Evidence reviews for managing anaemia with IV iron in people with GFR category G5 who are on dialysis

Evidence reviews for managing anaemia with IV iron in people with GFR category G5 who are on dialysis

Chronic kidney disease

Evidence review K

NICE Guideline, No. 203

London: National Institute for Health and Care Excellence (NICE); 2021 Aug.

ISBN-13: 978-1-4731-4233-6

Managing anaemia with IV iron in people with GFR category G5 who are on dialysis

1.1. Review question

For people with glomerular filtration rate (GFR) category G5 who are on dialysis, what amount of intravenous (IV) iron is most clinically and cost effective in managing anaemia and its associated outcomes?

1.1.1. Introduction

Many people with chronic kidney disease (CKD) or established renal failure also develop associated anaemia. The prevalence of anaemia associated with CKD increases progressively with GFR category (anaemia of CKD can occur across all stages of CKD, starting from category G2), especially when the patient reaches category G4 or G5. Anaemia of CKD contributes significantly to the burden of CKD. However, it is potentially reversible and manageable with appropriate identification and treatment.

The NICE guideline on chronic kidney disease: managing anaemia (NICE guideline NG8) was reviewed in 2017 as part of NICE’s surveillance programme. As part of the scoping process, NICE identified new areas not included in the surveillance report for which the evidence needed to be reviewed. One of these areas was IV iron for the treatment of anaemia associated with CKD.

The aim of this review is to determine what amount of IV iron is most clinically and cost effective in managing anaemia and its associated outcomes for people with GFR category G5who are on dialysis. This review identified randomised controlled trials (RCTs) that fulfilled the conditions specified in Table 1. For full details of the review protocol, see Appendix A.

1.1.2. Summary of the protocol

Table 1

PICO table for IV iron in people with GFR category G5 who are on dialysis.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in Appendix A and the methods section in Appendix B.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

The following methods were specific for this review:

The evidence is reported separately for adults and for children and young people (up to the age of 18 years) and pooled within the same age group.
Some of the evidence was divided based on IV iron dose into high and low dose based on the higher and lower doses given in the trials. This included 3 trials for children and young people (Goldstein 2013, Ruiz-Jaramillo 2004, and Warady 2005) and 5 trials for adults (Besarab 2000, Charytan 2013, MacDougall 2019, Nissenson 1999, and Wan 2018). The committee agreed that since it was interested in the relative effects, the actual dose and iron preparation were less important. Therefore, this evidence was divided into high and low dose irrespective of the IV iron preparation and based on what the trial reported as high or low.
The rest of trials reported different IV iron preparations in each arm with the same dose for all arms (Roe 1996, Bhandari 2015, Hsiao 2016, and Akcicek 1997). These trials were reported separately.
Wan (2018) was a crossover trial but the committee did not consider the washout period to be appropriate for patients receiving Erythropoeitin Stimulating Agents. Therefore, data were only extracted from the first study period.
For Akcicek (1997), data was taken only from the first study period from this crossover trial because paired t-tests were not reported and there was not enough data from the study to approximate a paired analysis. Therefore, this trial was regarded as a parallel trial rather than as a crossover trial.

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

A systematic search was carried out to identify RCTs and systematic reviews of RCTs, which found 554 references (see Appendix C for the literature search strategy). After screening at title and abstract level, 482 references were excluded. Full texts were ordered to be screened for 72 references. In total, 12 RCTs were included based on their relevance to the review protocol (Appendix A). The clinical evidence study selection is presented as a PRISMA diagram in Appendix D.

A second set of searches was conducted at the end of the guideline development process for all updated review questions using the original search strategies, to capture papers published whilst the guideline was being developed. This search returned 26 references for this review question, these were screened on title and abstract. Two references were ordered for full text screening. None of these references were included based on their relevance to the review protocol (Appendix A).

See section 1.1.12 References – included studies for a list of references for included studies.

1.1.4.2. Excluded studies

See Appendix K for a list of excluded studies with the primary reason for exclusion.

1.1.5. Summary of RCTs included in the effectiveness evidence

Table 2

IV iron high dose vs low dose in children and young people.

Table 3

IV iron high dose vs low dose in adults.

Table 4

IV iron dextran MW 267,000 vs IV iron dextran MW 96,000, adults.

Table 5

IV iron sucrose (500mg) vs IV iron isomaltoside 1000 (500mg), adults, week 6.

Table 6

IV iron sucrose (1000mg) vs IV ferric chloride hexahydrate (1000mg), adults, week 10.

Table 7

IV ferric saccharate (100mg/week) vs IV ferric saccharate (2 × 50mg/week), adults, 2 months.

See Appendix E for full evidence tables.

1.1.6. Summary of the effectiveness evidence

Children and young people

Table 8

IV iron high dose vs low dose.

Adults

Table 9

IV iron high dose vs low dose.

Table 10

IV iron dextran MW 267,000 vs IV iron dextran MW 96,000, adults.

Table 11

IV iron sucrose (500mg) vs IV iron isomaltoside 1000 (500mg), adults, week 6.

Table 12

IV iron sucrose (1000mg) vs IV ferric chloride hexahydrate (1000mg), adults, week 10.

Table 13

IV ferric saccharate (100mg/week) vs IV ferric saccharate (2 × 50mg/week), adults, 2 months.

See Appendix G for full GRADE tables.

1.1.7. Economic evidence

1.1.7.1. Included studies

A search was conducted to identify economic evaluations relevant to the review question (see Appendix C). The search was not date limited. A total of 530 records were returned, 519 of which were excluded on the basis of title and abstract. The remaining 11 studies were fully inspected, and none were included in the synthesis. No additional studies were identified during inspection of the full publications and reference lists.

1.1.7.2. Excluded studies

Details of excluded studies are provided in Appendix K.

1.1.8. Summary of included economic evidence

No economic evaluations relevant to the review question were found.

1.1.9. Economic model

No economic modelling was undertaken for this review question.

1.1.10. The committee’s discussion and interpretation of the evidence

1.1.10.1. The outcomes that matter most

The committee agreed that even though the majority of the studies included in the review only reported short term follow-ups and improvements in Hb or serum ferritin (most frequently reported outcomes), longer term outcomes were the key outcomes for people (adults, children and young people) with a clinical diagnosis of anaemia and CKD 5 who are on dialysis. This includes long term maintenance of Hb level and serum ferritin level as well as events such as all-cause mortality and CV mortality. The committee also agreed that Hb level, other markers of anaemia, adverse events, incidence of blood transfusions, and quality of life were also important outcomes.

1.1.10.2. The quality of the evidence

Overall, the quality of the evidence varied from high to very low (most of the evidence was low and very low), with the main reasons for downgrading being due to imprecision of the evidence on the effect size of the amount of IV iron in managing anaemia and risk of bias of included studies. In most of the pairwise comparisons, imprecision was considered to be serious (95% confidence interval crossing one end of the defined MID interval [0.8, 1.25 for dichotomous outcomes or 0.2 for continuous outcomes]) or very serious (95% confidence interval crossing both ends of the defined MID interval). Risk of bias for some of the included studies was due to lack of detailed report of the randomisation process, lack of report that protocols were pre-registered, or the assignment of interventions was not well described. The committee expressed some concern that the maximum follow-up for Hb measurements was 3 months.

The committee noted that many of the included studies had a small sample size, short follow-up and reported only biochemical or surrogate outcomes. One study of high quality was large and had long follow-up for most of the outcomes including all-cause mortality and CV mortality (PIVOTAL trial, MacDougall et al. 2019).

The committee noted that there was limited evidence for quality of life and that only 2 studies reported data on this outcome, and the data was not reported in an extractable format (raw data was not reported).

1.1.10.3. Benefits and harms

For the purposes of the review, the evidence was divided based on the amount of IV iron into ‘high’ and ‘low’ dose (when possible). The committee agreed that since they were interested in relative effects, this was an appropriate thing to do.

