler 2010


Garrido-Martin 2012

Includes non-anaemic participants

Gasche 1995

Not assessing the role of iron

Gedik 1995

The age group of participants is not stated; the study was conducted in the Paediatric Department of the hospital, suggesting that a significant proportion of (if not all) participants were children

Grote 2009

Intervention in non-anaemic participants

Harris 2009


Hussain 2013

Includes participants with chronic kidney disease and postpartum anaemia

Kaltwasser 1987


Kaltwasser 1989

Participants received different co-interventions

Kulnigg 2009


Kulnigg-Dabsch 2012


Lewinski 1973

Comparison between intravenous iron and oral iron in combination with blood transfusion

Liguori 1993


Lipsic 2010


Littlewood 2012


Liu 2004

Participants received different co-interventions

Mundy 2005

Anaemic participants were excluded

Munoz 2011



70

(Continued)

Munoz 2011a


Munoz 2012


Murgel 1969


Najean 1995


Onken 2013

Includes postpartal participants

Ravanbod 2013

Not clear whether the study was a randomised controlled trial. Study authors were contacted and replied but were unable to provide information on the method of randomisation

Raya 2010

Not clear whether participants were anaemic preoperatively

Rondinelli 2013


Schatz 2013


Serrano-Trenas 2011


Singh 2007

Includes participants with chronic kidney disease

Strauss 2013

Includes participants with chronic kidney disease

Wang 2003

Participants were undergoing haemodialysis for kidney failure

Weatherall 2004


Zauber 1992


Characteristics of studies awaiting assessment [ordered by study ID] Adsul 2005 Methods


Participants

Country: India Sample size: 60 Postrandomisation dropout(s): 0 (0%) Revised sample size: 60 Females: 41 (68.3%) Mean age: 36 years Inclusion criteria: • Clinical and laboratory diagnosis of iron deficiency anaemia (< 10 g/dL) • Aged between 18 and 65 years


71

Adsul 2005

(Continued)

Exclusion criteria: • Anaemia due to any cause other than nutritional deficiency • History of acid-peptic disorders • Oesophagitis • Hiatus hernia • Personal/ family history of thalassaemia or sickle cell anaemia • History of malabsorption syndrome • History of hypersensitivity to iron preparations • Haematinics within 24 hours before inclusion • Immunocompromised patients, terminally ill patients or those with sever cardiac, hepatic, renal or cerebrovascular disease • Malignancy • Chronic uncontrolled systemic disease (such as hypertension, diabetes, collagen disorders) • Patients who had participated in a new drug study in the previous 12 months Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 30) Further details: oral carbonyl iron 300 mg once daily (duration of treatment not stated) Group 2: preparation 2 (n = 30) Further details: oral ferrous fumarate 300 mg once daily (duration of treatment not available)

Outcomes


Notes

Attempts were made to contact study authors in Augusut 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Anthony 2011 Methods


Participants

Country: USA Sample size: 229 Postrandomisation dropout(s): 72 (31.4%) Revised sample size: 157 Females: 101 (64.3%) Mean age: 62 years Inclusion criteria: • ≥ 18 years of age with histological diagnosis of cancer (acute leukaemia or myeloproliferative syndrome excluded) receiving ongoing or planned chemotherapy • Hb level ≤ 10.0 g/dL • Body weight > 50 kg • Karnofsky performance status ≥ 60% Exclusion criteria: • Iron depletion • Active infection • Myelophthisic bone marrow (except for haematological malignancy) • Hypoplastic bone marrow


72

Anthony 2011

(Continued)

• Uncontrolled hypertension • Bleeding • Planned surgery Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 72) Further details: iron sucrose 7 mg/kg up to 500 mg maximum × 3 with 1 to 3 week intervals Group 2: control (n = 85) Further details: no intervention

Outcomes

Outcomes reported were changes in haemoglobin levels. In addition, the trial provided information on adverse events, but this information was reported in the ’as treated analysis.’ As a result, a proportion of participants with serious adverse events in the control group actually belonged to the intervention group (who had discontinuation of treatment). We did not obtain this information because of the significant bias that this would introduce Time of measurement: maximum haemoglobin rise during study period

Notes

Reason for postrandomisation dropout(s): required interventions (27); adverse events (18); participant requests (28) ; investigator decisions (7); intolerable signs and symptoms (11); other (17) A discrepancy is evident between number of postrandomisation dropouts and reasons for dropouts Attempts were made to contact study author in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Auerbach 2004 Methods


Participants

Country: USA Sample size: 157 Postrandomisation dropout(s): 2 (1.3%) Revised sample size: 155 Females: 65 (41.9%) Mean age: 65 years Inclusion criteria: • Patients with histological diagnosis of cancer • Hb < 10.5 g/dL • Serum ferritin ≤ 450 picomoles/L or ≤ 675 picomoles/L in combination with transferrin saturation ≤ 19% Exclusion criteria: • Patients with anaemia attributable to causes other than cancer or chemotherapy such as haemolysis, gastrointestinal bleeding or myelodysplastic syndromes • Prior transfusion, previous iron dextran therapy, allergy or intolerance to rHuEPO, rHuEPO within 4 weeks of enrolment, uncontrolled hypertension, active infection, prior gastric surgery and primary bone marrow malignancy or lymphoma metastatic to bone marrow

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (preparation 1) (n = 41) Further details: iron dextran by total dose infusion (intravenous) diluted in 500 mL normal saline administered at a rate of 175 mL/h Group 2: IV iron (preparation 2) (n = 37) Further details: iron dextran 100 mg intravenously in divided doses until chemotherapy


73

Auerbach 2004

(Continued)

Group 3: oral iron (n = 43) Further details: ferrous sulphate 325 mg twice daily until chemotherapy Group 4: control (n = 36) Further details: no intervention Outcomes

Outcomes reported were haemoglobin levels Time of measurements: 6 weeks from start of treatment or end of chemotherapy treatment

Notes

Reason for postrandomisation dropout(s): no postbaseline haemoglobin value Attempts were made to contact study authors in August 2012. Although they replied, they did not provide information on allocation concealment. So, we were unable to determine whether allocation concealment was adequate

Bisbe 2012 Methods


Participants

Country: Spain Number randomly assigned: 65 Postrandomisation dropouts: not stated Revised sample size: 65 Average age: not stated Females: not stated Inclusion criteria: • Patients undergoing total knee arthroplasty. • Postoperative anaemia (Hb < 12 g/dL; transferrin saturation < 20%) Exclusion criteria: • Patients who received transfusion before randomisation • Hb < 9 g/dL

Interventions

Participants were randomly assigned to 2 groups Group 1: IV iron (n = not stated) Further details: ferric carboxymaltose intravenous single total dose infusion 1 day after surgery Group 2: oral iron (n = not stated) Further details: ferrous sulphate 80 mg 3 times, orally 30 days after discharge

Outcomes

Outcomes reported were haemoglobin and quality of life

Notes

Time of measurement: 30 days from discharge The number of participants randomly assigned to each group was not stated. No significant differences in quality of life or haemoglobin levels were noted between the 2 groups Attempts were made to contact study authors in September 2013. No replies were received. So, we were unable to determine whether allocation concealment was adequate


74

Chen 2002 Methods


Participants

Country: China Number randomly assigned: 105 Postrandomisation dropouts: not stated Revised sample size: 105 Average age: 41 years Females: 94 (89.5%) Inclusion criteria: • Patients with iron deficiency anaemia Exclusion criteria: • Malignancy • Connective tissue disease • Uncontrolled blood loss • Received iron preparations or blood transfusion within 1 month

Interventions

Participants were randomly assigned to 2 groups: Group 1: preparation 1 (n = 31) Further details: polysaccharide iron complex 150 mg twice a day orally for 8 weeks Group 2: preparation 2 (n = 36) Further details: ferrous sulphate controlled release tablets 500 mg per day orally for 8 weeks Group 3: preparation 3 (n = 38) Further details: ferrous succinate 100 mg 3 times a day orally for 8 weeks

Outcomes


Notes

Attempts were made to contact study authors in November 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Devasthali 1991 Methods


Participants

Country: USA Sample size: 49 Postrandomisation dropout(s): 3 (6.1%) Revised sample size: 46 Females: 46 (100%) Mean age: not stated Inclusion criteria: • Menstruating, non-pregnant women between the ages of 18 and 40 years • Recent deferral from blood donation because hematocrit < 35% • Absence of known medical disorders • No iron supplementation since deferral from blood donation • Mean corpuscular volume < 85 fl and ferritin less than 12 µg/L at the beginning of the study • Signed informed consent for participation


75

Devasthali 1991

(Continued)

Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 21) Further details: iron carbonyl 100 mg oral daily for 16 weeks Group 2: preparation 2 (n = 25) Further details: ferrous sulphate 500 mg oral daily for 16 weeks

Outcomes

Outcomes reported were haemoglobin levels Time of measurement: 16 weeks from start of treatment

Notes

Reason for postrandomisation dropout(s): withdrew from study Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Erichsen 2005 Methods


Participants

Country: Norway Sample size: 19 Postrandomisation dropout(s): 2 (10.5%) Revised sample size: 17 Females: 13 (76.5%) Mean age: not stated Inclusion criteria: • Iron deficiency anaemia, defined by haemoglobin < 12 g/dL in females and< 13 g/dL in males and S-ferritin < 50 mg/L • Inflammatory bowel disease Exclusion criteria: • Pregnancy • Iron therapy or blood transfusions during the 6 weeks before inclusion • Indications of haemolysis • Deficiency of cobalamin or folic acid • Renal disease • Cancer • Infliximab therapy • Recent start of azathioprine therapy

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 9) Further details: iron sucrose (200 mg) thrice in 14 days Group 2: oral iron (n = 8) Further details: ferrous fumarate (120 mg) daily for 14 days

Outcomes

None of the outcomes of interest for the review were reported in this trial

Notes

Reason for postrandomisation dropout(s): Treatment was stopped after 6 days because of side effects of oral iron Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate


76

Ferrari 2012 Methods


Participants

Country: Italy Sample size: 24 Postrandomisation dropout(s): not stated Revised sample size: 24 Females: 14 (58.3%) Mean age: 61 years Inclusion criteria: • Mild non-chemotherapy-induced iron deficiency anaemia (Hb between 10 and 12 g/dL and ferritin < 30 mg/ mL) • Patients operated on for solid tumours

Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 12) Further details: oral ferrous bisglycinate chelate, 28 mg per day for 20 days, then 14 mg per day for 40 days Group 2: preparation 2 (n = 12) Further details: oral ferrous sulphate 60 mg per day for 60 days

Outcomes

Outcomes reported were serious adverse events and haemoglobin levels Time of measurement: end of treatment

Notes

Attempts were made to contact study authors in Augusut 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Giordano 2011 Methods


