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Journal ArticleDOI

Parenteral versus oral iron therapy for adults and children with chronic kidney disease

01 Nov 2012-Nephrology (John Wiley & Sons, Ltd)-Vol. 17, Iss: 8, pp 774-775
TL;DR: The required dose of erythropoiesis stimulating agents (ESA) was significantly reduced in dialysis patients receiving IV iron compared with oral iron, and hypotensive and allergic reactions were significantly more common with IV iron.
Abstract: Ferritin (Figure 1: mean difference 243 mg/L) and transferrin saturation levels (mean difference 10%) were significantly increased by intravenous (IV) iron compared with oral iron, while haemoglobin levels were slightly increased (mean difference 0.9 g/dl). The required dose of erythropoiesis stimulating agents (ESA) was significantly reduced in dialysis patients receiving IV iron compared with oral iron (Figure 2). Any change in ESA dose could not be assessed in nondialysis patients due to lack of trial data. All-cause mortality, cardiovascular mortality, quality of life and patients’ adherence to oral iron did not differ significantly but were reported in few studies. Gastrointestinal adverse effects were significantly more common with oral iron while hypotensive and allergic reactions were significantly more common with IV iron. What are the findings based on?

Summary (1 min read)

Introduction

  • To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD, including participants on dialysis, with kidney transplants and CKD not requiring dialysis.
  • The authors have very little confidence in the effect estimate: CI: Confidence interval; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; ESA: erythrocyte-stimulating agent; Hb: haemoglobin; HCT: haematocrit; IV: intravenous; RR: Risk ratio; TSAT: transferrin saturation GRADE Working Group grades of evidence High quality: Published by John Wiley & Sons, Ltd. 7 Cochrane Library Trusted evidence.

Inclusion criteria

  • The authors included adult and paediatric patients with CKD (stages 3 to 5D; glomerular filtration rate (GFR) < 60 mL/min/1.73 m2).
  • Studies in patients receiving HD, PD, or those not requiring dialysis, were included.
  • Studies of kidney transplant patients were also included.

Exclusion criteria

  • Studies of iron administration in patients comparing diKerent IV or oral iron preparations and diKerent doses of the same IV or oral preparation were excluded.
  • Cochrane Database of Systematic Reviews publications of the same study were identified, data were included from the most recent publication, and preferably, the definitive publication.
  • CN-01657325] *  Agarwal R, Rizkala AR, Bastani B, Kaskas MO, Leehey DJ, Besarab A. A randomized controlled trial of oral versus intravenous iron in chronic kidney disease, also known as [CENTRAL.

Risk of bias

  • Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk "randomly allocated" Allocation concealment (selection bias) Unclear risk Insufficient information to permit judgement Winney 1977 HD  Parenteral versus oral iron therapy for adults and children with chronic kidney disease Copyright © 2019 The Cochrane Collaboration.
  • Published by John Wiley & Sons, Ltd. 84 Cochrane Library Trusted evidence.