The evidence for adults showed that high-dose intravenous iron was clinically and significantly better than a low-dose regimen at increasing levels of serum ferritin and haemoglobin as well as increasing the percentage of haematocrit in the short to medium term. The committee agreed that the type of iron preparation was not relevant and that there was no reason to recommend a specific preparation. It did however note that not all iron compounds are the same and a bio-equivalent amount of iron would be needed. They also highlighted that there are differences between iron preparations that affect their bioequivalence. Therefore, pharmacist advice is likely to be needed when choosing iron preparations. The committee provided an example regimen for adults using a high dose of iron sucrose. The example regimen was chosen because it was the dose and formulation used in a recent, large high-quality, UK based randomised controlled trial (PIVOTAL trial, MacDougall et al. 2019). The committee agreed that providing a clear example from the evidence could help guide practice, however they were also very clear that the choice of preparation should be based on local availability and policies and that they did not want to recommend a specific formulation. Therefore, the committee highlighted that iron sucrose was only an example and this was the reason why they suggested to use a bioequivalent dose of iron. The committee further noted that the inclusion criteria for the trial (transferrin saturation <30%, serum ferritin 400 micrograms/litre) differed from the criteria for diagnosing iron deficiency in this NICE guideline (transferrin saturation <20%, serum ferritin <100 micrograms/litre). It agreed that the regimen was still appropriate when using the NICE diagnostic criteria. Ultimately, the choice of preparation should be based on local availability and policies. Therefore, it made a strong recommendation to use high dose iron in people diagnosed with iron deficiency because the trial was a large trial at low risk of bias that improved the certainty of the evidence.

The evidence for adults also showed that adverse events were not meaningfully different between high-dose and low-dose of intravenous iron. Therefore, it is likely that high-dose intravenous iron does not increase the risk of adverse events compared to low-dose.

The evidence for children and young people showed that high-dose intravenous iron was clinically and significantly better than a low-dose regimen at increasing levels of serum ferritin in the short to medium term. Based on this limited evidence, the committee agreed that using the highest value of IV iron recommended by the BNF for children was the appropriate amount of iron to give to children and young people, but noted that IV iron use in children is off license either in all children and young people, or in children under 14 (depending on the preparation). The committee also noted that for children and young people it was not uncommon to see a ‘functional iron deficiency’ with normal or high ferritin levels but low Hb and profound anaemia who only respond to very high doses of iron. It agreed that clinicians do not withhold the iv iron where ferritin is high if other, more precise estimates of iron status (e.g. reticulocyte haemoglobin, hypochromic red blood cells) are out of range In these cases clinical judgment would dictate whether or not to give or withhold IV iron. The committee were unsure of the long-term consequences of high ferritin levels in these children and young people and made a research recommendation to address this uncertainty.

The committee was aware that, in some areas, for people who are on home dialysis, the first dose of IV iron is administered in hospital or in a dialysis centre and the rest of the treatment is given at home or self-administered. The committee discussed the benefits and risks of this, but it was also aware of a MHRA alert on intravenous iron and serious hypersensitivity reactions. The MHRA information on administering intravenous iron states that ‘intravenous iron products should only be administered when staff trained to evaluate and manage anaphylactic or anaphylactoid reactions – as well as resuscitation facilities – are immediately available.’ The committee therefore agreed that intravenous iron should not be administered at home.

Most of the evidence was from studies including participants who were on haemodialysis and receiving ESA therapy. Therefore, the committee agreed that more research would help to inform future guidance on intravenous iron for people with GFR category G5 who are on peritoneal dialysis or who are on dialysis but not having ESA therapy.

1.1.10.4. Cost effectiveness and resource use

The committee was not presented with any formal cost effectiveness evidence. Recommendations are not expected to result in a substantial resource impact, as the committee advised that recommendations are consistent with current practice and IV iron is reasonably inexpensive. Furthermore, in the PIVOTAL trial, people in the high-dose iron group received a lower dose of erythropoiesis-stimulating agent compared with people in the low-dose iron group (Macdougall et al. 2019). Given the high costs associated with erythropoiesis-stimulating agents, any excess treatment costs, including changing the frequency of treatment, associated with high-dose compared with low-dose iron are likely to be offset by the reduction in erythropoiesis-stimulating agent dose.

1.1.10.5. Other factors the committee took into account

The committee agreed that there were no equality issues that could arise from the recommendations they made. They highlighted that there were no physiological differences that could affect the response to treatment with IV iron. The committee agreed to remove a statement from recommendation 1.9.25 which contradicted updated guidance on IV iron in people having in-centre haemodialysis. The 2015 guideline recommended to administered IV iron at a low dose. The updated guideline recommends high-dose IV iron.

1.1.11. Recommendations supported by this evidence review

This evidence review supports recommendations 1.9.18 and the research recommendations on IV iron for adults, children and young people with GFR category 5 who are on peritoneal dialysis and on the long-term consequences of high ferritin levels (>800 micrograms/litre) in children and young people with CKD (see Appendix L for further details about the research recommendation).

1.1.12. References – included studies

1.1.12.1. Effectiveness

Akcicek, F, Ozkahya, M, Cirit, M et al. (1997) The efficiency of fractionated parenteral iron treatment in CAPD patients.. Advances in peritoneal dialysis. Conference on Peritoneal Dialysis 13: 109–12 [PubMed: 9360661]
Besarab, A, Amin, N, Ahsan, M et al. (2000) Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients.. Journal of the American Society of Nephrology : JASN 11(3): 530–8 [PubMed: 10703677]
Bhandari, Sunil, Kalra, Philip A, Kothari, Jatin et al. (2015) A randomized, open-label trial of iron isomaltoside 1000 (Monofer) compared with iron sucrose (Venofer) as maintenance therapy in haemodialysis patients.. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 30(9): 1577–89 [PMC free article: PMC4550440] [PubMed: 25925701]
Charytan, Chaim, Bernardo, Marializa V, Koch, Todd A et al. (2013) Intravenous ferric carboxymaltose versus standard medical care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multi-center study.. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 28(4): 953–64 [PubMed: 23222534]
Goldstein, Stuart L; Morris, David; Warady, Bradley A (2013) Comparison of the safety and efficacy of 3 iron sucrose iron maintenance regimens in children, adolescents, and young adults with CKD: a randomized controlled trial.. American journal of kidney diseases : the official journal of the National Kidney Foundation 61(4): 588–97 [PubMed: 23245582]
Hsiao P.-J., Chan J.-S., Wu K.-L. et al. (2016) Comparison of short-term efficacy of iron sucrose with those of ferric chloride in hemodialysis patients: An open-label study. Journal of Research in Medical Sciences 21(7): 102 [PMC free article: PMC5244645] [PubMed: 28163745]
Macdougall, Iain C, White, Claire, Anker, Stefan D et al. (2019) Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.. The New England journal of medicine 380(5): 447–458 [PubMed: 30365356]
Nissenson, A R, Lindsay, R M, Swan, S et al. (1999) Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American Clinical Trial.. American journal of kidney diseases : the official journal of the National Kidney Foundation 33(3): 471–82 [PubMed: 10070911]
Roe, D J, Harford, A M, Zager, P G et al. (1996) Iron utilization after iron dextran administration for iron deficiency in patients with dialysis-associated anemia: a prospective analysis and comparison of two agents.. American journal of kidney diseases : the official journal of the National Kidney Foundation 28(6): 855–60 [PubMed: 8957037]
Ruiz-Jaramillo, Ma de la Cruz, Guizar-Mendoza, Juan Manuel, Gutierrez-Navarro, Maria de Jesus et al. (2004) Intermittent versus maintenance iron therapy in children on hemodialysis: a randomized study.. Pediatric nephrology (Berlin, Germany) 19(1): 77–81 [PubMed: 14634860]
Wan, Li and Zhang, Dongliang (2018) Effect of frequency of intravenous iron administration on hemoglobin variability in maintenance hemodialysis patients.. International urology and nephrology 50(8): 1511–1518 [PubMed: 29946818]
Warady, Bradley A, Zobrist, R Howard, Wu, Jingyang et al. (2005) Sodium ferric gluconate complex therapy in anemic children on hemodialysis.. Pediatric nephrology (Berlin, Germany) 20(9): 1320–7 [PubMed: 15971073]

1.1.12.2. Other

Pergola PE, Pecoits-Filho R, Winkelmayer WC, et al. (2019) Economic Burden and Health-Related Quality of Life Associated with Current Treatments for Anaemia in Patients with CKD not on Dialysis: A Systematic Review. Pharmacoecon Open. 2019 Apr 9 [Epub ahead of print] [PMC free article: PMC6861396] [PubMed: 30968369]
Norman GR, Sloan JA, Wyrwich KW (2003) Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care. 2003 May;41(5):582–92. [PubMed: 12719681]

Appendices

Appendix A. Review protocols

Review protocol for managing anaemia with IV iron in people with GFR category G5 who are on dialysis (PDF, 263K)

Appendix B. Methods

Priority screening

The reviews undertaken for this guideline all made use of the priority screening functionality with the EPPI-reviewer systematic reviewing software. This uses a machine learning algorithm (specifically, an SGD classifier) to take information on features (1, 2 and 3 word blocks) in the titles and abstract of papers marked as being ‘includes’ or ‘excludes’ during the title and abstract screening process, and re-orders the remaining records from most likely to least likely to be an include, based on that algorithm. This re-ordering of the remaining records occurs every time 25 additional records have been screened.