Participants

Country: Italy Sample size: 24 Postrandomisation dropout(s): not stated Revised sample size: 24 Females: not stated Mean age: 68 years Inclusion criteria: • Patients with myelodysplastic syndrome • Anaemia refractory to erythropoietin

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 12) Further details: sodium ferrigluconate 62.5 mg IV diluted in normal saline (duration not stated) Group 2: oral iron (n = 12) Further details: lipofer 14 mg 2 tablets orally (duration not stated)

Outcomes

None of the outcomes of interest were reported


77

Giordano 2011

Notes

(Continued)

Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Gordeuk 1987 Methods


Participants

Country: USA Sample size: 50 Postrandomisation dropout(s): 14 (28%) Revised sample size: 36 Females: 36 (100%) Mean age: not stated Inclusion criteria: • Blood donors • Menstruating non-pregnant women between the ages of 18 and 40 years • Deferral for repeat blood donation because of hematocrit < 38%

Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 18) Further details: oral ferrous carbonyl 600 mg thrice daily for 3 weeks Group 2: preparation 2 (n = 18) Further details: oral ferrous sulphate 300 mg thrice daily for 3 weeks

Outcomes


Notes

Reason for postrandomisation dropout(s): side effects (6), non-compliance (3), moved (2), discovery of pregnancy (1) and normal serum ferritin concentrations (2) Attempts were made to contact study authors in Augusut 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Henry 2007 Methods


Participants

Country: USA Sample size: 189 Postrandomisation dropout(s): 60 (31.7%) Revised sample size: 129 Females: 89 (69%) Mean age: 65 years Inclusion criteria: • Patients with non-myeloid malignancy with anaemia (Hb < 11 g/dL) • At least 18 years of age • Eastern Cooperative Oncology Group performance status score of 0 to 2. 3. Life expectancy at least 24 weeks • Serum ferritin at least 100 ng/mL or transferrin saturation at least 15%


78

Henry 2007

(Continued)

• No iron or epoetin alfa in preceding 30 days Exclusion criteria: • Haemolysis • Gastrointestinal bleeding • Folate or vitamin B12 deficiency • Raised ferritin level (> 900 ng/mL) or iron saturation (> 35%) • Pregnancy or lactation • Renal or liver disorder • Active infection requiring systemic antibiotics • Personal or family history of haemochromatosis • Co-morbidities precluding study participation such as hypersensitivity to ferric gluconate or its components, contraindication to epoetin alfa therapy • Red blood cell (RBC) transfusion within past 2 weeks • Any investigational agent within 30 days before enrolment Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 41) Further details: ferrous gluconate 125 mg IV weekly for 8 weeks Group 2: oral iron (n = 44) Further details: ferrous sulphate 325 mg oral daily for 8 weeks Group 3: control (n = 44) Further details: no treatment

Outcomes

Outcomes reported were mortality, blood transfusion requirements, haemoglobin levels and serious adverse events Time of measurements: 4 weeks after start of treatment

Notes

Reason for postrandomisation dropout(s): Did not receive drugs as planned for various reasons including discontinuation of treatment. Information was obtained for as many participants as possible Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Izuel-Rami 2006 Methods

Awaiting full text

Participants Interventions Outcomes Notes

This reference obtained from The Cochrane Library appears to be incorrect, and the correct article could not be obtained


79

Jacobs 2000 Methods


Participants

Country: South Africa Sample size: 173 Postrandomisation dropout(s): 82 (47.4%) Revised sample size: 91 Females: not stated Mean age: not stated Inclusion criteria: • Blood donors with iron deficiency anaemia (Hb < 13.6 g/dL for males, < 12 g/dL for females)

Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 71) Further details: oral iron (polymaltose) 100 mg twice daily for 12 weeks Group 2: preparation 2 (n = 20) Further details: oral ferrous sulphate 100 mg twice daily for 12 weeks

Outcomes


Notes

Reason for postrandomisation dropout(s): not stated Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Jakobsen 2013 Methods


Participants

Country: Germany Number randomly assigned: 81 Postrandomisation dropouts: not stated Revised sample size: 81 Average age: not stated Females: not stated Inclusion criteria: • Adult inflammatory bowel disease patients with haemoglobin < 12 g/dL and ferritin < 30 ng/mL or transferrin saturation < 16%

Interventions

Participants were randomly assigned to 2 groups: Group 1: IV iron (n = 40) Further details: ferric carboxymaltose 500 mg intravenously administered within 2 minutes Group 2: IV iron (n = 41) Further details: ferric carboxymaltose 500 mg intravenously administered in 15 minutes

Outcomes

Outcomes reported were serious adverse events and haemoglobin

Notes

Time of measurement: not stated Numerical details of serious adverse events and haemoglobin were not reported No differences in serious adverse events or rise in haemoglobin levels was noted between the 2 groups


80

Jakobsen 2013

(Continued)

Attempts were made to contact study authors in September 2013. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Kanakaraddi 1973 Methods


Participants

Country: India Sample size: 50 Postrandomisation dropout(s): not stated Revised sample size: 50 Females: 17 (34%) Mean age: not stated Inclusion criteria: • Patients admitted to medical ward with severe anaemia (< 7.6 g/dL)

Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 25) Further details: total dose iron in the form of iron-dextran complex (Hb deficiency% × 0.255 = total grams to be infused) diluted in 1 pint of 5% glucose given intravenously 20 drops per minute for first half an hour, then 40 to 60 drops per minute Group 2: preparation 2 (n = 25) Further details: intramuscular iron-dextran complex

Outcomes

Outcome reported was haemoglobin rise Time of measurements: 3 weeks after start of treatment

Notes


Kang 2006 Methods

Awaiting full text

Participants Interventions Outcomes Notes

This appears to be the same as another included reference (Kim 2009), but we could not confirm this, as this article was not available


81

Kim 2007 Methods


Participants

Country: South Korea Sample size: 75 Postrandomisation dropout(s): not stated Revised sample size: 75 Females: 75 (100%) Mean age: 52 years Inclusion criteria: • Patients diagnosed as having cervical cancer and treated with concurrent chemoradiotherapy • Patients with mild anaemia < 12 g/dL

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 30) Further details: intravenous iron sucrose (5400 mg ferric hydroxide sucrose complex) diluted with 200 mL normal saline for injection Group 2: control (n = 45) Further details: no intervention

Outcomes

Outcomes reported were blood transfusion requirements, haemoglobin levels and serious adverse events Time of measurements: end of chemotherapy cycle

Notes


Kim 2009 Methods


Participants

Country: South Korea Sample size: 76 Postrandomisation dropout(s): 20 (26.3%) Revised sample size: 56 Females: 56 (100%) Mean age: 42 years Inclusion criteria: • Patients with menorrhagia with established iron deficiency anaemia (haemoglobin levels < 9.0 g/dL) • Scheduled to undergo surgical treatment Exclusion criteria: • Anaemia from causes other than iron deficiency • Current administration of iron • Previous iron therapy or transfusion within 3 months • History of haematological disease • Chronic disease

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 30) Further details: iron sucrose 200 mg thrice weekly beginning 3 weeks before surgery until target haemoglobin of 10 grams was reached


82

Kim 2009

(Continued)

Group 2: oral iron (n = 26) Further details: protein succinylate (80 mg of elementary iron per day) beginning 3 weeks before surgery until calculated dose was achieved Outcomes

Outcomes reported were haemoglobin levels and serious adverse events Reasons for postrandomisation dropouts: < 80% compliance Time of measurements: not stated

Notes

Reason for postrandomisation dropout(s): less than 80% compliance Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Kulnigg 2008 Methods


Participants

Country: international multi-centric trial Sample size: 200 Postrandomisation dropout(s): 4 (2%) Revised sample size: 196 Females: 117 (59.7%) Mean age: 42 years Inclusion criteria: • Patients with Crohn’s disease or ulcerative colitis and iron deficiency anaemia (defined by Hb ≤ 10 g/dL modified to 11 g/dL after 4 months of recruitment because of poor recruitment and transferrin saturation < 20%, or serum ferritin < 100 mcg/L) • Age between 18 and 80 years • Negative pregnancy test Exclusion criteria: • Untreated vitamin B12 or folate deficiency • Other types of anaemia • Erythropoietin treatment within 8 weeks before enrolment • Iron replacement therapy or blood transfusion within 30 days

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 136) Further details: ferric carboxymaltose 50 mg ferric iron (iii) per millilitre in water that was diluted in sodium chloride and administered at a maximum rate of 16.7 mL per minute up to the maximum dose over several visits . Group 2: oral iron (n = 60) Further details: ferrous sulphate 100 mg twice a day for 12 weeks

Outcomes

Outcomes reported were mortality, quality of life, haemoglobin levels and serious adverse events Time of measurements: not stated

Notes

Reason for postrandomisation dropout(s): no efficacy data available (these participants could be included for safety analyses) Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate


83

Langstaff 1993 Methods


Participants

Country: UK Sample size: 126 Postrandomisation dropout(s): 22 (17.5%) Revised sample size: 104 Females: 90 (86.5%) Mean age: 51 years Inclusion criteria: • Adult patients (≥ 18 years of age) with iron deficiency anaemia (8.5 to 12 g/dL; MCH < 28 pg; MCHC < 33 g/dL) Exclusion criteria: • Anaemia complicated by other deficiency states or due to malabsorption • Hypersensitivity to iron-containing preparation • Pregnancy • Mental incapacity

Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 52) Further details: Ferrum Hausmman oral 100 mg twice a day for 9 weeks Group 2: preparation 2 (n = 52) Further details: ferrous sulphate oral 60 mg thrice a day for 9 weeks

Outcomes

Outcomes reported were mortality, haemoglobin levels and serious adverse events Time of measurement: end of treatment

Notes

Reason for postrandomisation dropout(s): unreliable data (5); did not return for follow-up (12); did not undergo tests (5) Attempts were made to contact study authors in Augusut 2012. Although authors replied, they could not provide information on allocation concealment. So, we were unable to determine whether allocation concealment was adequate

Li 2005 Methods


Participants

Country: China Sample size: 140 Postrandomisation dropout(s): 9 (6.4%) Revised sample size: 131 Females: 119 (90.8%) Mean age: 39 years Inclusion criteria: • Age between 18 and 65 years • Met iron deficiency anaemia criteria • Did not participate in other drug clinical trials for past month


84

Li 2005

(Continued)

Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 64) Further details: oral ferrous threonate thrice daily (exact dose not clear) for 8 weeks Group 2: preparation 2 (n = 67) Further details: oral ferrous sulphate thrice daily (exact dose not clear) for 8 weeks

Outcomes


Notes

Reason for postrandomisation dropout(s): unclear Attempts were made to contact study author in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Michalopoulou 2009 Methods


Participants

Country: Greece Sample size: 64 Postrandomisation dropout(s): not stated Revised sample size: 64 Females: not stated Mean age: not stated Inclusion criteria: • Severe congestive heart failure (NYHA III or IV; left ventricular ejection fraction (EF) ≤ 35% despite maximally tolerated doses of CHF medication) and whose haemoglobin levels (Hb) were < 12 g/dL