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Cochrane Database of Systematic Reviews
Parenteral versus oral iron therapy for adults and children with
chronic kidney disease (Review)
O'Lone EL, Hodson EM, Nistor I, Bolignano D, Webster AC, Craig JC
O'LoneEL, HodsonEM, NistorI, BolignanoD, WebsterAC, CraigJC.
Parenteral versus oral iron therapy for adults and children with chronic kidney disease.
Cochrane Database of Systematic Reviews 2019, Issue 2. Art. No.: CD007857.
DOI: 10.1002/14651858.CD007857.pub3.
www.cochranelibrary.com
Parenteral versus oral iron therapy for adults and children with chronic kidney disease (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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T A B L E  O F  C O N T E N T S
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 7
OBJECTIVES.................................................................................................................................................................................................. 8
METHODS..................................................................................................................................................................................................... 8
RESULTS........................................................................................................................................................................................................ 10
Figure 1.................................................................................................................................................................................................. 11
Figure 2.................................................................................................................................................................................................. 12
Figure 3.................................................................................................................................................................................................. 13
Figure 4.................................................................................................................................................................................................. 15
Figure 5.................................................................................................................................................................................................. 16
DISCUSSION.................................................................................................................................................................................................. 18
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 20
ACKNOWLEDGEMENTS................................................................................................................................................................................ 20
REFERENCES................................................................................................................................................................................................ 21
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 29
DATA AND ANALYSES.................................................................................................................................................................................... 80
Analysis 1.1. Comparison 1 Patient centred outcomes, Outcome 1 Death (all causes).................................................................... 81
Analysis 1.2. Comparison 1 Patient centred outcomes, Outcome 2 Cardiovascular death.............................................................. 82
Analysis 1.3. Comparison 1 Patient centred outcomes, Outcome 3 Quality of life........................................................................... 82
Analysis 1.4. Comparison 1 Patient centred outcomes, Outcome 4 Number of non-dialysis patients needing to commence
dialysis...................................................................................................................................................................................................
82
Analysis 1.5. Comparison 1 Patient centred outcomes, Outcome 5 Number requiring transfusion................................................ 83
Analysis 1.6. Comparison 1 Patient centred outcomes, Outcome 6 Type of adverse event............................................................. 83
Analysis 2.1. Comparison 2 Laboratory/pharmaceutical outcomes, Outcome 1 Number achieving target haemoglobin or
increase 1 g/dL...................................................................................................................................................................................
86
Analysis 2.2. Comparison 2 Laboratory/pharmaceutical outcomes, Outcome 2 Haemoglobin: final or change (all patients)........ 86
Analysis 2.3. Comparison 2 Laboratory/pharmaceutical outcomes, Outcome 3 Ferritin: final or change (all patients)................. 87
Analysis 2.4. Comparison 2 Laboratory/pharmaceutical outcomes, Outcome 4 Transferrin saturation: final or change............... 88