Research is currently ongoing as to what are the appropriate thresholds where reviewing of abstract can be stopped, assuming a defined threshold for the proportion of relevant papers it is acceptable to miss on primary screening. As a conservative approach until that research has been completed, the following rules were adopted during the production of this guideline:

In every review, at least 50% of the identified abstract (or 1,000 records, if that is a greater number) were always screened.
After this point, screening was only terminated if a pre-specified threshold was met for a number of abstracts being screened without a single new include being identified. This threshold was set according to the expected proportion of includes in the review (with reviews with a lower proportion of includes needing a higher number of papers without an identified study to justify termination), and was always a minimum of 250.
A random 10% sample of the studies remaining in the database when the threshold were additionally screened, to check if a substantial number of relevant studies were not being correctly classified by the algorithm, with the full database being screened if concerns were identified.

As an additional check to ensure this approach did not miss relevant studies, the included studies lists of included systematic reviews were searched to identify any papers not identified through the primary search.

Evidence synthesis and meta-analyses

Where possible, meta-analyses were conducted to combine the results of quantitative studies for each outcome. For continuous outcomes analysed as mean differences, where change from baseline data were reported in the trials and were accompanied by a measure of spread (for example standard deviation), these were extracted and used in the meta-analysis. Where measures of spread for change from baseline values were not reported, the corresponding values at study end were used and were combined with change from baseline values to produce summary estimates of effect. These studies were assessed to ensure that baseline values were balanced across the treatment groups; if there were significant differences at baseline these studies were not included in any meta-analysis and were reported separately. For continuous outcomes analysed as standardised mean differences, where only baseline and final time point values were available, change from baseline standard deviations were estimated, assuming a correlation coefficient of 0.5.

Evidence of effectiveness of interventions

Quality assessment

Individual RCTs and quasi-randomised controlled trials were quality assessed using the Cochrane Risk of Bias Tool. Other study designs were quality assessed using the ROBINS-I tool. Each individual study was classified into one of the following three groups:

Low risk of bias – The true effect size for the study is likely to be close to the estimated effect size.
Moderate risk of bias – There is a possibility the true effect size for the study is substantially different to the estimated effect size.
High risk of bias – It is likely the true effect size for the study is substantially different to the estimated effect size.

Each individual study was also classified into one of three groups for directness, based on if there were concerns about the population, intervention, comparator and/or outcomes in the study and how directly these variables could address the specified review question. Studies were rated as follows:

Direct – No important deviations from the protocol in population, intervention, comparator and/or outcomes.
Partially indirect – Important deviations from the protocol in one of the population, intervention, comparator and/or outcomes.
Indirect – Important deviations from the protocol in at least two of the following areas: population, intervention, comparator and/or outcomes.

Methods for combining intervention evidence

Meta-analyses of interventional data were conducted with reference to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al. 2011).

A pooled relative risk was calculated for dichotomous outcomes (using the Mantel–Haenszel method) reporting numbers of people having an event, and a pooled incidence rate ratio was calculated for dichotomous outcomes reporting total numbers of events. Both relative and absolute risks were presented, with absolute risks calculated by applying the relative risk to the pooled risk in the comparator arm of the meta-analysis (all pooled trials).

Fixed- and random-effects models (der Simonian and Laird) were fitted for all syntheses, with the presented analysis dependent on the degree of heterogeneity in the assembled evidence. Fixed-effects models were the preferred choice to report, but in situations where the assumption of a shared mean for fixed-effects model were clearly not met, even after appropriate pre-specified subgroup analyses were conducted, random-effects results are presented. Fixed-effects models were deemed to be inappropriate if one or both of the following conditions was met:

Significant between study heterogeneity in methodology, population, intervention or comparator was identified by the reviewer in advance of data analysis. This decision was made and recorded before any data analysis was undertaken.
The presence of significant statistical heterogeneity in the fixed-effect meta-analysis, defined as I²≥50%.

In any meta-analyses where some (but not all) of the data came from studies at high risk of bias, a sensitivity analysis was conducted, excluding those studies from the analysis. Results from both the full and restricted meta-analyses are reported. Similarly, in any meta-analyses where some (but not all) of the data came from indirect studies, a sensitivity analysis was conducted, excluding those studies from the analysis.

Meta-analyses were performed in Cochrane Review Manager V5.3, with the exception of incidence rate ratio analyses which were carried out in R version 3.3.4.

Appendix C. Literature search strategies

RQ: For people with GFR category G5 who are on dialysis, what amount of intravenous (IV) iron is most clinically and cost effective in managing anaemia and its associated outcomes?

Background to the search

A NICE information specialist conducted the literature searches for the evidence review. The searches were originally run between the 17^th and 20^th of June 2019 and updated between the 15^th and 16^th of September 2020. This search report is compliant with the requirements of PRISMA-S.

The principal search strategy was developed in MEDLINE (Ovid interface) and adapted, as appropriate, for use in the other sources listed in the protocol, taking into account their size, search functionality and subject coverage.

The MEDLINE strategy below was quality assured (QA) by trained NICE information specialist. All translated search strategies were peer reviewed to ensure their accuracy. Both procedures were adapted from the 2016 PRESS Checklist.

The search results were managed in EPPI-Reviewer v5. Duplicates were removed in EPPI-R5 using a two-step process. First, automated deduplication is performed using a high-value algorithm. Second, manual deduplication is used to assess ‘low-probability’ matches. All decisions made for the review can be accessed via the deduplication history.

English language limits were applied in adherence to standard NICE practice and the review protocol.

Limits to exclude conferences in Embase were applied in adherence to standard NICE practice and the review protocol.

The limit to remove animal studies in the searches was the standard NICE practice, which has been adapted from: Dickersin, K., Scherer, R., & Lefebvre, C. (1994). Systematic Reviews: Identifying relevant studies for systematic reviews. BMJ, 309(6964), 1286. [PMC free article: PMC2541778] [PubMed: 7718048]

Clinical searches

Download PDF (374K)

Cost-effectiveness searches

Download PDF (340K)

Appendix D. Effectiveness evidence study selection

Download PDF (146K)

Appendix E. Effectiveness evidence tables

Download PDF (707K)

Appendix F. Forest plots

Children and young people (PDF, 192K)

Adults (PDF, 282K)

Appendix G. GRADE tables

Download PDF (416K)

Appendix H. Economic evidence study selection

Download PDF (134K)

Appendix I. Economic evidence tables

None – no economic evaluations relevant to the review question were found.

Appendix J. Health economic model

None – no economic evaluations relevant to the review question were found.

Appendix K. Excluded studies

Clinical studies

Table

- Does not contain a population of people on dialysis Mixed conservative management and RRT

Economic studies

Table

Appendix L. Research recommendations – full details

L.1.1. Research recommendation

For adults, children and young people with GFR category G5 who are undergoing peritoneal dialysis, what amount of intravenous (IV) iron is most clinically and cost effective in managing anaemia and its associated outcomes (including quality of life)?

L.1.2. Why this is important

Most of the evidence for intravenous iron in managing anaemia was derived from RCTs that recruited people with GFR category G5 who were on haemodialysis. There were only 2 trials recruiting participants on peritoneal dialysis with small sample sizes (Akcicek 1997 [n=17]; Goldstein 2013 [n=36]). As a result, the new recommendation was based on the evidence for haemodialysis.

Further research needs to explore the clinical and cost-effectiveness of intravenous iron in managing anaemia in a larger group of people with GFR category G5 who are on peritoneal dialysis.

L.1.3. Rationale for research recommendation

Download PDF (168K)

L.1.4. Modified PICO table

Download PDF (150K)

L.1.5. Research recommendation

What are the long-term consequences of high ferritin levels (>800 micrograms/litre) in children and young people with CKD?

L.1.6. Why this is important

The committee agreed that for some children and young people where estimates of iron status (e.g. reticulocyte haemoglobin, hypochromic red blood cells) are out of range, iron would be given clinically even if serum ferritin levels were high. It therefore agreed that it was important to understand the long-term consequences of high serum ferritin.