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 32) Further details: iron sucrose IV 200 mg/wk for 6 weeks Group 2: control (n = 32) Further details: normal saline

Outcomes

Outcomes reported were haemoglobin levels Time of measurements: not stated

Notes


Mimura 2008 Methods


Participants

Country: Brazil Number randomly assigned: 18 Postrandomisation dropouts: not stated Revised sample size: 18 Average age: 59 years


85

Mimura 2008

(Continued)

Females: 8 (44.4%) Inclusion criteria: • Patients with iron deficiency anaemia after gastrectomy (Hb < 12 g/dL transferrin saturation < 16%, and serum ferritin level < 20 g/L) Interventions

Participants were randomly assigned to 2 groups: Group 1: preparation 1 (n = 9) Further details: ferrous glycinate chelate 250 mg/d for 4 months (frequency not stated) Group 2: preparation 2 (n = 9) Further details: ferrous sulphate 400 mg/d for 4 months (frequency not stated)

Outcomes


Notes

Attempts were made to contact study authors in November 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

NCT00199277 Methods


Participants

Adults with anaemia and surgically resectable colorectal neoplasm

Interventions

Iron sucrose (intravenous) vs ferrous sulphate (oral)

Outcomes

Mortality, blood transfusion requirements and haemoglobin levels

Notes

Recruitment status of this study is not known

NCT00236951 Methods


Participants

Adults with anaemia and with ongoing or planned chemotherapy

Interventions

Iron sucrose (intravenous) vs no intervention

Outcomes

Adverse events, quality of life and change in haemoglobin levels

Notes

Study completed


86

NCT00482716 Methods


Participants

Adults with anaemia and non-myeloid malignancies

Interventions

Iron dextran complex (intravenous) or iron sucrose injection vs no intervention

Outcomes

None of the outcomes of interest for this review were measured in this trial

Notes

Study active, not recruiting

NCT00704028 Methods


Participants

Adults with anaemia

Interventions

Ferric carboxymaltose (intravenous) vs iron dextran complex (intravenous)

Outcomes

Safety

Notes

Study completed

NCT00706667 Methods


Participants

Adults with iron deficiency anaemia and undergoing orthopaedic surgery

Interventions

Ferric carboxymaltose (intravenous) vs placebo

Outcomes

Change in haemoglobin

Notes

Study completed

NCT00810030 Methods


Participants

Adults with iron deficiency anaemia and inflammatory bowel disease

Interventions

Ferric carboxymaltose (intravenous) vs iron sucrose (intravenous)

Outcomes

Adverse events and quality of life

Notes

Study completed


87

NCT00978575 Methods


Participants

Adults with anaemia and acute upper gastrointestinal bleeding

Interventions

Ferric carboxymaltose (intravenous) vs ferrous sulphate (oral) vs placebo (after discharge)

Outcomes

Haemoglobin and quality of life

Notes

Study completed

NCT00982007 Methods


Participants

Adults with anaemia

Interventions

Ferric carboxymaltose (intravenous) vs other intravenous iron (standard of care) vs ferrous sulphate (oral)

Outcomes


Notes

Study completed

NCT01017614 Methods


Participants


Interventions

Iron oligosaccharide (intravenous) vs iron sulphate

Outcomes


Notes

Study completed

NCT01100879 Methods


Participants

Adults with anaemia and multiple myeloma

Interventions

Ferric carboxymaltose (intravenous) vs standard of care

Outcomes


Notes

Study completed


88

NCT01101399 Methods


Participants

Adults with anaemia and non-Hodgkin’s lymphoma, multiple myeloma, leukaemia or any chemotherapy excluding anthracycline-containing chemotherapy

Interventions

Ferric carboxymaltose (intravenous) vs standard of care

Outcomes


Notes

Study ongoing but not recruiting

NCT01114139 Methods


Participants

Adults with iron deficiency anaemia

Interventions

Ferumoxytol (intravenous) vs placebo

Outcomes


Notes

Study has been completed

NCT01114204 Methods


Participants


Interventions

Ferumoxytol (intravenous) vs iron sucrose (intravenous)

Outcomes


Notes


NCT01145638 Methods


Participants

Adults with iron deficiency anaemia and non-myeloid malignancies who are going to receive at least 2 more chemotherapy cycles

Interventions

Iron isomaltoside (intravenous) vs iron sulphate

Outcomes

Drug-related serious adverse events and change in haemoglobin


89

NCT01145638

Notes

(Continued)

Study currently ongoing but not recruiting

NCT01160198 Methods


Participants

Adult Indian participants with iron deficiency anaemia

Interventions

Ferrous bisglycinate chelate 120 mg (oral) vs ferrous bisglycinate chelate 60 mg (oral) vs ferrous ascorbate (oral)

Outcomes


Notes


NCT01180894 Methods


Participants

Adults with iron deficiency anaemia and requiring intensive care for trauma

Interventions

Iron sucrose (intravenous) vs placebo

Outcomes

Mortality and blood transfusion

Notes

Study currently recruiting

NCT01307007 Methods


Participants

Adults with anaemia and heavy menstrual bleeding

Interventions

Ferric carboxymaltose (intravenous) vs iron dextran injection (intravenous)

Outcomes

None of the outcomes of interest for this review were included in this trial

Notes

Study ongoing but not recruiting

NCT01309659 Methods


Participants

Adults with unexplained anaemia

Interventions

Iron sucrose (intravenous) started immediately vs iron sucrose (intravenous) started after 12 weeks


90

NCT01309659

(Continued)

Outcomes

Change in haemoglobin, clinical events, adverse events, quality of life

Notes

Study terminated because of lack of recruitment

NCT01340872 Methods


Participants


Interventions

Ferric trimaltol (oral) vs placebo

Outcomes

Adverse events, quality of life, change in haemoglobin

Notes


NCT01352221 Methods


Participants


Interventions

Ferric trimaltol (oral) vs placebo

Outcomes

Adverse events, change in haemoglobin, quality of life

Notes


NCT01425463 Methods


Participants

Adult Chinese participants with iron deficiency anaemia

Interventions

Ferrous (II) glycine sulphate complex (oral) vs polyferose (oral)

Outcomes

Change in haemoglobin from baseline

Notes

Study active, not recruiting; awaiting follow-up of participants


91

NCT01428843 Methods


Participants


Interventions

Ferric oxide, saccharated (intravenous) vs placebo

Outcomes

Haemoglobin and quality of life

Notes


NCT01690585 Methods


Participants

Adults with anaemia and lower gastrointestinal bleeding not requiring surgical treatment

Interventions


Outcomes

Adverse events and haemoglobin

Notes


NCT01701310 Methods


Participants

Adults with anaemia and colorectal adenocarcinoma

Interventions

Ferric carboxymaltose (intravenous) vs ferrous sulphate

Outcomes

Mortality, morbidity, haemoglobin, quality of life, length of hospital stay

Notes


NCT01725789 Methods


Participants

Adults with anaemia after gastrectomy for cancer

Interventions


Outcomes

Adverse events and haemoglobin

Notes



92

NCT01733979 Methods


Participants

Adults with anaemia

Interventions

Heme-iron polypeptide (oral) vs heme-iron (oral) vs organic iron (oral) vs placebo

Outcomes


Notes


NCT01837082 Methods


Participants

Adults with iron deficiency anaemia and congestive cardiac failure

Interventions


Outcomes

None of the outcomes of interest for this review were included as outcomes in this trial

Notes


NCT01857011 Methods


Participants

Adults with iron deficiency anaemia after bariatric abdominoplasty

Interventions

Iron sucrose (intravenous) vs iron(III)-hydroxide polymaltose complex (oral)

Outcomes

Haemoglobin levels

Notes


NCT01927328 Methods


Participants

Adults with anaemia and suitable for palliative chemotherapy for oesophageal cancer

Interventions

Iron isomaltoside (intravenous) vs standard of care

Outcomes

Blood transfusion requirements, haemoglobin, quality of life

Notes



93

NCT01950247 Methods


Participants


Interventions

Ferric carboxymaltose (intravenous) vs intravenous iron (standard of care)

Outcomes

Quality of life

Notes


Okonko 2008 Methods


Participants

Country: international multi-centric trial in Europe Sample size: 18 Postrandomisation dropout(s): 0 (0%) Revised sample size: 18 Females: 7 (38.9%) Mean age: not stated Inclusion criteria: • Age 21 years or older • Symptomatic chronic heart failure (CHF) • Exercise limitation • Average of 2 screening Hb concentrations 12.5 g/dL (anaemic group) • Ferritin < 100 mcg/L or between 100 mcg/L and 300 mcg/L with transferrin saturation < 20% • Left ventricular ejection fraction ≤ 45% measured within the preceding 6 months using echocardiography or magnetic resonance imaging • Use of maximally tolerated doses of optimal CHF therapy for at least 4 weeks before recruitment and without dose changes for at least 2 weeks • Resting blood pressure ≤ 160/100 mmHg • Normal red cell folate and vitamin B12 (according to local laboratory reference ranges) Exclusion criteria: • Use of erythropoietin, iron (oral or IV) or blood transfusion within previous 30 days • History of acquired iron overload or haemochromatosis (or a first relative with haemochromatosis) • Earlier hypersensitivity to parenteral iron preparations or a history of allergic disorders • Active infection, bleeding, malignancy or haemolytic anaemia • Presence of any condition that precluded exercise testing, such as decompensated heart failure, significant musculoskeletal disease, unstable angina pectoris, obstructive cardiomyopathy, severe uncorrected valvular disease or uncontrolled bradyarrhythmias or tachyarrhythmias • Concurrent immunosuppressive or renal replacement therapy • Chronic liver disease (alanine transaminase > 3 times upper limit of normal range)

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 12) Further details: study drug and dosing schedule; iron sucrose IV 200 mg weekly (therapeutic phase) unless ferritin was ≥ 500 ng/mL, then at weeks 4, 8, 12 and 16 (maintenance phase) Group 2: control (n = 6) Further details: no intervention


94

Okonko 2008

(Continued)

Outcomes

Outcomes reported were mortality and haemoglobin levels Time of measurements: 2 weeks after end of treatment

Notes


Olijhoek 2001 Methods


Participants

Country: Europe (multi-centric trial) Number randomly assigned: 110 Postrandomisation dropouts: 3 (2.7%) Revised sample size: 107 Average age: 66 years Females: 99 (92.5%) Inclusion criteria: • > 18 years of age and scheduled for an elective orthopaedic surgery that was estimated to require 2 to 4 units (900 to 1800 mL) of blood • Each patient had pretreatment Hb level > 10 to < 13 g/dL and was in generally good health • Serum total iron-binding capacity (TIBC) ratio had to be > 15% and serum ferritin level > 50 ng/mL • Female patients were postmenopausal for at least 1 year, surgically sterile or using an acceptable form of birth control • Patients had not participated in a preoperative autologous blood donation programme, nor had they received a transfusion within 1 month of study entry Exclusion criteria: • Clinically significant systemic, infectious or neoplastic disease • Significant ongoing blood loss • Laboratory abnormalities • Androgen therapy within 1 month of study entry • History of drug or alcohol abuse within past 2 years • Previous exposure to epoetin alfa