Analysis 2.5. Comparison 2 Laboratory/pharmaceutical outcomes, Outcome 5 Haematocrit........................................................ 89
Analysis 2.6. Comparison 2 Laboratory/pharmaceutical outcomes, Outcome 6 End of treatment or change in ESA dose............ 89
Analysis 2.7. Comparison 2 Laboratory/pharmaceutical outcomes, Outcome 7 eGFR end or change............................................ 90
ADDITIONAL TABLES.................................................................................................................................................................................... 90
APPENDICES................................................................................................................................................................................................. 95
WHAT'S NEW................................................................................................................................................................................................. 99
HISTORY........................................................................................................................................................................................................ 99
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 99
DECLARATIONS OF INTEREST..................................................................................................................................................................... 100
INDEX TERMS............................................................................................................................................................................................... 100
Parenteral versus oral iron therapy for adults and children with chronic kidney disease (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Parenteral versus oral iron therapy for adults and children with chronic
kidney disease
Emma L O'Lone
1
, Elisabeth M Hodson
2
, Ionut Nistor
3
, Davide Bolignano
4
, Angela C Webster
1,5
, Jonathan C Craig
2,6
1
Sydney School of Public Health, The University of Sydney, Sydney, Australia.
2
Cochrane Kidney and Transplant, Centre for Kidney
Research, The Children's Hospital at Westmead, Westmead, Australia.
3
Nephrology Department, "Grigore T. Popa" University of Medicine
and Pharmacy, Iasi, Romania.
4
Institute of Clinical Physiology, CNR - Italian National Council of Research, Reggio Calabria, Italy.
5
Centre
for Transplant and Renal Research, Westmead Millennium Institute, The University of Sydney at Westmead, Westmead, Australia.
6
College of Medicine and Public Health, Flinders University, Adelaide, Australia
Contact address: Elisabeth M Hodson, Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at
Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. elisabeth.hodson@health.nsw.gov.au.
Editorial group: Cochrane Kidney and Transplant Group.
Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 2, 2019.
Citation: O'LoneEL, HodsonEM, NistorI, BolignanoD, WebsterAC, CraigJC. Parenteral versus oral iron therapy for adults
and children with chronic kidney disease. Cochrane Database of Systematic Reviews 2019, Issue 2. Art. No.: CD007857. DOI:
10.1002/14651858.CD007857.pub3.
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through dierent routes,
with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV)
compared with oral iron are justified. This is an update of a review first published in 2012.
Objectives
To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD,
including participants on dialysis, with kidney transplants and CKD not requiring dialysis.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 7 December 2018 through contact with the Information
Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and
EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.
Selection criteria
We included randomised controlled trials (RCTs) and quasi-RCTs in which IV and oral routes of iron administration were compared in adults
and children with CKD.
Data collection and analysis
Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95%
confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean dierence (MD) was used or standardised mean
dierence (SMD) if dierent scales had been used. Statistical analyses were performed using the random-eects model. Subgroup analysis
and univariate meta-regression were performed to investigate between study dierences. The certainty of the evidence was assessed using
GRADE.
Parenteral versus oral iron therapy for adults and children with chronic kidney disease (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Main results
We included 39 studies (3852 participants), 11 of which were added in this update. A low risk of bias was attributed to 20 (51%) studies for
sequence generation, 14 (36%) studies for allocation concealment, 22 (56%) studies for attrition bias and 20 (51%) for selective outcome
reporting. All studies were at a high risk of performance bias. However, all studies were considered at low risk of detection bias because
the primary outcome in all studies was laboratory-based and unlikely to be influenced by lack of blinding.
There is insuicient evidence to suggest that IV iron compared with oral iron makes any dierence to death (all causes) (11 studies, 1952