L.1.7. Rationale for research recommendation

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L.1.8. Modified PICO table

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Final

Evidence reviews underpinning recommendation 1.9.18 and research recommendations in the NICE guideline

This evidence reviews were developed by the Guideline Updates Team

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK574724PMID: 34672501

Table 1PICO table for IV iron in people with GFR category G5 who are on dialysis

Population	Inclusion: Adults, children and young people with a clinical diagnosis of anaemia and GFR category G5 and who are on dialysis. Exclusion: Management of anaemia in people whose anaemia is not principally caused by CKD. Ferumoxytol (withdrawn due to safety concerns)
Intervention	IV iron Ferric carboxymaltose Iron dextran Iron isomaltoside 1000 Iron polymaltose Iron sucrose Sodium ferric gluconate complex (SFGC)
Comparator	Other doses/schedules/formulations of IV iron
Outcome	All measured over the follow up time of the studies: Primary outcomes: Haemoglobin (Hb) level Other markers of anaemia (for example serum ferritin) All-cause mortality CV specific mortality Adverse events (infection, vascular access thrombosis, hypertension, hospitalization, anaphylaxis) Secondary outcomes: Incidence of blood transfusions QoL

Table 2IV iron high dose vs low dose in children and young people

Study

Population

Intervention

Comparator

Outcome measure(s)

Goldstein (2013)

N=145

Follow-up:

12 weeks

Age: 2 to 21 years
Haemoglobin ≥11.0 to ≤13.5 g/dL
Ferritin 800 ng/mL≤
Transferrin saturation ≥20% to ≤50%
Erythropoietic stimulating agent: stable therapy (±25% of current dose) for 8 weeks or longer prior to the qualifying screening visit
Other parameters: dialysis stable regimen for at least 3 months

IV iron sucrose (high dose = 2.0 mg/kg)

IV iron sucrose (very low dose = 0.5 mg/kg)

IV iron sucrose (low dose = 1.0 mg/kg)

Hb level

Ruiz-Jaramillo (2004)

N=40

Follow-up:

6 months

Age: <16 years
Other parameters
- Anaemia and absolute iron deficiency (ferritin <100 µg/l and transferrin saturation <20%) or functional iron deficiency (ferritin >100 µg/l and transferrin saturation <20% or haematocrit <33%)

IV Iron dextran (dose depended on ferritin levels = low dose [6 mg/kg per month])

IV Iron dextran (10-dose courses on body weight = high dose [14.4 mg/g per month])

Hb level
Other markers of anaemia
- Ferritin
Blood transfusion

Warady (2005)

N=66

Follow-up:

4 weeks

Age: 2 to 15 years
Erythropoietic stimulating agent: receiving concomitant recombinant human erythropoietin therapy with stable dosing regimen (defined as ≤25% change in the dose during the 4 weeks before treatment assignment)
Other parameters
- need for iron-repletion therapy as reflected by a transferrin saturation of <20% and/or a serum ferritin of <100 ng mL-1

IV sodium ferric gluconate complex (low dose = 1.5 mg kg-1)

IV sodium ferric gluconate complex (high dose = 3.0 mg kg-1)

Hb level
Other markers of anaemia
- Serum ferritin
Adverse events

Table 3IV iron high dose vs low dose in adults

Study	Population	Intervention	Comparator	Outcome measure(s)
Besarab (2000) N=47 Follow-up: 6 weeks	Age: >18 years Haemoglobin ≥9.5 g/dl Ferritin between 150 and 600 ng/ml Transferrin saturation between 19 and 30% Erythropoietic stimulating agent: stable dose for anaemia management over the previous 3 mo (±25%) Medications: no prior adverse reactions to parenteral iron Other parameters: mean cell volume of >80 fl	IV iron dextran (low dose = TSAT 20 to 30%)	IV iron dextran (high dose = TSAT 30 to 50%)	Hb level Other markers of anaemia Ferritin All-cause mortality CV specific mortality Adverse events
Charytan (2013) N=97 Follow-up: 30 days	Age: 18–85 years of age if they had at least a 6- month history of dialysis CKD Haemoglobin ≤12.5 g/dL Ferritin ≤500 ng/mL Transferrin saturation ≤30% Other parameters: eligible if they did not anticipate needing repletion therapy (>200 mg of IV iron) during the 30-day study period.	IV ferric carboxymaltose (low dose = mean dose 200 mg)	Standard medical care (high dose = mean dose 561 mg)	Hb level Other markers of anaemia Ferritin CV specific mortality Adverse events
MacDougall (2019) N=2141 Follow-up: Median 2.1 years	Age: >18 years Ferritin <400 μg/L Transferrin saturation <30% Erythropoietic stimulating agent: on ESA therapy Other parameters: Patients established on a chronic haemodialysis program for end-stage renal failure; Clinically stable per the judgment of the investigator; 0–12 months since commencing haemodialysis; Patients who have switched to haemodialysis from peritoneal dialysis or have received previous haemodialysis or renal transplants are eligible to enter the study. Consent: Written informed consent	IV iron sucrose (high dose-proactive = 400 mg monthly)	IV iron sucrose (low dose-reactive = 0 to 400 mg monthly)	All-cause mortality CV specific mortality Adverse events Blood transfusion Subgroup analysis
Nissenson (1999) N=88 Follow-up: 30 days	Age: Adults Haemoglobin <10 g/dL Haematocrit ≤32% Ferritin <100 ng/m Transferrin saturation <18%	IV sodium ferric gluconate complex in sucrose (high dose = 1000mg)	IV sodium ferric gluconate complex in sucrose (low dose = 500mg)	Hb level Other markers of anaemia Serum ferritin; haematocrit
Wan (2018) N=47 Follow-up: 3 months	Age: Adults Haemoglobin maintained at 100–130 (g/l) Ferritin 100–500 (ng/ml) Erythropoietic stimulating agent: treated with recombinant human erythropoietin Other parameters Regular haemodialysis patients (4 h per session and three times a week) with duration of stable haemodialysis more than 6 months; intact parathyroid hormone < 800 (pg/ml); Kt/V of each haemodialysis session >1.2 during the screening period	IV iron sucrose (continuous administration = high dose [1000 mg reached at 1 month])	IV iron sucrose (intermittent administration = low dose [1000 mg reached at 3 months])	Hb level Other markers of anaemia Serum ferritin reported as median (25th, 75th range); haematocrit

Table 4IV iron dextran MW 267,000 vs IV iron dextran MW 96,000, adults

Study

Population

Intervention

Comparator

Outcome measure(s)

Roe (1996)

N=20

Follow-up:

30 days

Ag: 18 years or older
Ferritin <100 µg/L
Transferrin saturation <20%
Other parameters
- life expectancy greater than 60 days, were receiving erythropoietin therapy for dialysis associated anaemia (haemoglobin 9 to 12 g/dL)

IV iron dextran MW 267,000 (500 mg)

IV iron dextran MW 96,000 (500 mg)

Hb level
Other markers of anaemia
- Serum ferritin

Table 5IV iron sucrose (500mg) vs IV iron isomaltoside 1000 (500mg), adults, week 6

Study

Population

Intervention

Comparator

Outcome measure(s)

Bhandari (2015)

Follow-up:

6 weeks

Age: ≥18 years of age with a diagnosis of CKD and on haemodialysis therapy for at least 90 days
Haemoglobin between 9.5 and 12.5 g/dL
Ferritin <800 ng/mL
Transferrin saturation <35%
Erythropoietic stimulating agent:
dose stable for the previous 4 weeks prior to screening
Medications: No IV iron or an average of no >100 mg/week for the previous 4 weeks
Other parameters: Life expectancy beyond 12 months
Consent: Willing to provide written informed consent

IV iron isomaltoside 1000 (500mg)

IV iron sucrose (500mg)

Hb level
All-cause mortality
Adverse events

Table 6IV iron sucrose (1000mg) vs IV ferric chloride hexahydrate (1000mg), adults, week 10

Study

Population

Intervention

Comparator

Outcome measure(s)

Hsiao (2016)

N=56

Follow-up:

10 weeks

Age: ≥18 years
Haematocrit between 22% and 32%
Ferritin <200 μg/L
Transferrin saturation <40%
Other parameters: regular haemodialysis for at least 3 months; normal serum Vitamin B12 and folic acid concentrations; no blood transfusion in the last 3 months

IV iron sucrose (1000mg)

IV ferric chloride hexahydrate (1000mg)

Other markers of anaemia
- Serum ferritin
- Haematocrit

Table 7IV ferric saccharate (100mg/week) vs IV ferric saccharate (2 × 50mg/week), adults, 2 months