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 25) Further details: IV iron saccharate (200 mg) on days 1 and 8 Group 2: oral iron (n = 24) Further details: oral iron (200 mg) for 14 days Group 3: IV iron (n = 29) Further details: same as group 1 with epoetin alfa Group 4: oral iron (n = 29) Further details: same as group 2 with epoetin alfa

Outcomes

Outcomes reported were mortality, serious adverse events and haemoglobin levels

Notes

Time of measurement: 14 days after start of treatment Reasons for postrandomisation dropouts: preoperative autologous blood donation (1); did not store drug properly (1); drug-related serious adverse event (1)


95

Olijhoek 2001

(Continued)

Attempts were made to contact study authors in September 2013. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Oliver 2010 Methods


Participants

Country: Spain Sample size: 165 Postrandomisation dropout(s): 102 (61.8%) Revised sample size: 63 Females: 9 (14.3%) Mean age: 63 years Inclusion criteria: • Adult patients undergoing major urological surgery • No preoperative anaemia • > 20% loss of preoperative red cell mass

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 31) Further details: iron sucrose (no other details) Group 2: control (n = 32) Further details: no intervention

Outcomes

Outcomes reported were blood transfusion requirements and haemoglobin levels Time of measurements: 30 days from start of treatment

Notes

Reason for postrandomisation dropout(s): not reported Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Pedrazzoli 1988 Methods


Participants

Country: Italy Sample size: 40 Postrandomisation dropout(s): 2 (5%) Revised sample size: 38 Females: 33 (86.8%) Mean age: 41 years Inclusion criteria: • Patients with overt sideropenic anaemia • > 18 years of age • Serum Hb between 7 and 11 g/dL • Serum iron concentration < 40 mcg/dL, transferrin saturation rate < 15%, total iron binding capacity > 400 mcg/dL, serum ferritin concentration < 15 mcg/L Exclusion criteria:


96

Pedrazzoli 1988

(Continued)

• Sideropenic anaemia of unknown aetiology or caused by blood losses or associated with other aetiology or due to chronic inflammatory processes • Haemorrhagic conditions • Gastrointestinal disease with malformation or mechanical or functional obstruction • Acute or chronic vomiting or diarrhoea • Severe renal or hepatic failure, hypothyroidism or collagenopathies Interventions

Participants were randomly assigned to the following groups: Group 1: preparation 1 (n = 20) Further details: oral iron succinylprotein complex (80 mg of elemental iron daily) for 2 months Group 2: preparation 2 (n = 18) Further details: oral iron gluconate complex (125 mg of elemental iron daily) for 2 months

Outcomes


Notes

Reason for postrandomisation dropout(s): severe side effects Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Pedrazzoli 2008 Methods


Participants

Country: Italy Sample size: 149 Postrandomisation dropout(s): 0 (0%) Revised sample size: 149 Females: 104 (69.8%) Mean age: not stated Inclusion criteria: • Patients with diagnosis of breast, colorectal, lung or gynaecological cancer and at least 12 additional weeks planned cancer chemotherapy • ≥ 18 years of age • Eastern Cooperative Oncology Group performance status ≥ 2 • Life expectancy ≥ 6 months • Adequate renal and hepatic function • Anaemia (i.e. haemoglobin (Hb) level ≤ 11 g/dL within 24 hours of random assignment, secondary to malignancy and chemotherapy treatment • No absolute or functional iron deficiency (i.e. having serum ferritin level ≥ 100 mL and transferrin saturation ≥ 20%) Exclusion criteria: • Patients with anaemia attributable to factors other than cancer or chemotherapy (i.e. B12 or folate deficiency; haemolysis; gastrointestinal bleeding; myelodysplastic syndromes) • Iron overload (defined as serum ferritin > 800 mcg/L and TSAT > 40% • Received > 2 RBC transfusions within 4 weeks of random assignment or any RBC transfusions within 14 days of first dose or had received therapy with ESA within 4 weeks of random assignment • Pregnant, breastfeeding or not using adequate birth control measures


97

Pedrazzoli 2008

(Continued)

• History of seizure disorders, active cardiac disease, thromboembolic disease or uncontrolled hypertension • Active infection Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = 73) Further details: sodium ferric gluconate IV 125 mg/wk for 6 weeks Group 2: control (n = 76) Further details: no intervention

Outcomes

Outcomes reported were mortality and serious adverse events Time of measurements: 12 weeks after end of treatment

Notes


Prasad 2009 Methods


Participants

Country: UK Sample size: 68 Postrandomisation dropout(s): 2 (2.9%) Revised sample size: 66 Females: 55 (83.3%) Mean age: 82 years Inclusion criteria: • Patients with postoperative anaemia (Hb between 8 and 12 g% in males and 8 and 11 g% in females) following operation for acute hip fracture Exclusion criteria: • Postoperative Hb < 8 g% • Postoperative Hb > 12 g% in males and 11 g% in females • Preoperative serum ferritin < 15 pg/L or > 200 pg/L • Admission CRP > 3 • Serum iron/total iron binding capacity ratio (TIBC) < 15, TIBC > 60 • Patients already taking iron tablets • Patients with preexisting anaemic disorders • Underlying medical conditions (malignancy, chronic renal failure, inflammatory bowel disease, chronic peptic ulcer, oesophageal varices, rheumatoid arthritis) • Medication interfering with iron absorption (e.g. antacids, tetracyclines, bisphosphonates) • No consent

Interventions

Participants were randomly assigned to the following groups: Group 1: oral iron (n = 34) Further details: oral ferrous sulphate 200 mg thrice daily for 4 weeks Group 2: control (n = 32) Further details: no intervention

Outcomes

Outcomes reported were haemoglobin levels Time of measurement: 30 days from start of treatment


98

Prasad 2009

Notes

(Continued)

Reason for postrandomisation dropout(s): lost to follow-up Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Prassler 1998 Methods


Participants

Country: Germany Sample size: 36 Postrandomisation dropout(s): not stated Revised sample size: 36 Females: 15 (41.7%) Mean age: 66 years Inclusion criteria: • Patients with gastrointestinal bleeding with haemoglobin levels between 7 and 11 g/dL Exclusion criteria: • Recurrent bleeding • Required blood transfusion

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 12) Further details: ferric gluconate 125 mg over 30 minutes from day 3 to day 8 Group 2: oral iron (n = 12) Further details: ferrous glycine sulphate 200 mg/d starting from day 3 to day 8 Group 3: control (n = 12) Further details: no intervention

Outcomes

Outcomes reported were haemoglobin levels Time of measurements: end of treatment

Notes


Roe 1968 Methods


Participants

Country: Uganda Sample size: 120 Postrandomisation dropout(s): not stated Revised sample size: 120 Females: not stated Mean age: not stated Inclusion criteria: • Patients admitted into medical unit with anaemia Exclusion criteria: • Known sufferer of asthma


99

Roe 1968

(Continued)

• Known to have had drug sensitivity Interventions

Participants were randomly assigned to 6 groups of 20 participants each with total dose infusion at 5%, 7.5%, 10%, 15%, 20% and 25%

Outcomes

The only outcome reported was death in 1 participant in the 20% total dose infusion group Time of measurements: not stated

Notes


Schroder 2005 Methods


Participants

Country: Germany Sample size: 46 Postrandomisation dropout(s): 11 (23.9%) Revised sample size: 35 Females: not stated Mean age: not stated Inclusion criteria: • Patients with inflammatory bowel disease with iron deficiency anaemia (haemoglobin (Hb) concentration ≤ 10.5 g/dL (females) or 11.0 g/dL (males) with a transferrin saturation ≤ 20% and/or serum ferritin concentrations ≤ 20 mcg/dL • Age between 18 and 85 years Exclusion criteria: • Anaemia not attributable to iron deficiency • Iron overload or disturbances in utilisation of iron • Known hypersensitivity to iron monosaccharide or disaccharide complexes • Use of erythropoietin within last 2 weeks before screening • Serum ferritin concentration > 300 mcg/L • Haemolysis with haptoglobin < 50 mg/dL • Renal insufficiency (serum creatinine > 1.2 mg/dL) • Suspicion of hypoplastic bone marrow failure states or haematological malignancy • Pregnancy, lactation or use of inadequate forms of birth control • Severe concurrent illness • Participation in a clinical trial within the past 1 month • Blood transfusion or parenteral iron infusion in the 2 weeks before screening

Interventions

Participants were randomly assigned to the following groups: Group 1: IV iron (n = 18) Further details: iron sucrose IV 7 mg/kg body weight administered as a drip infusion over 3.5 hours in 0.9% sodium chloride followed by a dose of 200 mg iron infused over 30 minutes 1 to 2 times weekly during 5 weeks Group 2: oral iron (n = 17) Further details: iron sulphate 100 to 200 mg per day for 6 weeks

Outcomes

Outcomes reported were haemoglobin levels Time of measurements: 6 weeks after start of treatment


100

Schroder 2005

Notes

(Continued)

Reason for postrandomisation dropout(s): did not complete the study Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Seid 2006 Methods


Participants

Country: USA Sample size: 584 Postrandomisation dropout(s): not stated Revised sample size: 584 Females: not stated Mean age: not stated Inclusion criteria: • Patients with iron deficiency anaemia

Interventions

Participants were randomly assigned to the following groups: Group 1: iron (n = not reported) Further details: single dose of iron carboxymaltose (15 mg/kg up to a maximum of 1000 mg) in normal saline Group 2: control (n = not reported) Further details: placebo

Outcomes

Outcomes reported were serious adverse events Time of measurements: not reported

Notes

Number of participants belonging to each group was not reported. No serious adverse events were reported in either group Attempts were made to contact study authors in August 2012. No replies were received. So, we were unable to determine whether allocation concealment was adequate

Velhal 1991 Methods


Participants

Country: India Sample size: 254 Postrandomisation dropout(s): not stated Revised sample size: 254 Females: not stated Mean age: not stated Inclusion criteria: • Patients with Hb < 10 g% and transferrin saturation < 16% • Age > 14 years

Interventions

Participants were randomly assigned to the following groups: Group 1: IM iron (n = 115)


101

Velhal 1991

(Continued)

Further details: imferon 100 mg deep IM every day for 3 months Group 2: oral iron (n = 139) Further details: ferrous sulphate 200 mg twice a day for 3 months Outcomes

Outcomes reported were haemoglobin levels and severe adverse events Time of measurements: 45 days from start of treatment

Notes


Characteristics of ongoing studies [ordered by study ID] NCT01692418 Trial name or title

Preoperative intravenous iron to treat anaemia in major surgery

Methods


Participants

Adults undergoing major abdominal surgery and anaemia

Interventions

Ferric carboxymaltose vs placebo

Outcomes

Mortality, blood transfusion, haemoglobin levels, quality of life, adverse events, length of hospital stay

Starting date

2013

Contact information

Mr Toby Richards (University College London)

Notes

The study has not started recruiting

Accessed as up-to-date November 2014.