participants: RR 1.12, 95% CI 0.64, 1.94) (absolute eect: 33 participants per 1000 with IV iron versus 31 per 1000 with oral iron), the number
of participants needing to start dialysis (4 studies, 743 participants: RR 0.81, 95% CI 0.41, 1.61) or the number needing blood transfusions
(5 studies, 774 participants: RR 0.86, 95% CI 0.55, 1.34) (absolute eect: 87 per 1,000 with IV iron versus 101 per 1,000 with oral iron). These
analyses were assessed as having low certainty evidence. It is uncertain whether IV iron compared with oral iron reduces cardiovascular
death because the certainty of this evidence was very low (3 studies, 206 participants: RR 1.71, 95% CI 0.41 to 7.18). Quality of life was
reported in five studies with four reporting no dierence between treatment groups and one reporting improvement in participants treated
with IV iron.
IV iron compared with oral iron may increase the numbers of participants, who experience allergic reactions or hypotension (15 studies,
2607 participants: RR 3.56, 95% CI 1.88 to 6.74) (absolute harm: 24 per 1000 with IV iron versus 7 per 1000) but may reduce the number of
participants with all gastrointestinal adverse eects (14 studies, 1986 participants: RR 0.47, 95% CI 0.33 to 0.66) (absolute benefit: 150 per
1000 with IV iron versus 319 per 1000). These analyses were assessed as having low certainty evidence.
IV iron compared with oral iron may increase the number of participants who achieve target haemoglobin (13 studies, 2206 participants:
RR 1.71, 95% CI 1.43 to 2.04) (absolute benefit: 542 participants per 1,000 with IV iron versus 317 per 1000 with oral iron), increased
haemoglobin (31 studies, 3373 participants: MD 0.72 g/dL, 95% CI 0.39 to 1.05); ferritin (33 studies, 3389 participants: MD 224.84 g/L, 95%
CI 165.85 to 283.83) and transferrin saturation (27 studies, 3089 participants: MD 7.69%, 95% CI 5.10 to 10.28), and may reduce the dose
required of erythropoietin-stimulating agents (ESAs) (11 studies, 522 participants: SMD -0.72, 95% CI -1.12 to -0.31) while making little or
no dierence to glomerular filtration rate (8 studies, 1052 participants: 0.83 mL/min, 95% CI -0.79 to 2.44). All analyses were assessed as
having low certainty evidence. There were moderate to high degrees of heterogeneity in these analyses but in meta-regression, definite
reasons for this could not be determined.
Authors' conclusions
The included studies provide low certainty evidence that IV iron compared with oral iron increases haemoglobin, ferritin and transferrin
levels in CKD participants, increases the number of participants who achieve target haemoglobin and reduces ESA requirements. However,
there is insuicient evidence to determine whether IV iron compared with oral iron influences death (all causes), cardiovascular death and
quality of life though most studies reported only short periods of follow-up. Adverse eects were reported in only 50% of included studies.
We therefore suggest that further studies that focus on patient-centred outcomes with longer follow-up periods are needed to determine
if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious
adverse eects.
P L A I N  L A N G U A G E  S U M M A R Y
Iron treatment for adults and children with reduced kidney function
What is the issue?
Anaemia (reduction in the number of circulating red blood cells) oen occurs in people who have kidney damage, especially those who
need dialysis treatment. Anaemia can cause tiredness, reduce exercise tolerance and increase heart size. A common cause of anaemia is
reduced production of a hormone, erythropoietin. Iron deficiency can make anaemia worse, and reduce the response to medications that
stimulate erythropoietin production. Iron can be taken orally (by mouth) or injected intravenously (via a vein). Intravenous (IV) iron is given
under supervision in hospitals. There is uncertainty about whether IV iron should be used rather than oral iron.
What did we do?
We reviewed 39 studies (3852 participants) which compared IV iron supplements with oral iron in participants with chronic kidney disease.
What did we find?
We found that IV iron may increase blood levels of haemoglobin and iron compared with oral iron. However, IV iron may increase the
number of allergic reactions though it may reduce side eects such as constipation, diarrhoea, nausea and vomiting seen with oral iron.
We did not find suicient evidence to determine whether IV iron compared with oral iron improved quality of life, altered overall death
rate or death due to heart disease.
Conclusions
Parenteral versus oral iron therapy for adults and children with chronic kidney disease (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Although the results suggest that IV iron compared with oral iron may be more eective in raising iron and haemoglobin levels, we found
insuicient data to determine if the benefits of IV iron are justified by improved quality of life or mortality despite the small risk of potentially
serious allergic eects in some patients given IV iron.
Parenteral versus oral iron therapy for adults and children with chronic kidney disease (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3