Study

Population

Intervention

Comparator

Outcome measure(s)

Akcicek (1997)

N=17

Follow-up:

6 weeks

Age: Adults
Haemoglobin <10 g/dL
Haematocrit equivalent levels to haemoglobin levels
Erythropoietic stimulating agent: average dose 80 ±28 U/kg/week

IV ferric saccharate (100mg/week)

IV ferric saccharate (2 × 50mg/week)

Other markers of anaemia
- Ferritin
- Haematocrit

Table 8IV iron high dose vs low dose

Outcome	Sample size	Effect size (95% CI)	Quality	Interpretation of effect
Hb g/dL - Week 2	56	MD 0.00 (−0.64, 0.64)	MODERATE^a	Could not differentiate
Hb g/dL - Week 4	56	MD 0.10 (−0.78, 0.98)	LOW^b	Could not differentiate
Hb 10.5-14.0 g/dL – Week 12	53	RR 0.76 (0.42, 1.34)	VERY LOW^c	Could not differentiate
Hb 10.5-14.0 g/dL – Week 12	53	RR 0.71 (0.40, 1.25)	VERY LOW^c	Could not differentiate
Hb 10.5-14.0 g/dL – Week 12	58	RR 0.94 (0.60, 1.47)	VERY LOW^c	Could not differentiate
Serum ferritin µg/L or ng mL - Week 2	56	MD 117.20 (5.37, 229.03)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (113.7)
Serum ferritin µg/L or ng mL - Week 4	56	MD 65.30 (−62.19, 192.79)	LOW^b	Could not differentiate
Serum ferritin µg/L or ng mL – 4 months	40	MD 268.00 (51.81, 484.19)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (143.15)
Blood transfusions, 6 months	40	RR 7.00 (0.38, 127.32)	VERY LOW^c	Could not differentiate
Adverse events, week 4	66	RR 0.94 (0.06, 14.42)	VERY LOW^c	Could not differentiate

(a): Serious risk of bias

(b): Serious risk of bias; serious imprecision

(c): Serious risk of bias; very serious imprecision

Table 9IV iron high dose vs low dose

Outcome	Sample size	Effect size (95% CI)	Quality	Interpretation of effect
Hb level ≤12.5 g/dL - Day 30	93	RR 1.15 (0.67, 1.97)	VERY LOW^a	Could not differentiate
Hb g/dL - Day 2	83	MD 0.70 (0.14, 1.26)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (0.50)
Hb g/dL - Day 14	83	MD 0.80 (0.21, 1.39)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (0.50)
Hb g/dL - Day 30	175	MD 0.43 (−0.14, 1.00)	VERY LOW^c	Could not differentiate
Hb g/dL - Month 3	34	MD 0.38 (−0.41, 1.17)	LOW^b	Could not differentiate
Ferritin ng/mL - Day 2	80	MD 190.00 (32.89, 347.11)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (90.40)
Ferritin ng/mL - Day 14	80	MD 67.00 (−54.82, 188.82)	VERY LOW^a	Could not differentiate
Ferritin ng/mL - Day 30	173	MD 59.03 (21.41, 96.65)	MODERATE^d	Favours high dose. There is an effect, but it is less than the defined MID (125.99)
Haematocrit % - Day 2	83	MD 2.00 (0.20, 3.80)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (1.77)
Haematocrit % - Day 14	83	MD 2.20 (0.22, 4.18)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (1.76)
Haematocrit % - Day 30	83	MD 2.10 (0.12, 4.08)	LOW^b	Favours high dose. Clinically significant effect higher than the MID (1.85)
Haematocrit % - Month 3	34	MD 1.35 (−0.89, 3.59)	LOW^b	Could not differentiate
All-cause mortality - 6 months	42	RR 2.50 (0.11, 58.06)	LOW^b	Could not differentiate
All-cause mortality - time-to-first event (median follow-up 2.1 years)	2,141	RR 0.88 (0.75, 1.02)	MODERATE^e	Could not differentiate
All-cause mortality: subgroups - Catheter access	884	RR 0.77 (0.61, 0.96)	HIGH	Favours high dose. Clinically significant effect exceeding the line of no effect
All-cause mortality: subgroups - Fistula access	1,257	RR 0.97 (0.79, 1.19)	MODERATE^e	Could not differentiate
All-cause mortality: subgroups - Diabetes	944	RR 0.86 (0.71, 1.04)	MODERATE^e	Could not differentiate
All-cause mortality: subgroups - Non-diabetes	1,198	RR 0.89 (0.70, 1.12)	MODERATE^e	Could not differentiate
All-cause mortality: subgroups - Duration of dialysis <5 months	986	RR 0.87 (0.69, 1.10)	MODERATE^e	Could not differentiate
All-cause mortality: subgroups - Duration of dialysis ≥5 months	1,155	RR 0.88 (0.73, 1.07)	MODERATE^e	Could not differentiate
CV mortality - Day 30	97	RR 5.31 (0.26, 107.85)	LOW^b	Could not differentiate
CV mortality - 6 months	42	RR 0.17 (0.01, 3.27)	LOW^b	Could not differentiate
CV mortality - time-to-first event (median follow-up 2.1 years)	2,141	RR 0.91 (0.69, 1.20)	MODERATE^e	Could not differentiate
Adverse events - ≥1 event, day 30	97	RR 0.96 (0.60, 1.55)	VERY LOW^a	Could not differentiate
Adverse events - time-to-first event (median follow-up 2.1 years)	2,141	RR 1.01 (0.95, 1.08)	HIGH	No meaningful difference
Adverse events: infection - 6 months	36	RR 0.77 (0.32, 1.83)	VERY LOW^a	Could not differentiate
Adverse events: infection - time-to-first event (median follow-up 2.1 years)	2,141	RR 1.00 (0.88, 1.13)	HIGH	No meaningful difference
Adverse events: hospitalisations - 6 months	36	RR 0.89 (0.50, 1.60)	VERY LOW^a	Could not differentiate
Adverse events: hospitalisations - time-to-first event (median follow-up 2.1 years)	2,141	RR 1.01 (0.94, 1.09)	HIGH	No meaningful difference
Adverse events: vascular access thrombosis - time-to-first event (median follow-up 2.1 years)	2,141	RR 1.15 (0.98, 1.35)	MODERATE^e	Could not differentiate
Blood transfusion - time-to-first event (median follow-up 2.1 years)	2,141	RR 0.84 (0.71, 1.00)	MODERATE^e	Could not differentiate

(a): Serious risk of bias; very serious imprecision

(b): Serious risk of bias; serious imprecision

(c): Serious risk of bias; serious inconsistency; serious imprecision

(d): Serious risk of bias

(e): Serious imprecision

Table 10IV iron dextran MW 267,000 vs IV iron dextran MW 96,000, adults

Outcome	Sample size	Effect size (95% CI)	Quality	Interpretation of effect
Hb g/dL - week 1	20	MD 0.59 (−0.16, 1.34)	VERY LOW^a	Could not differentiate
Hb g/dL - week 2	20	MD 0.30 (−0.49, 1.09)	VERY LOW^b	Could not differentiate
Hb g/dL - week 3	20	MD 0.77 (0.08, 1.46)	VERY LOW^a	Favours MW 267,000. Clinically significant effect higher than the MID (0.42)
Hb g/dL - week 4	20	MD 0.77 (0.06, 1.48)	VERY LOW^a	Favours MW 267,000. Clinically significant effect higher than the MID (0.46)
Serum ferritin μg/L - week 1	20	MD 341.50 (−386.54, 1069.54)	VERY LOW^b	Could not differentiate
Serum ferritin μg/L - week 2	20	MD 5.20 (−85.87, 96.27)	VERY LOW^b	Could not differentiate
Serum ferritin μg/L - week 3	20	MD 3.70 (−84.66, 92.06)	VERY LOW^b	Could not differentiate
Serum ferritin μg/L - week 4	20	MD −24.10 (−113.35, 65.15)	VERY LOW^b	Could not differentiate

(a): Very serious risk of bias; serious imprecision

(b): Very serious risk of bias; very serious imprecision

Table 11IV iron sucrose (500mg) vs IV iron isomaltoside 1000 (500mg), adults, week 6

Outcome

Sample size

Effect size (95% CI)

Quality

Interpretation of effect

Hb >12.5 g/dL

341

RR 0.98

(0.49, 1.96)