102

DATA AND ANALYSES

Comparison 1. Oral iron vs inactive control

Outcome or subgroup title 1 Mortality 2 Proportion requiring blood transfusion 3 Length of hospital stay 4 Haemoglobin 4.1 Final haemoglobin 4.2 Change in haemoglobin 5 Quality of life 6 Serious adverse events

No. of studies

No. of participants

4 3

659 546

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

1.05 [0.68, 1.61] 0.74 [0.55, 0.99]

731

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected 0.96 [0.76, 1.22]

1 4 3 1 1 5

Statistical method

Effect size

Comparison 2. Parenteral iron vs inactive control

Outcome or subgroup title 1 Mortality 2 Proportion requiring blood transfusion 3 Haemoglobin 3.1 Final haemoglobin 3.2 Change in haemoglobin 4 Quality of life 5 Serious adverse events

No. of studies

No. of participants

10 8

2141 1315


1.04 [0.63, 1.69] 0.84 [0.66, 1.06]

1802

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected 1.00 [0.74, 1.34]

9 6 3 4 7

Statistical method

Effect size

Comparison 3. Parenteral iron vs oral iron

Outcome or subgroup title 1 Mortality 2 Proportion requiring blood transfusion 3 Mean blood transfused 4 Haemoglobin 4.1 Final haemoglobin 4.2 Change in haemoglobin 5 Quality of life

No. of studies

No. of participants

6 2

1009 371


1.49 [0.56, 3.94] 0.61 [0.24, 1.58]

1 6 3 3 3

769 148 621 771

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI)

Totals not selected -0.50 [-0.73, -0.27] -0.47 [-0.74, -0.21] -0.41 [-1.29, 0.46] -0.02 [-0.16, 0.13]

Statistical method


Effect size

103

6 Serious adverse events

7

1100

Risk Ratio (M-H, Random, 95% CI)

1.23 [0.99, 1.54]

Comparison 4. Iron: different preparations

Outcome or subgroup title 1 Mortality 1.1 Intravenous iron: ferrumoxytol vs iron sucrose 2 Haemoglobin 2.1 Intravenous iron: ferric carboxymaltose vs iron sucrose 2.2 Intravenous iron: ferrumoxytol vs iron sucrose 3 Serious adverse events 3.1 Intravenous iron: ferric carboxymaltose vs iron sucrose 3.2 Intravenous iron: ferrumoxytol vs iron sucrose

No. of studies

No. of participants

Statistical method

Effect size

1 1


Totals not selected 0.0 [0.0, 0.0]

2 1

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)


1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2 1



1


0.0 [0.0, 0.0]

Comparison 5. Subgroup analysis

Outcome or subgroup title 1 Mortality (parenteral iron vs inactive control stratified by clinical setting) 1.1 Blood loss 1.2 Cancer 1.3 Preoperative anaemic patients 1.4 Chronic heart failure 1.5 Other settings 2 Mortality (parenteral iron vs inactive control stratified by erythropoietin use) 2.1 Supplementary erythropoietin 2.2 No supplementary erythropoietin 3 Mortality (parenteral iron vs oral iron stratified by clinical setting) 3.1 Blood loss

No. of studies

No. of participants

10

2141


1.04 [0.63, 1.69]

2 4 1

41 1028 80

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.0 [0.0, 0.0] 1.03 [0.48, 2.25] 0.0 [0.0, 0.0]

2 1 10

184 808 2141

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.87 [0.16, 4.82] 0.66 [0.06, 7.22] 1.04 [0.63, 1.69]

3

701


0.81 [0.34, 1.91]

7

1440


1.50 [0.58, 3.90]

5

861


1.49 [0.56, 3.94]

2

473


0.0 [0.0, 0.0]

Statistical method


Effect size

104

3.2 Cancer 3.3 Chronic heart failure

2 1

371 17


1.33 [0.47, 3.73] 3.64 [0.20, 65.86]

Analysis 1.1. Comparison 1 Oral iron vs inactive control, Outcome 1 Mortality. Review:

Iron therapy in anaemic adults without chronic kidney disease

Comparison: 1 Oral iron vs inactive control Outcome: 1 Mortality

Study or subgroup

Oral iron

Inactive control

Risk Ratio MH,Random,95% CI

Weight


n/N

n/N

Abrahamsen 1965

0/10

0/10

Beck-da-Silva 2013

0/7

1/6

2.0 %

0.29 [ 0.01, 6.07 ]

29/150

29/150

87.9 %

1.00 [ 0.63, 1.59 ]

Steensma 2010

6/163

3/163

10.0 %

2.00 [ 0.51, 7.86 ]

Total (95% CI)

330

329

100.0 %

1.05 [ 0.68, 1.61 ]

Parker 2010

Not estimable

Total events: 35 (Oral iron), 33 (Inactive control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.58, df = 2 (P = 0.45); I2 =0.0% Test for overall effect: Z = 0.20 (P = 0.84) Test for subgroup differences: Not applicable

0.01

0.1

Favours oral iron

1

10

100

Favours inactive control


105

Analysis 1.2. Comparison 1 Oral iron vs inactive control, Outcome 2 Proportion requiring blood transfusion. Review:


Comparison: 1 Oral iron vs inactive control Outcome: 2 Proportion requiring blood transfusion

Study or subgroup

Oral iron

Lidder 2007 Pieracci 2009 Steensma 2010

Total (95% CI)

Inactive control


Weight


n/N

n/N

3/6

10/14

11.4 %

0.70 [ 0.29, 1.66 ]

29/97

46/103

61.2 %

0.67 [ 0.46, 0.97 ]

21/163

22/163

27.4 %

0.95 [ 0.55, 1.67 ]

266

280

100.0 %

0.74 [ 0.55, 0.99 ]

Total events: 53 (Oral iron), 78 (Inactive control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.12, df = 2 (P = 0.57); I2 =0.0% Test for overall effect: Z = 2.01 (P = 0.045) Test for subgroup differences: Not applicable

0.01

0.1

1

Favours oral iron

10

100


Analysis 1.3. Comparison 1 Oral iron vs inactive control, Outcome 3 Length of hospital stay. Review:


Comparison: 1 Oral iron vs inactive control Outcome: 3 Length of hospital stay

Study or subgroup

Parker 2010

Oral iron

Mean Difference

Inactive control

N

Mean(SD)[days]

N

Mean(SD)[days]

150

18.8 (17.4)

150

21.3 (20.6)

IV,Random,95% CI

IV,Random,95% CI -2.50 [ -6.82, 1.82 ]

-10

-5

Favours oral iron


Mean Difference

0

5

10


106

Analysis 1.4. Comparison 1 Oral iron vs inactive control, Outcome 4 Haemoglobin. Review:


Comparison: 1 Oral iron vs inactive control Outcome: 4 Haemoglobin

Study or subgroup

Inactive control

Mean Difference

Oral iron

Mean Difference

N

Mean(SD)[g/dL]

N

Mean(SD)[g/dL]

IV,Fixed,95% CI

IV,Fixed,95% CI

5

10.87 (0.6)

5

11.41 (0.44)

-0.54 [ -1.19, 0.11 ]

Parker 2010

150

11.7 (1.2)

150

12 (1.1)

-0.30 [ -0.56, -0.04 ]

Sutton 2004

37

12.1 (1.2)

35

12.4 (1.1)

-0.30 [ -0.83, 0.23 ]

10

1.7 (1.2)

10

4.8 (1.1)

-3.10 [ -4.11, -2.09 ]

1 Final haemoglobin Beck-da-Silva 2013

2 Change in haemoglobin Abrahamsen 1965

-4

-2

0

Favours oral iron

2

4


Analysis 1.5. Comparison 1 Oral iron vs inactive control, Outcome 5 Quality of life. Review:


Comparison: 1 Oral iron vs inactive control Outcome: 5 Quality of life

Study or subgroup

Steensma 2010

Inactive control

Std. Mean Difference

Oral iron

N

Mean(SD)

N

Mean(SD)

138

0.5 (2.28)

138

0.2 (2.23)

IV,Random,95% CI

IV,Random,95% CI 0.13 [ -0.10, 0.37 ]

-0.2

-0.1

Favours oral iron



0

0.1

0.2


107

Analysis 1.6. Comparison 1 Oral iron vs inactive control, Outcome 6 Serious adverse events. Review:


Comparison: 1 Oral iron vs inactive control Outcome: 6 Serious adverse events

Study or subgroup

Oral iron

Inactive control

n/N

n/N

Abrahamsen 1965

0/10

0/10

Not estimable

Beck-da-Silva 2013

0/7

0/6

Not estimable

0/150

0/150

Not estimable

72/163

75/163

0/35

0/37

365

366

Parker 2010 Steensma 2010 Sutton 2004

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

100.0 %

0.96 [ 0.76, 1.22 ] Not estimable

100.0 %

0.96 [ 0.76, 1.22 ]

Total events: 72 (Oral iron), 75 (Inactive control) Heterogeneity: not applicable Test for overall effect: Z = 0.33 (P = 0.74) Test for subgroup differences: Not applicable

0.02

0.1

Favours oral iron

1

10

50



108

Analysis 2.1. Comparison 2 Parenteral iron vs inactive control, Outcome 1 Mortality. Review:


Comparison: 2 Parenteral iron vs inactive control Outcome: 1 Mortality

Study or subgroup

Parenteral iron

Inactive control


Weight


n/N

n/N

0/10

0/10

Anker 2009

1/110

1/58

3.1 %

0.53 [ 0.03, 8.28 ]

Auerbach 2010

8/117

13/121

28.1 %

0.64 [ 0.27, 1.48 ]

21/203

15/193

43.9 %

1.33 [ 0.71, 2.51 ]

Beck-da-Silva 2013

2/10

1/6

4.9 %

1.20 [ 0.14, 10.58 ]

Hedenus 2007

0/33

4/34

2.9 %

0.11 [ 0.01, 2.04 ]

Karkouti 2006

0/11

0/10

Not estimable

Madi-Jebara 2004

0/40

0/40

Not estimable

Steensma 2010

8/164

3/163

13.0 %

2.65 [ 0.72, 9.81 ]

Vadhan-Raj 2013

2/608

1/200

4.1 %

0.66 [ 0.06, 7.22 ]

Total (95% CI)

1306

835

100.0 %

1.04 [ 0.63, 1.69 ]

Abrahamsen 1965

Bastit 2008

Not estimable

Total events: 42 (Parenteral iron), 38 (Inactive control) Heterogeneity: Tau2 = 0.04; Chi2 = 6.52, df = 6 (P = 0.37); I2 =8% Test for overall effect: Z = 0.14 (P = 0.89) Test for subgroup differences: Not applicable

0.005

0.1

Favours parenteral iron

1

10

200



109

Analysis 2.2. Comparison 2 Parenteral iron vs inactive control, Outcome 2 Proportion requiring blood transfusion. Review:


Comparison: 2 Parenteral iron vs inactive control Outcome: 2 Proportion requiring blood transfusion

Study or subgroup

Parenteral iron

Inactive control

n/N

n/N

0/110

0/58

Auerbach 2010

42/116

49/122

52.0 %

0.90 [ 0.65, 1.25 ]

Bastit 2008

16/200

25/196

15.4 %

0.63 [ 0.35, 1.14 ]

Edwards 2009

2/9

5/9

3.0 %

0.40 [ 0.10, 1.55 ]

Hedenus 2007

2/33

1/34

1.0 %

2.06 [ 0.20, 21.65 ]

Karkouti 2006

2/11

4/10

2.6 %

0.45 [ 0.10, 1.97 ]

10/40

9/40

8.9 %

1.11 [ 0.51, 2.44 ]

20/164

22/163

17.1 %

0.90 [ 0.51, 1.59 ]

683

632

100.0 %

0.84 [ 0.66, 1.06 ]

Anker 2009

Madi-Jebara 2004 Steensma 2010

Total (95% CI)


Weight

Risk Ratio MH,Random,95% CI Not estimable

Total events: 94 (Parenteral iron), 115 (Inactive control) Heterogeneity: Tau2 = 0.0; Chi2 = 4.05, df = 6 (P = 0.67); I2 =0.0% Test for overall effect: Z = 1.46 (P = 0.14) Test for subgroup differences: Not applicable

0.01

0.1


1

10

100



110

Analysis 2.3. Comparison 2 Parenteral iron vs inactive control, Outcome 3 Haemoglobin. Review:


Comparison: 2 Parenteral iron vs inactive control Outcome: 3 Haemoglobin

Study or subgroup

Inactive control

Mean Difference

Parenteral iron

Mean Difference

N

Mean(SD)[g/dL]

N

Mean(SD)[g/dL]

IV,Random,95% CI

IV,Random,95% CI

34

12 (1.3)

91

13 (1.6)

-1.00 [ -1.55, -0.45 ]

Beck-da-Silva 2013

5

10.87 (0.6)

8

11.21 (0.58)

-0.34 [ -1.00, 0.32 ]

Edwards 2009

9

11.9 (2.7)

9

11.2 (1.9)

0.70 [ -1.46, 2.86 ]

Hedenus 2007

34

11.8 (2.7)

33

13 (1.9)

-1.20 [ -2.32, -0.08 ]

Karkouti 2006

10

12 (1.3)

11

12.7 (0.6)

-0.70 [ -1.58, 0.18 ]

Madi-Jebara 2004

31

11.9 (1.2)

30

12.2 (1)

-0.30 [ -0.85, 0.25 ]

10

1.7 (2)

10

4.7 (1.9)

-3.00 [ -4.71, -1.29 ]

Auerbach 2010

122

1.3 (2)

116

1.9 (1.9)

-0.60 [ -1.10, -0.10 ]

Vadhan-Raj 2013

200

0.1 (0.9)

608

2.6 (1.5)

-2.50 [ -2.67, -2.33 ]

1 Final haemoglobin Anker 2009

2 Change in haemoglobin Abrahamsen 1965

-4

-2



0

2

4


111

Analysis 2.4. Comparison 2 Parenteral iron vs inactive control, Outcome 4 Quality of life. Review:


Comparison: 2 Parenteral iron vs inactive control Outcome: 4 Quality of life

Study or subgroup

Inactive control


Parenteral iron


N

Mean(SD)

N

Mean(SD)

IV,Random,95% CI

Anker 2009

47

61.53 (18.75)

104

65.38 (17.79)

-0.21 [ -0.56, 0.13 ]

Bastit 2008

196

2.17 (10.9)

200

2.4 (11.3)

-0.02 [ -0.22, 0.18 ]

Steensma 2010

138

0.5 (2.28)

136

0.4 (2.18)

0.04 [ -0.19, 0.28 ]

Vadhan-Raj 2013

200

6.8 (9.5)

608

11.7 (11.7)

-0.44 [ -0.60, -0.28 ]

-0.5

-0.25



0

0.25

IV,Random,95% CI

0.5


112

Analysis 2.5. Comparison 2 Parenteral iron vs inactive control, Outcome 5 Serious adverse events. Review:


Comparison: 2 Parenteral iron vs inactive control Outcome: 5 Serious adverse events Study or subgroup

Parenteral iron

Inactive control

n/N

n/N

0/10

0/10

Anker 2009

13/110

4/58

6.9 %

1.71 [ 0.59, 5.02 ]

Bastit 2008

21/203

26/193

21.4 %

0.77 [ 0.45, 1.32 ]

Beck-da-Silva 2013

0/10

0/6

Hedenus 2007

6/33

11/34

10.0 %

0.56 [ 0.24, 1.34 ]

Steensma 2010

89/164

75/163

52.6 %

1.18 [ 0.95, 1.47 ]

Vadhan-Raj 2013

16/608

6/200

9.0 %

0.88 [ 0.35, 2.21 ]

Total (95% CI)

1138

664

100.0 %

1.00 [ 0.74, 1.34 ]

Abrahamsen 1965


Weight

Risk Ratio MH,Random,95% CI Not estimable

Not estimable

Total events: 145 (Parenteral iron), 122 (Inactive control) Heterogeneity: Tau2 = 0.03; Chi2 = 5.36, df = 4 (P = 0.25); I2 =25% Test for overall effect: Z = 0.01 (P = 0.99) Test for subgroup differences: Not applicable

0.2

0.5


1

2

5



113

Analysis 3.1. Comparison 3 Parenteral iron vs oral iron, Outcome 1 Mortality. Review:


Comparison: 3 Parenteral iron vs oral iron Outcome: 1 Mortality

Study or subgroup

Parenteral iron

Oral iron


Weight


n/N

n/N

Abrahamsen 1965

0/10

0/10

Beck-da-Silva 2013

2/10

0/7

Dangsuwan 2010

0/22

0/22

Not estimable

Maccio 2010

0/73

0/75

Not estimable

Steensma 2010

8/164

6/163

Van Wyck 2009

0/228

0/225

507

502

Total (95% CI)

Not estimable 11.3 %

88.7 %

3.64 [ 0.20, 65.86 ]

1.33 [ 0.47, 3.73 ] Not estimable

100.0 %

1.49 [ 0.56, 3.94 ]

Total events: 10 (Parenteral iron), 6 (Oral iron) Heterogeneity: Tau2 = 0.0; Chi2 = 0.42, df = 1 (P = 0.52); I2 =0.0% Test for overall effect: Z = 0.80 (P = 0.43) Test for subgroup differences: Not applicable

0.01

0.1


1

10

100

Favours oral iron


114

Analysis 3.2. Comparison 3 Parenteral iron vs oral iron, Outcome 2 Proportion requiring blood transfusion. Review:


Comparison: 3 Parenteral iron vs oral iron Outcome: 2 Proportion requiring blood transfusion

Study or subgroup

Parenteral iron


Weight


n/N

n/N

5/22

14/22

45.0 %

0.36 [ 0.16, 0.82 ]

20/164

21/163

55.0 %

0.95 [ 0.53, 1.68 ]

186

185

100.0 %

0.61 [ 0.24, 1.58 ]

Dangsuwan 2010 Steensma 2010

Oral iron

Total (95% CI)

Total events: 25 (Parenteral iron), 35 (Oral iron) Heterogeneity: Tau2 = 0.34; Chi2 = 3.59, df = 1 (P = 0.06); I2 =72% Test for overall effect: Z = 1.02 (P = 0.31) Test for subgroup differences: Not applicable

0.2

0.5

1


2

5

Favours oral iron

Analysis 3.3. Comparison 3 Parenteral iron vs oral iron, Outcome 3 Mean blood transfused. Review:


Comparison: 3 Parenteral iron vs oral iron Outcome: 3 Mean blood transfused

Study or subgroup

Dangsuwan 2010

Parenteral iron

Mean Difference

Oral iron

N

Mean(SD)[units]

N

Mean(SD)[units]

22

0.32 (0.65)

22

0.86 (0.77)

IV,Random,95% CI

IV,Random,95% CI -0.54 [ -0.96, -0.12 ]

-1

-0.5



Mean Difference

0

0.5

1

Favours oral iron

115

Analysis 3.4. Comparison 3 Parenteral iron vs oral iron, Outcome 4 Haemoglobin. Review:


Comparison: 3 Parenteral iron vs oral iron Outcome: 4 Haemoglobin

Study or subgroup

Oral iron

Mean Difference

Parenteral iron

Weight

IV,Random,95% CI

Mean Difference

N

Mean(SD)[g/dL]

N

Mean(SD)[g/dL]

IV,Random,95% CI

Beck-da-Silva 2013

5

10.87 (0.6)

8

11.21 (0.58)

12.3 %

-0.34 [ -1.00, 0.32 ]

Dangsuwan 2010

22

9.5 (0.9)

22

10 (0.8)

21.3 %

-0.50 [ -1.00, 0.00 ]

Lindgren 2009

46

12.5 (0.9)

45

13 (0.8)

44.1 %

-0.50 [ -0.85, -0.15 ]

1 Final haemoglobin

Subtotal (95% CI)

73

77.8 % -0.47 [ -0.74, -0.21 ]

75

Heterogeneity: Tau2 = 0.0; Chi2 = 0.19, df = 2 (P = 0.91); I2 =0.0% Test for overall effect: Z = 3.53 (P = 0.00041) 2 Change in haemoglobin Abrahamsen 1965

10

4.8 (3.8)

10

4.7 (3.6)

0.5 %

0.10 [ -3.14, 3.34 ]

Maccio 2010

75

1.8 (2.3)

73

1.6 (3.6)

5.7 %

0.20 [ -0.78, 1.18 ]

225

2.3 (3.8)

228

3.2 (2.3)

16.1 %

-0.90 [ -1.48, -0.32 ]

Van Wyck 2009

Subtotal (95% CI)

310

311

22.2 % -0.41 [ -1.29, 0.46 ]

Heterogeneity: Tau2 = 0.27; Chi2 = 3.79, df = 2 (P = 0.15); I2 =47% Test for overall effect: Z = 0.93 (P = 0.35)

Total (95% CI)

383

100.0 % -0.50 [ -0.73, -0.27 ]

386

Heterogeneity: Tau2 = 0.0; Chi2 = 4.16, df = 5 (P = 0.53); I2 =0.0% Test for overall effect: Z = 4.23 (P = 0.000023) Test for subgroup differences: Chi2 = 0.02, df = 1 (P = 0.90), I2 =0.0%