LOW^a

Could not differentiate

All-cause mortality

351

RR 0.28

(0.01, 5.46)

MODERATE^b

Could not differentiate

Adverse events

346

RR 1.06

(0.85, 1.33)

MODERATE^b

Could not differentiate

(a): Very serious imprecision

(b): Serious imprecision

Table 12IV iron sucrose (1000mg) vs IV ferric chloride hexahydrate (1000mg), adults, week 10

Outcome

Sample size

Effect size (95% CI)

Quality

Interpretation of effect

Serum ferritin μg/L

MD 129.00

(−34.41, 292.41)

LOW^a

Could not differentiate

Haematocrit (%)

MD 1.00

(−0.83, 2.83)

LOW^a

Could not differentiate

(a): Serious risk of bias; serious imprecision

Table 13IV ferric saccharate (100mg/week) vs IV ferric saccharate (2 × 50mg/week), adults, 2 months

Outcome

Sample size

Effect size (95% CI)

Quality

Interpretation of effect

Serum ferritin μg/L

MD 9.00

(−49.90, 67.90)

VERY LOW^a

Could not differentiate

Haematocrit (%)

MD −2.80

(−6.20, 0.60)

VERY LOW^b

Could not differentiate

(a): Very serious risk of bias; very serious imprecision

(b): Very serious risk of bias; serious imprecision

Study	Reason for exclusion
Adhikary, L and Acharya, S (2011) Efficacy of IV iron compared to oral iron for increment of haemoglobin level in anemic chronic kidney disease patients on erythropoietin therapy. JNMA; journal of the nepal medical association 51(183): 133–136 [PubMed: 22922860]	- Not a relevant study design
Agarwal, Rajiv; Kusek, John W; Pappas, Maria K (2015) A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney international 88(4): 905–14 [PMC free article: PMC4589436] [PubMed: 26083656]	- Does not contain a population of people on dialysis
Agarwal, Rajiv, Leehey, David J, Olsen, Scott M et al. (2011) Proteinuria induced by parenteral iron in chronic kidney disease--a comparative randomized controlled trial. Clinical journal of the American Society of Nephrology : CJASN 6(1): 114–21 [PMC free article: PMC3022232] [PubMed: 20876669]	- Does not contain a population of people on dialysis
Ahsan, N (2000) Infusion of total dose iron versus oral iron supplementation in ambulatory peritoneal dialysis patients: a prospective, cross-over trial. Advances in peritoneal dialysis. Conference on peritoneal dialysis 16: 80–84 [PubMed: 11045266]	- Comparator in study does not match that specified in protocol
Albaramki Jumana, Hodson Elisabeth M, Craig Jonathan C, Webster Angela C (2012) Parenteral versus oral iron therapy for adults and children with chronic kidney disease. Cochrane Database of Systematic Reviews: Reviews issue1 [PubMed: 22258974]	- Comparator in study does not match that specified in protocol
Albaramki Jumana, Hodson Elisabeth M, Craig Jonathan C, Webster Angela C (2012) Parenteral versus oral iron therapy for adults and children with chronic kidney disease. Cochrane Database of Systematic Reviews: Reviews issue1 [PubMed: 22258974]	- Duplicate reference
Allegra, V; Mengozzi, G; Vasile, A (1991) Iron deficiency in maintenance hemodialysis patients: assessment of diagnosis criteria and of three different iron treatments. Nephron 57(2): 175–182 [PubMed: 1902285]	- Not a relevant study design
Anirban, Ganguli, Kohli, H S, Jha, Vivekanand et al. (2008) The comparative safety of various intravenous iron preparations in chronic kidney disease patients. Renal failure 30(6): 629–38 [PubMed: 18661414]	- Does not contain a population of people on dialysis Mixed conservative management and RRT
Auerbach, M, Winchester, J, Wahab, A et al. (1998) A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients. American journal of kidney diseases : the official journal of the National Kidney Foundation 31(1): 81–6 [PubMed: 9428456]	- Data not reported in an extractable format
Bregman D.B. and Goodnough L.T. (2014) Experience with intravenous ferric carboxymaltose in patients with iron deficiency anemia. Therapeutic Advances in Hematology 5(2): 48–60 [PMC free article: PMC3949301] [PubMed: 24688754]	- Review article but not a systematic review
Broumand, B, Ghods, A, Taheri, FM et al. (1998) Intravenous versus oral iron supplementation in the management of anemia in end stage renal disease. 35th congress. European renal association. European dialysis and transplantation association; 1998 jun 6–9; rimini, italy: 330	- Full text paper not available
Chertow, Glenn M, Mason, Phillip D, Vaage-Nilsen, Odd et al. (2004) On the relative safety of parenteral iron formulations. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 19(6): 1571–5 [PubMed: 15150356]	- Not a relevant study design
DeVita, M V, Frumkin, D, Mittal, S et al. (2003) Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients. Clinical nephrology 60(5): 335–40 [PubMed: 14640239]	- Study does not contain a relevant intervention RCT using single formulation but with different target levels for Hb
Dull, R B and Davis, E (2015) Heme iron polypeptide for the management of anaemia of chronic kidney disease. Journal of clinical pharmacy and therapeutics 40(4): 386–90 [PubMed: 25953602]	- Study does not contain a relevant intervention
Fishbane S., Shapiro W., Dutka P. et al. (2001) A randomized trial of iron deficiency testing strategies in hemodialysis patients. Kidney International 60(6): 2406–2411 [PubMed: 11737617]	- Study does not contain a relevant intervention
Fishbane, S; Frei, G L; Maesaka, J (1995) Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. American journal of kidney diseases : the official journal of the National Kidney Foundation 26(1): 41–6 [PubMed: 7611266]	- Comparator in study does not match that specified in protocol iv vs oral
Fudin, R, Jaichenko, J, Shostak, A et al. (1998) Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron 79(3): 299–305 [PubMed: 9678430]	- Comparator in study does not match that specified in protocol no vs iv vs oral
Fukao, Wataru, Hasuike, Yukiko, Yamakawa, Tomo et al. (2018) Oral Versus Intravenous Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients on Maintenance Hemodialysis-Effect on Fibroblast Growth Factor-23 Metabolism. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 28(4): 270–277 [PubMed: 29703633]	- Comparator in study does not match that specified in protocol
Gillespie, Robert S and Wolf, Fredric M (2004) Intravenous iron therapy in pediatric hemodialysis patients: a meta-analysis. Pediatric nephrology (Berlin, Germany) 19(6): 662–6 [PubMed: 15052462]	- Systematic review used as source of primary studies
Gupta, A, Amin, NB, Besarab, A et al. (1999) Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney international 55(5): 1891–1898 [PubMed: 10231452]	- Not a relevant study design
Hougen I., Collister D., Bourrier M. et al. (2018) Safety of intravenous iron in dialysis: A systematic review and meta-analysis. Clinical Journal of the American Society of Nephrology 13(3): 457–467 [PMC free article: PMC5967668] [PubMed: 29463597]	- Systematic review used as source of primary studies
Jacobs, Claude; Frei, Dieter; Perkins, Alan C (2005) Results of the European Survey on Anaemia Management 2003 (ESAM 2003): current status of anaemia management in dialysis patients, factors affecting epoetin dosage and changes in anaemia management over the last 5 years. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20suppl3: iii3–24 [PubMed: 15824128]	- Not a relevant study design - Study does not contain a relevant intervention
Johnson, DW, Herzig, KA, Gissane, R et al. (2001) A prospective crossover trial comparing intermittent intravenous and continuous oral iron supplements in peritoneal dialysis patients. Nephrology, dialysis, transplantation 16(9): 1879–1884 [PubMed: 11522873]	- Comparator in study does not match that specified in protocol
Kao, H H, Chen, K S, Tsai, C J et al. (2000) Clinical characteristic of parenteral iron supplementation in hemodialysis patients receiving erythropoietin therapy. Chang Gung medical journal 23(10): 608–13 [PubMed: 11126152]	- Full text paper not available
Kato, A, Hamada, M, Suzuki, T et al. (2001) Effect of weekly or successive iron supplementation on erythropoietin doses in patients receiving hemodialysis. Nephron 89(1): 110–112 [PubMed: 11528242]	- Comparator in study does not match that specified in protocol
Kotaki, M, Uday, K, Henriquez, M et al. (1997) Maintenance therapy with intravenous iron in hemodialysis patients receiving erythropoietin. Clinical nephrology 48(1): 63–4 [PubMed: 9247787]	- Letter to editor
Kuji T., Toya Y., Fujikawa T. et al. (2015) Acceleration of iron utilization after intravenous iron administration during activated erythropoiesis in hemodialysis patients: A randomized study. Therapeutic Apheresis and Dialysis 19(2): 131–137 [PubMed: 25257861]	- Aim of study does not match protocol to evaluate the effect of different timings of iron administration during erythropoiesis activated by continuous erythropoietin receptor activator (CERA) on reticulocyte iron uptake
Kuragano, T, Yahiro, M, Kida, A et al. (2014) Effect of protoconized therapy for renal anemia on adverse events of patients with maintenance hemodialysis. International journal of artificial organs 37(12): 865–874 [PubMed: 25450320]	- Study does not contain a relevant intervention mixture of oral and sometimes IV iron