-4

-2



0

2

4

Favours oral iron

116

Analysis 3.5. Comparison 3 Parenteral iron vs oral iron, Outcome 5 Quality of life. Review:


Comparison: 3 Parenteral iron vs oral iron Outcome: 5 Quality of life

Study or subgroup

Oral iron


Parenteral iron

Weight

N

Mean(SD)

N

Mean(SD)

22

128 (18.7)

22

122.3 (18.3)

5.6 %

0.30 [ -0.29, 0.90 ]

Steensma 2010

138

0.2 (2.23)

136

0.4 (2.18)

35.5 %

-0.09 [ -0.33, 0.15 ]

Van Wyck 2009

225

71.9 (17.6)

228

71.9 (17.9)

58.8 %

0.0 [ -0.18, 0.18 ]

100.0 %

-0.02 [ -0.16, 0.13 ]

Dangsuwan 2010

Total (95% CI)

385

IV,Random,95% CI

Std. Mean Difference IV,Random,95% CI

386

Heterogeneity: Tau2 = 0.0; Chi2 = 1.51, df = 2 (P = 0.47); I2 =0.0% Test for overall effect: Z = 0.21 (P = 0.83) Test for subgroup differences: Not applicable

-2

-1



0

1

2

Favours oral iron

117

Analysis 3.6. Comparison 3 Parenteral iron vs oral iron, Outcome 6 Serious adverse events. Review:


Comparison: 3 Parenteral iron vs oral iron Outcome: 6 Serious adverse events Study or subgroup

Parenteral iron

Oral iron

n/N

n/N

Abrahamsen 1965

0/10

0/10

Not estimable

Beck-da-Silva 2013

0/10

0/7

Not estimable

Dangsuwan 2010

0/22

0/22

Not estimable

Lindgren 2009

1/45

0/46

Maccio 2010

0/73

0/75

Steensma 2010

89/164

72/163

Van Wyck 2009

0/228

0/225

552

548

Total (95% CI)


Weight

0.5 %


3.07 [ 0.13, 73.32 ] Not estimable

99.5 %

1.23 [ 0.98, 1.53 ] Not estimable

100.0 %

1.23 [ 0.99, 1.54 ]

Total events: 90 (Parenteral iron), 72 (Oral iron) Heterogeneity: Tau2 = 0.0; Chi2 = 0.32, df = 1 (P = 0.57); I2 =0.0% Test for overall effect: Z = 1.86 (P = 0.063) Test for subgroup differences: Not applicable

0.01

0.1


1

10

100

Favours oral iron


118

Analysis 4.1. Comparison 4 Iron: different preparations, Outcome 1 Mortality. Review:


Comparison: 4 Iron: different preparations Outcome: 1 Mortality

Study or subgroup

Preparation 1

Preparation 2

n/N

n/N



1 Intravenous iron: ferrumoxytol vs iron sucrose Hetzel 2012

1/406

0/199

1.47 [ 0.06, 36.03 ]

0.02

0.1

1

Favours preparation1

10

50


Analysis 4.2. Comparison 4 Iron: different preparations, Outcome 2 Haemoglobin. Review:


Comparison: 4 Iron: different preparations Outcome: 2 Haemoglobin

Study or subgroup

Preparation 2 N

Mean Difference

Preparation 1 Mean(SD)[g/dL]

Mean Difference

N

Mean(SD)[g/dL]

IV,Random,95% CI

IV,Random,95% CI

12.7 (2.2)

240

12.9 (3.1)

-0.20 [ -0.68, 0.28 ]

2.4 (4.8)

406

2.7 (4.7)

-0.30 [ -1.11, 0.51 ]

1 Intravenous iron: ferric carboxymaltose vs iron sucrose Evstatiev 2011

239


199

-1

-0.5

Favours preparation 1


0

0.5

1

Favours preparation 2

119

Analysis 4.3. Comparison 4 Iron: different preparations, Outcome 3 Serious adverse events. Review:


Comparison: 4 Iron: different preparations Outcome: 3 Serious adverse events

Study or subgroup

Preparation 1

Preparation 2

n/N

n/N



1 Intravenous iron: ferric carboxymaltose vs iron sucrose Evstatiev 2011

1/244

0/239

2.94 [ 0.12, 71.78 ]

5/199

1.67 [ 0.62, 4.45 ]


17/406

0.02

0.1



1

10

50


120

Analysis 5.1. Comparison 5 Subgroup analysis, Outcome 1 Mortality (parenteral iron vs inactive control stratified by clinical setting). Review:


Comparison: 5 Subgroup analysis Outcome: 1 Mortality (parenteral iron vs inactive control stratified by clinical setting)

Study or subgroup

Intravenous iron

Inactive control


Weight


n/N

n/N

Abrahamsen 1965

0/10

0/10

Not estimable

Karkouti 2006

0/11

0/10

Not estimable

21

20

Not estimable

1 Blood loss

Subtotal (95% CI)

Total events: 0 (Intravenous iron), 0 (Inactive control) Heterogeneity: not applicable Test for overall effect: not applicable 2 Cancer Auerbach 2010

8/117

13/121

28.1 %

0.64 [ 0.27, 1.48 ]

21/203

15/193

43.9 %

1.33 [ 0.71, 2.51 ]

Hedenus 2007

0/33

4/34

2.9 %

0.11 [ 0.01, 2.04 ]

Steensma 2010

8/164

3/163

13.0 %

2.65 [ 0.72, 9.81 ]

517

511

87.8 %

1.03 [ 0.48, 2.25 ]

Bastit 2008

Subtotal (95% CI)

Total events: 37 (Intravenous iron), 35 (Inactive control) Heterogeneity: Tau2 = 0.29; Chi2 = 6.10, df = 3 (P = 0.11); I2 =51% Test for overall effect: Z = 0.08 (P = 0.93) 3 Preoperative anaemic patients Madi-Jebara 2004

0/40

0/40

Not estimable

Subtotal (95% CI)

40

40

Not estimable

Total events: 0 (Intravenous iron), 0 (Inactive control) Heterogeneity: not applicable Test for overall effect: not applicable 4 Chronic heart failure Anker 2009

1/110

1/58

3.1 %

0.53 [ 0.03, 8.28 ]

Beck-da-Silva 2013

2/10

1/6

4.9 %

1.20 [ 0.14, 10.58 ]

Subtotal (95% CI)

120

64

8.1 %

0.87 [ 0.16, 4.82 ]

Total events: 3 (Intravenous iron), 2 (Inactive control) Heterogeneity: Tau2 = 0.0; Chi2 = 0.21, df = 1 (P = 0.65); I2 =0.0% Test for overall effect: Z = 0.15 (P = 0.88) 5 Other settings

0.01

0.1

1


10

100


(Continued . . . )


121

(. . . Study or subgroup

Intravenous iron

Vadhan-Raj 2013

Subtotal (95% CI)

Inactive control


Weight

Continued) Risk Ratio MH,Random,95% CI

n/N

n/N

2/608

1/200

4.1 %

0.66 [ 0.06, 7.22 ]

608

200

4.1 %

0.66 [ 0.06, 7.22 ]

835

100.0 %

1.04 [ 0.63, 1.69 ]

Total events: 2 (Intravenous iron), 1 (Inactive control) Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.73)

Total (95% CI)

1306

Total events: 42 (Intravenous iron), 38 (Inactive control) Heterogeneity: Tau2 = 0.04; Chi2 = 6.52, df = 6 (P = 0.37); I2 =8% Test for overall effect: Z = 0.14 (P = 0.89) Test for subgroup differences: Chi2 = 0.14, df = 2 (P = 0.93), I2 =0.0%

0.01

0.1

1



10

100


122

Analysis 5.2. Comparison 5 Subgroup analysis, Outcome 2 Mortality (parenteral iron vs inactive control stratified by erythropoietin use). Review:


Comparison: 5 Subgroup analysis Outcome: 2 Mortality (parenteral iron vs inactive control stratified by erythropoietin use)

Study or subgroup

Parenteral iron

Inactive control


Weight


n/N

n/N

8/117

13/121

28.1 %

0.64 [ 0.27, 1.48 ]

21/203

15/193

43.9 %

1.33 [ 0.71, 2.51 ]

0/33

4/34

2.9 %

0.11 [ 0.01, 2.04 ]

353

348

74.9 %

0.81 [ 0.34, 1.91 ]

1 Supplementary erythropoietin Auerbach 2010 Bastit 2008 Hedenus 2007

Subtotal (95% CI)

Total events: 29 (Parenteral iron), 32 (Inactive control) Heterogeneity: Tau2 = 0.28; Chi2 = 4.10, df = 2 (P = 0.13); I2 =51% Test for overall effect: Z = 0.49 (P = 0.62) 2 No supplementary erythropoietin Abrahamsen 1965

0/10

0/10

1/110

1/58

3.1 %

0.53 [ 0.03, 8.28 ]

Beck-da-Silva 2013

2/10

1/6

4.9 %

1.20 [ 0.14, 10.58 ]

Karkouti 2006

0/11

0/10

Not estimable

Madi-Jebara 2004

0/40

0/40

Not estimable

Steensma 2010

8/164

3/163

13.0 %

2.65 [ 0.72, 9.81 ]

Vadhan-Raj 2013

2/608

1/200

4.1 %

0.66 [ 0.06, 7.22 ]

953

487

25.1 %

1.50 [ 0.58, 3.90 ]

835

100.0 %

1.04 [ 0.63, 1.69 ]

Anker 2009

Subtotal (95% CI)

Not estimable

Total events: 13 (Parenteral iron), 6 (Inactive control) Heterogeneity: Tau2 = 0.0; Chi2 = 1.78, df = 3 (P = 0.62); I2 =0.0% Test for overall effect: Z = 0.84 (P = 0.40)

Total (95% CI)

1306

Total events: 42 (Parenteral iron), 38 (Inactive control) Heterogeneity: Tau2 = 0.04; Chi2 = 6.52, df = 6 (P = 0.37); I2 =8% Test for overall effect: Z = 0.14 (P = 0.89) Test for subgroup differences: Chi2 = 0.91, df = 1 (P = 0.34), I2 =0.0%

0.01

0.1

1



10

100


123

Analysis 5.3. Comparison 5 Subgroup analysis, Outcome 3 Mortality (parenteral iron vs oral iron stratified by clinical setting). Review:


Comparison: 5 Subgroup analysis Outcome: 3 Mortality (parenteral iron vs oral iron stratified by clinical setting)

Study or subgroup

Parenteral iron

Oral iron


Weight


n/N

n/N

0/10

0/10

Not estimable

0/228

0/225

Not estimable

238

235

Not estimable

0/22

0/22

Not estimable

8/164

6/163

88.7 %

1.33 [ 0.47, 3.73 ]

186

185

88.7 %

1.33 [ 0.47, 3.73 ]