Leehey, David J, Palubiak, David J, Chebrolu, Srivasa et al. (2005) Sodium ferric gluconate causes oxidative stress but not acute renal injury in patients with chronic kidney disease: a pilot study. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20(1): 135–40 [PubMed: 15522899]	- NAC was given prior to each iron infusion to prevent oxidative stress
Li, H and Wang, SX (2009) Intravenous iron sucrose in maintenance dialysis patients with renal anemia: a clinical study. Zhonghua yi xue za zhi 89(7): 457–462 [PubMed: 19567093]	- Study not reported in English
Li, Han and Wang, Shi-xiang (2008) Intravenous iron sucrose in Chinese hemodialysis patients with renal anemia. Blood purification 26(2): 151–6 [PubMed: 18212498]	- Comparator in study does not match that specified in protocol
Li, Han and Wang, Shi-Xiang (2008) Intravenous iron sucrose in peritoneal dialysis patients with renal anemia. Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis 28(2): 149–54 [PubMed: 18332450]	- Comparator in study does not match that specified in protocol
Macdougall I.C., Tucker B., Thompson J. et al. (1996) A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney International 50(5): 1694–1699 [PubMed: 8914038]	- Comparator in study does not match that specified in protocol
Macdougall, IC, Bock, A, Carrera, F et al. (2013) FIND-CKD: a 56-week randomized trial of intravenous ferric carboxymaltose versus oral iron in anemic patients with chronic kidney disease and iron defi ciency. Journal of the american society of nephrology : JASN 24(abstracts): 3b	- Conference abstract
McMahon, Lawrence P, Kent, Annette B, Kerr, Peter G et al. (2010) Maintenance of elevated versus physiological iron indices in non-anaemic patients with chronic kidney disease: a randomized controlled trial. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 25(3): 920–6 [PubMed: 19906658]	- Comparator in study does not match that specified in protocol
McMahon, LP, Kent, AB, Roger, SD et al. (2007) IV iron sucrose versus oral iron for the anemia of chronic kidney disease (CKD) - a randomized controlled trial. Journal of the american society of nephrology : JASN 18(abstractsue): 813a	- Conference abstract
Michael, Beckie, Coyne, Daniel W, Fishbane, Steven et al. (2002) Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney international 61(5): 1830–9 [PubMed: 11967034]	- Comparator in study does not match that specified in protocol historical control vs placebo vs iv
Michelis R.; Sela S.; Kristal B. (2005) Intravenous iron-gluconate during haemodialysis modifies plasma beta2-microglobulin properties and levels. Nephrology Dialysis Transplantation 20(9): 1963–1969 [PubMed: 15956071]	- Not a relevant study design
O’Lone, Emma L, Hodson, Elisabeth M, Nistor, Ionut et al. (2019) Parenteral versus oral iron therapy for adults and children with chronic kidney disease. The Cochrane database of systematic reviews 2: cd007857 [PMC free article: PMC6384096] [PubMed: 30790278]	- Study does not contain a relevant intervention
Park, Jongha, Chang, Jai Won, Lee, Jong Soo et al. (2009) Efficacy of low-dose i.v. iron therapy in haemodialysis patients. Nephrology (Carlton, Vic.) 14(8): 716–21 [PubMed: 20025679]	- Comparator in study does not match that specified in protocol
Pollock, R.F. and Muduma, G. (2020) A patient-level cost-effectiveness analysis of iron isomaltoside versus ferric carboxymaltose for the treatment of iron deficiency anemia in the United Kingdom. Journal of Medical Economics 23(7): 751–759 [PubMed: 32208038]	- Does not contain a population of people on dialysis
Ragab M.; Mahmoud K.; Ragab A. (2007) Maintenance intravenous iron sucrose therapy in children under regular hemodialysis. Journal of Medical Sciences 7(7): 1112–1116	- Comparator in study does not match that specified in protocol
Rath, Thomas, Florschutz, Kai, Kalb, Klaus et al. (2010) Low-molecular-weight iron dextran in the management of renal anaemia in patients on haemodialysis--the IDIRA Study. Nephron. Clinical practice 114(1): c81–8 [PubMed: 19887827]	- Not a relevant study design
Roger, Simon D, Tio, Martin, Park, Hyeong-Cheon et al. (2017) Intravenous iron and erythropoiesis-stimulating agents in haemodialysis: A systematic review and meta-analysis. Nephrology (Carlton, Vic.) 22(12): 969–976 [PMC free article: PMC5725690] [PubMed: 27699922]	- Systematic review used as source of primary studies
Rozen-Zvi, Benaya, Gafter-Gvili, Anat, Paul, Mical et al. (2008) Intravenous versus oral iron supplementation for the treatment of anemia in CKD: systematic review and meta-analysis. American journal of kidney diseases : the official journal of the National Kidney Foundation 52(5): 897–906 [PubMed: 18845368]	- Comparator in study does not match that specified in protocol
Saltissi, D; Sauvage, D; Westhuyzen, J (1998) Comparative response to single or divided doses of parenteral iron for functional iron deficiency in hemodialysis patients receiving erythropoietin (EPO). Clinical nephrology 49(1): 45–48 [PubMed: 9491286]	- Data not reported in an extractable format
Sav, Tansu, Tokgoz, Bulent, Sipahioglu, Murat Hayri et al. (2007) Is there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran?. Renal failure 29(4): 423–6 [PubMed: 17497463]	- Does not contain a population of people on dialysis Mixed pop with 35% not on dialysis
Shepshelovich, Daniel, Rozen-Zvi, Benaya, Avni, Tomer et al. (2016) Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis. American journal of kidney diseases : the official journal of the National Kidney Foundation 68(5): 677–690 [PubMed: 27321965]	- Comparator in study does not match that specified in protocol
Sirken, G; Raja, R; Rizkala, A R (2006) Association of different intravenous iron preparations with risk of bacteremia in maintenance hemodialysis patients. Clinical nephrology 66(5): 348–56 [PubMed: 17140164]	- Not a relevant study design
St. Peter W.L.; Lambrecht L.J.; Macres M. (1996) Randomized cross-over study of adverse reactions and cost implications of intravenous push compared with infusion of iron dextran in hemodialysis patients. American Journal of Kidney Diseases 28(4): 523–528 [PubMed: 8840941]	- Data not reported in an extractable format
Sunder-Plassmann, G and Horl, W H (1995) Importance of iron supply for erythropoietin therapy. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 10(11): 2070–6 [PubMed: 8643170]	- Not a relevant study design
Susantitaphong, P., Siribumrungwong, M., Takkavatakarn, K. et al. (2020) Effect of Maintenance Intravenous Iron Treatment on Erythropoietin Dose in Chronic Hemodialysis Patients: A Multicenter Randomized Controlled Trial. Canadian Journal of Kidney Health and Disease 7 [PMC free article: PMC7307402] [PubMed: 32612843]	- Study does not contain a relevant intervention Unclear what iron supplement was used
Svára, F, Sulková, S, Kvasnićka, J et al. (1996) Iron supplementation during erythropoietin therapy in patients on hemodialysis. Vnitrni lekarstvi 42(12): 849–852 [PubMed: 9072885]	- Full text paper not available
Tsuchida A., Paudyal B., Paudyal P. et al. (2010) Effectiveness of oral iron to manage anemia in long-term hemodialysis patients with the use of ultrapure dialysate. Experimental and Therapeutic Medicine 1(5): 777–781 [PMC free article: PMC3445869] [PubMed: 22993601]	- Study does not contain a relevant intervention
Visciano, B, Nazzaro, P, Tarantino, G et al. (2013) Liposomial iron: a new proposal for the treatment of anaemia in chronic kidney disease. Giornale italiano di nefrologia 30(5) [PubMed: 24402627]	- Study not reported in English
Warady B.A., Kausz A., Lerner G. et al. (2004) Iron therapy in the pediatric hemodialysis population. Pediatric Nephrology 19(6): 655–661 [PubMed: 15064942]	- Comparator in study does not match that specified in protocol
Weiss, Gunter and Kronenberg, Florian (2015) Intravenous iron administration: new observations and time for the next steps. Kidney international 87(1): 10–2 [PubMed: 25549119]	- Not a relevant study design Commentary
Wingard, R L, Parker, R A, Ismail, N et al. (1995) Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin. American journal of kidney diseases : the official journal of the National Kidney Foundation 25(3): 433–9 [PubMed: 7872321]	- Study does not contain a relevant intervention
Wu, Chih-Jen, Lin, Hsin-Chang, Lee, Kun-Feng et al. (2010) Comparison of parenteral iron sucrose and ferric chloride during erythropoietin therapy of haemodialysis patients. Nephrology (Carlton, Vic.) 15(1): 42–7 [PubMed: 20377770]	- Data not reported in an extractable format Reported as medians
Yin, L, Chen, X, Chen, J et al. (2012) Multi-frequency low-dose intravenous iron on oxidative stress in maintenance hemodialysis patients. Zhong nan da xue xue bao. Yi xue ban [Journal of Central South University. Medical sciences] 37(8): 844–848 [PubMed: 22954919]	- Study not reported in English
Ziedan A. and Bhandari S. (2019) Protocol and baseline data for a prospective open-label explorative randomized single-center comparative study to determine the effects of various intravenous iron preparations on markers of oxidative stress and kidney injury in chronic kidney disease (IRON-CKD). Trials 20(1): 194 [PMC free article: PMC6449958] [PubMed: 30947751]	- Not a relevant study design Protocol
Zitt E., Sturm G., Kronenberg F. et al. (2014) Iron supplementation and mortality in incident dialysis patients: An observational study. PLoS ONE 9(12): e114144 [PMC free article: PMC4252084] [PubMed: 25462819]	- Not a relevant study design