1 Blood loss Abrahamsen 1965 Van Wyck 2009

Subtotal (95% CI)

Total events: 0 (Parenteral iron), 0 (Oral iron) Heterogeneity: not applicable Test for overall effect: not applicable 2 Cancer Dangsuwan 2010 Steensma 2010

Subtotal (95% CI)

Total events: 8 (Parenteral iron), 6 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.53 (P = 0.59) 3 Chronic heart failure Beck-da-Silva 2013

2/10

0/7

11.3 %

3.64 [ 0.20, 65.86 ]

Subtotal (95% CI)

10

7

11.3 %

3.64 [ 0.20, 65.86 ]

434

427

100.0 %

1.49 [ 0.56, 3.94 ]

Total events: 2 (Parenteral iron), 0 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.87 (P = 0.38)

Total (95% CI)

Total events: 10 (Parenteral iron), 6 (Oral iron) Heterogeneity: Tau2 = 0.0; Chi2 = 0.42, df = 1 (P = 0.52); I2 =0.0% Test for overall effect: Z = 0.80 (P = 0.43) Test for subgroup differences: Chi2 = 0.41, df = 1 (P = 0.52), I2 =0.0%

0.01

0.1


1

10

100

Favours oral iron


124

ADDITIONAL TABLES Table 1. World Health Organization (WHO) definition of anaemia

Group characteristics

Haemoglobin (g/L)

Haematocrit (mmol/L)*

Haematocrit (litres/L)a

Children (6 months to 59 110 months)

6.83

0.33

Children (5 to 11 years)

115

7.13

0.34

Children (12 to 14 years)

120

7.45

0.36

Non-pregnant women (over 15 120 years of age)

7.45

0.36

Pregnant women

110

6.83

0.33

Men (over 15 years of age)

130

8.07

0.39

a Haematocrit

is the volume of packed red blood cells expressed in terms of fraction or percentages in a whole blood specimen (NCBI-Hematocrit).

Table 2. Details of participants and interventions

Participant characteristics

Clinical setting

Co-interventions

SamFeple Mean males size age (af(years) ter postrandomisation dropouts)

CanBlood cer loss conditions

Preoperative

AuChronictoimheart mune failure

MiscelAdded Added laery- oral neous thro- iron poietin

Yes

No

No

No

Study name

Abrahamsen 1965

30

Postrandomisation dropouts

Not Not 0 stated stated (0%)

No

No


No

Routes and methods of administration of parenteral iron Comparison Par- Par- Total enteral enteral dose iron- iron- infuininsion tratravenous muscular

Not No applicable

Yes

No

Parenteral iron vs

125


(Continued)

oral iron vs inactive control Anker 2009

Auerbach 2010

Bastit 2008

Beck-

158


No

No

No

Yes

No

No

No

No

Yes

No

No

Parenteral iron vs inactive control

238

63

158 (66. 4%)

5 (2. No 1%)

Yes

No

No

No

No

Yes

Oral Yes iron was allowed as part of standard treatment

No

No


396

61

240 (60. 6%)

2 (0. No 5%)

Yes

No

No

No

No

Yes

Oral Yes iron was allowed as part of standard treatment

No

No


23

66

7

Not No stated

No

No

Yes

No

No

No

Not Yes applicable

No

No

Parenteral iron vs oral

daSilva 2013


126


(Continued)

iron vs inactive control Dan- 44 gsuwan 2010

51

No

Yes

No

No

No

No

No

Not Yes applicable

No

No

Parenteral iron vs oral iron

18 Edwards 2009

Not Not Not No stated stated stated

No

Yes

No

No

No

No

No

Yes

No

No


Evs- 483 tatiev 2011

39

284 (58. 8%)

2 (0. No 4%)

No

No

No

Yes

No

No

No

Yes

No

Yes

Different preparations

67

76

42 (62. 7%)

0 (0%)

No

Yes

No

No

No

No

Yes

No

Yes

No

No


605

Not Not Not No stated stated stated

No

No

No

No

Yes

No

No

Yes

No

No

Different preparations

21

62

No

No

No

No

No

No

Yes

Yes

No

No

Parenteral iron

Hedenus 2007

Hetzel 2012

Karkouti 2006

44 0 (100%) (0%)

5 (23. 8%)

5 (19. 2%)

Yes


127


(Continued)

vs inactive control Lidder 2007

Lindgren 2009

Maccio 2010

Madi-

20

Not 9 Not No stated (45%) stated

No

Yes

No

No

No

No

Not applicable

91

42

63 (69. 2%)

Not No stated

No

No

No

Yes

No

No

148

68

59 (39. 9%)

0 (0%)

No

Yes

No

No

No

No

80


No

No

Yes

No

No

300

82

245 (81. 7%)

0 (0%)

Yes

No

No

No

200

57

103 (51. 5%)

0 (0%)

No

No

No

No

Not applicable

Not applicable

Not applicable

Oral iron vs inactive control

Not Yes applicable

No

No


Yes

Not Yes applicable

No

No


No

No

No

Yes

No

No


No

No

No

Not applicable

Not applicable

Not applicable

Not applicable


No

Yes

No

Not applicable

Not applicable

Not applicable

Not applicable

Oral iron vs inac-

Jebara 2004

Parker 2010

Pieracci 2009


128


(Continued)

tive control 490 Steensma 2010

64

320 (65. 3%)

12 (2. 4%)

No

Yes

No

No

No

No

Yes

Not Yes applicable

No

No

Parenteral iron vs oral iron vs inactive control

Sutton 2004

72

70

30 (41. 7%)

Not Yes stated

No

No

No

No

No

No

Not applicable

Not applicable

Not applicable

Not applicable


VadhanRaj 2013

808

45

720

4 (0. No 5%)

No

No

No

No

Yes

No

No

Yes

No

No


Van

453

39

453 24 (100%) (5%)

No

No

No

No

No

No

Not Yes applicable

No

No


Wyck 2009

Yes


129

APPENDICES Appendix 1. Search strategies Cochrane Central Register of Controlled Trials #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) 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 (Ovid SP) 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) and Conference Proceedings Citation Index-Science (CPCI-S) # 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 metaanalys*) # 4 #3 AND #2 AND #1 CINAHL Plus (EBSCO) S1 (MH “Clinical Trials+”) S2 PT Clinical trial S3 TX clinic* n1 trial* or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) S4 TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) S5 TX randomi* control* trial* S6 (MH “Random Assignment”) S7 TX random* allocat* S8 TX placebo* S9 (MH “Placebos”) S10 (MH “Quantitative Studies”) S11 TX allocat* random* S12 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 S13 (MH “Iron”) S14 (iron OR ferrous OR ferric) S15 S13 or S14 Iron therapy in anaemic adults without chronic kidney disease (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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S16 (MH “Anemia+”) S17 (anemi* OR anaemi*) S18 S16 or 17 S19 S15 and S18 S20 S12 and S20 Clinicaltrials.gov Search terms: Randomized Study type: Interventional Studies Conditions: anemia OR anaemic Interventions: iron OR ferrous OR ferric

CONTRIBUTIONS OF AUTHORS KS Gurusamy identified trials, extracted data, performed data analysis, interpreted data and wrote the review. M Nagendran independently identified trials and extracted data. JF Broadhurst, SD Anker and T Richards made intellectual contributions to the review. T Richards independently identified trials and critically commented on the review.

DECLARATIONS OF INTEREST KSG: none known. MN: none known. JFB: none known. SDA: (in part through employer) has received grants and fees for lectures, consultancy and/or board membership from Abbott Vascular, Amgen, Bayer, BG Medicine, Bioventrix, Brahms, Cardiomems, Novartis, BG Medicine, Impulse Dynamics, Medical Sensible, Pluristem, Psioxus, Relypsa, Servier and/or Vifor. TR: UCL received an educational grant from Vifor Pharma in 2009. This funded a research fellow who undertook an audit of anaemia in surgical patients. These data have been presented at national and international meetings. TR is currently Chief Investigator for an NIHR HTA trial that is being conducted to assess the role of Intravenous iron in the treatment of individuals with anaemia before major surgery (PREVENTT). No funding was provided for this Cochrane review, and no input was received from anyone other than study authors. TR received travel funds from the BBTS, NATA, Pharmocosmos, Vifor Pharma and other industry.

SOURCES OF SUPPORT

Internal sources • UCL Department of Surgery, Other.


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External sources • No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW • We did not search Google Scholar and the WHO trial register, as the search resulted in sixteen thousand references, making it impossible to complete a review in which the searches are current. • We excluded trials for which allocation concealment was unclear. • We have clarified that we performed a sensitivity analysis excluding trials in which mean or standard deviation was imputed for continuous outcomes only in the presence of at least two trials, as sensitivity analysis cannot be performed by excluding the only trial that contributed to the outcome. • We performed subgroup analysis only for the primary outcome because of issues of multiplicity.


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Intravenous iron and chronic kidney disease.

Body mass index and preclinical kidney disease in Indian adults aged 40 years and above without chronic kidney disease.

Red cell distribution width predicts incident dipstick albuminuria in Korean adults without chronic kidney disease.

Combination therapy in chronic kidney disease?

Safety of intravenous iron use in chronic kidney disease.

Approximation of Corrected Calcium Concentrations in Advanced Chronic Kidney Disease Patients with or without Dialysis Therapy.

Improving compliance with iron infusion therapy in the treatment of chronic anemia in haemodialysis patients with chronic kidney disease.

Restoration of Haemoglobin Level Using Hydrodynamic Gene Therapy with Erythropoietin Does Not Alleviate the Disease Progression in an Anaemic Mouse Model for TGFβ1-Induced Chronic Kidney Disease.

"Angiography without contrast": Severe vascular calcification in chronic kidney disease.

Androgens for the anaemia of chronic kidney disease in adults.

Correlation between periodontitis and chronic kidney disease in Korean adults.

Effects of Long-Term Statin Therapy in Coronary Artery Disease Patients with or without Chronic Kidney Disease.

Online clinical pathway for managing adults with chronic kidney disease.

chemokine response.

Exercise as an Adjunct Therapy In Chronic Kidney Disease.

Iron indices and survival in maintenance hemodialysis patients with and without polycystic kidney disease.

Can one evaluate bone disease in chronic kidney disease without a biopsy?

Inappropriateness of medication prescriptions about chronic kidney disease patients without dialysis therapy in a Chinese tertiary teaching hospital.

A perspective on anti-CCN2 therapy for chronic kidney disease.

Should we use statins in all patients with chronic kidney disease without dialysis therapy? The current state of knowledge.

The prevalence and epidemiology of genetic renal disease amongst adults with chronic kidney disease in Australia.

Iron Indices in Patients with Functional Anemia in Chronic Kidney Disease.

Changes in Echocardiographic Parameters in Iron Deficiency Patients with Heart Failure and Chronic Kidney Disease Treated with Intravenous Iron.

Chronic anticoagulation in chronic kidney disease.