Study	Reason
Aiello, Andrea, Berto, Patrizia, Conti, Paolo et al. (2020) Economic impact of ferric carboxymaltose in haemodialysis patients. Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia 37(suppl75) [PubMed: 32749086]	Study not reported in English
Besarab, A, Amin, N, Ahsan, M et al. (2000) Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. Journal of the American Society of Nephrology: JASN 11(3): 530–8 [PubMed: 10703677]	Does not include quality of life data.
Bhandari, Sunil (2011) A hospital-based cost minimization study of the potential financial impact on the UK health care system of introduction of iron isomaltoside 1000. Therapeutics and clinical risk management 7: 103–13 [PMC free article: PMC3071347] [PubMed: 21479141]	Does not include quality of life data.
Dahl N.V., Kaper R.F., Strauss W.E. et al. (2017) Cost-effectiveness analysis of intravenous ferumoxytol for the treatment of iron deficiency anemia in adult patients with non-dialysis-dependent chronic kidney disease in the USA. ClinicoEconomics and Outcomes Research 9: 557–567 [PMC free article: PMC5614742] [PubMed: 29033594]	Does not include quality of life data.
Darba, Josep and Ascanio, Meritxell (2018) Budget Impact Analysis of Oral Fisiogen Ferro Forte versus Intravenous Iron for the Management of Iron Deficiency in Chronic Kidney Disease in Spain. Clinical drug investigation 38(9): 801–811 [PubMed: 29934762]	Does not include quality of life data.
Fragoulakis V., Kourlaba G., Goumenos D. et al. (2012) Economic evaluation of intravenous iron treatments in the management of anemia patients in Greece. ClinicoEconomics and Outcomes Research 4(1): 127–134 [PMC free article: PMC3358814] [PubMed: 22629113]	Does not include quality of life data.
Pollock, R.F. and Muduma, G. (2020) A patient-level cost-effectiveness analysis of iron isomaltoside versus ferric carboxymaltose for the treatment of iron deficiency anemia in the United Kingdom. Journal of Medical Economics 23(7): 751–759 [PubMed: 32208038]	Does not contain a population of people with CKD
Rognoni, Carla, Ortalda, Vittorio, Biasi, Caterina et al. (2019) Economic Evaluation of Ferric Carboxymaltose for the Management of Hemodialysis Patients with Iron Deficiency Anemia in Italy. Advances in therapy 36(11): 3253–3264 [PMC free article: PMC6822962] [PubMed: 31489572]	Does not include quality of life data
Sepandj, F, Jindal, K, West, M et al. (1996) Economic appraisal of maintenance parenteral iron administration in treatment of anaemia in chronic haemodialysis patients. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 11(2): 319–22 [PubMed: 8671786]	Does not include quality of life data.
Wilson, Paul D, Hutchings, Adam, Jeans, Aruna et al. (2013) An analysis of the health service efficiency and patient experience with two different intravenous iron preparations in a UK anaemia clinic. Journal of medical economics 16(1): 108–14 [PubMed: 22989163]	Does not include quality of life data.
Wong, Germaine, Howard, Kirsten, Hodson, Elisabeth et al. (2013) An economic evaluation of intravenous versus oral iron supplementation in people on haemodialysis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 28(2): 413–20 [PubMed: 23182811]	Compares oral versus IV rather than IV versus IV iron.

Evidence reviews for managing anaemia with IV iron in people with GFR category G5 who are on dialysis

Managing anaemia with IV iron in people with GFR category G5 who are on dialysis

1.1. Review question

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

1.1.4.2. Excluded studies

1.1.5. Summary of RCTs included in the effectiveness evidence

1.1.6. Summary of the effectiveness evidence

Children and young people

Adults

1.1.7. Economic evidence

1.1.7.1. Included studies

1.1.7.2. Excluded studies

1.1.8. Summary of included economic evidence

1.1.9. Economic model

1.1.10. The committee’s discussion and interpretation of the evidence

1.1.10.1. The outcomes that matter most

1.1.10.2. The quality of the evidence

1.1.10.3. Benefits and harms

1.1.10.4. Cost effectiveness and resource use

1.1.10.5. Other factors the committee took into account

1.1.11. Recommendations supported by this evidence review

1.1.12. References – included studies

1.1.12.1. Effectiveness

1.1.12.2. Other

Appendices

Appendix A. Review protocols

Appendix B. Methods

Priority screening

Evidence synthesis and meta-analyses

Evidence of effectiveness of interventions

Quality assessment

Methods for combining intervention evidence

Minimal clinically important differences (MIDs)

GRADE for pairwise meta-analyses of interventional evidence

Health economics

Appendix C. Literature search strategies

Background to the search

Clinical searches

Cost-effectiveness searches

Appendix D. Effectiveness evidence study selection

Appendix E. Effectiveness evidence tables

Appendix F. Forest plots

Appendix G. GRADE tables

Appendix H. Economic evidence study selection

Appendix I. Economic evidence tables

Appendix J. Health economic model

Appendix K. Excluded studies

Clinical studies

Economic studies

Appendix L. Research recommendations – full details

L.1.1. Research recommendation

L.1.2. Why this is important

L.1.3. Rationale for research recommendation

L.1.4. Modified PICO table

L.1.5. Research recommendation

L.1.6. Why this is important

L.1.7. Rationale for research recommendation

L.1.8. Modified PICO table

Table 1PICO table for IV iron in people with GFR category G5 who are on dialysis

Table 2IV iron high dose vs low dose in children and young people

Table 3IV iron high dose vs low dose in adults

Table 4IV iron dextran MW 267,000 vs IV iron dextran MW 96,000, adults

Table 5IV iron sucrose (500mg) vs IV iron isomaltoside 1000 (500mg), adults, week 6

Table 6IV iron sucrose (1000mg) vs IV ferric chloride hexahydrate (1000mg), adults, week 10

Table 7IV ferric saccharate (100mg/week) vs IV ferric saccharate (2 × 50mg/week), adults, 2 months

Table 8IV iron high dose vs low dose

Table 9IV iron high dose vs low dose

Table 10IV iron dextran MW 267,000 vs IV iron dextran MW 96,000, adults

Table 11IV iron sucrose (500mg) vs IV iron isomaltoside 1000 (500mg), adults, week 6

Table 12IV iron sucrose (1000mg) vs IV ferric chloride hexahydrate (1000mg), adults, week 10

Table 13IV ferric saccharate (100mg/week) vs IV ferric saccharate (2 × 50mg/week), adults, 2 months