Citations
More filters
Journal ArticleDOI
TL;DR: The clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment are discussed.

953 citations

Journal ArticleDOI
17 Nov 2015-JAMA
TL;DR: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose, and the risk following total iron repletion of 1000 mg administered within a 12-week period was highest.
Abstract: Importance All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established. Objective To compare the risk of anaphylaxis among marketed IV iron products. Design, Setting, and Participants Retrospective new user cohort study of IV iron recipients (n = 688 183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. Exposures Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data. Main Outcomes and Measures Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups. Results A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100 000 persons for iron dextran (95% CI, 57.8-78.7 per 100 000) and 24 per 100 000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100 000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P Conclusions and Relevance Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

166 citations


Cites background from "Parenteral versus oral iron therapy..."

  • ...Prespecified sensitivity analyses examined the robustness of the results to variations in the outcome definition, including (1) anaphylaxis cases diagnosed up to 2 days after IV iron administration, (2) anaphylaxis or death occurring on the same day as IV iron administration, (3) cases only meeting anaphylaxis criteria A and B as defined in eAppendix 1 in the Supplement, and (4) restricting the population to patients with Medicare Part D information to account for potential imbalance on relevant concomitant medications....

    [...]

Journal ArticleDOI
TL;DR: This is the third edition of the guidelines for renal anemia published by the JSDT, and the purpose is to improve the prognosis of chronic kidney disease patients, including after renal transplantation, through the treatment of renalAnemia.
Abstract: Renal anemia is a complication of chronic kidney disease. Guidelines for safe and effective treatment in patients with renal anemia are needed. The Japanese Society for Dialysis Therapy (JSDT) published guidelines for the treatment of renal anemia in chronic hemodialysis patients in 2004 and in hemodialysis, peritoneal dialysis, predialysis, and pediatric patients in 2008. These two publications provide excellent guidance with respect to clinical practice issues, including the definition and diagnosis of renal anemia, the criteria for the initiation of treatment, target hemoglobin levels, iron supplementation therapy, blood transfusion, and side effects. The guidelines significantly improved the treatment of renal anemia in Japan. However, since 2008, many studies have assessed the treatment of renal anemia, and erythropoiesis-stimulating agents (ESAs) are now available. Therefore, the Executive Board of the JSDT decided that it was time to revise the guidelines to make them more appropriate to the situation of chronic kidney disease patients in Japan. This is the third edition of the guidelines for renal anemia published by the JSDT. The purpose is to improve the prognosis of chronic kidney disease patients, including after renal transplantation, through the treatment of renal anemia. The intended users of the guidelines are all healthcare professionals engaged in the treatment of chronic kidney disease. Regarding the treatment of adult dialysis and predialysis patients, statements and commentary are provided in the context of answers to clinical questions in Chapter 2 (Target Hb level and criteria for starting renal anemia treatment) and Chapter 4 (Evaluation of iron status and iron therapy). Furthermore, the essential information is provided alongside the critical issues in Chapter 1 (Diagnosis of renal anemia), Chapter 3 (Administration of ESAs—administration route and dose), Chapter 5 (ESA hyporesponsiveness), Chapter 6 (Side effects and concomitant symptoms of ESAs), and Chapter 7 (Red blood cell transfusion). In addition, the treatment of pediatric patients and post-renal transplant patients is discussed in Chapter 8 and Chapter 9, respectively.

131 citations


Cites background from "Parenteral versus oral iron therapy..."

  • ...deterioration of absorption, low compatibility with other agents, and digestive symptoms including nausea and vomiting [148]....

    [...]

Journal ArticleDOI
TL;DR: A systematic review of PubMed database, Cochrane Database of systemic reviews and international guidelines on diagnosis and clinical management of ID from 2010 to 2016 showed that serum ferritin and transferrin saturation are the key tests in early decision-making process to identify iron deficiency anemia.

76 citations


Cites background from "Parenteral versus oral iron therapy..."

  • ...In CKD, iron oral supplementation is recommended in patients with IDA not receiving ESAs and not on HD [66]....

    [...]

Journal ArticleDOI
TL;DR: Individualization of hemoglobin targets using EPO-stimulating agents and iron supplementation may be considered in younger, healthier patients with kidney disease to improve health-related quality of life.
Abstract: Purpose of reviewThis review describes the current state of anemia management with erythropoietin (EPO)-stimulating agents and iron supplementation in both chronic kidney disease and dialysis patients, with a focus on novel therapies.Recent findingsWe review the benefits and risks of EPO-stimulating

21 citations

References
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Journal ArticleDOI
TL;DR: The included studies provide strong evidence for increased ferritin and transferrin saturation levels, together with a small increase in haemoglobin, in patients with CKD who were treated with IV iron compared with oral iron.
Abstract: Background The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through different routes, with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV) compared with oral iron are justified. Objectives To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD. Search methods In March 2010 we searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE and EMBASE without language restriction. Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs in which oral and IV routes of iron administration were compared in adults and children with CKD. Data collection and analysis Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes and for continuous outcomes the mean difference (MD) was used or standardised mean difference (SMD) if different scales had been used. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed to investigate between study differences. Main results Twenty eight studies (2098 participants) were included. Risk of bias attributes were poorly performed and/or reported with low risk of bias reported in 12 (43%) studies for sequence generation, incomplete outcome reporting and selective outcome reporting and in 6 (16%) studies for allocation concealment. No study was blinded for participants, investigators and outcome assessors but all were considered at low risk of bias because the primary outcome of haemoglobin was a laboratory outcome and unlikely to be influenced by lack of blinding. Haemoglobin (22 studies, 1862 patients: MD 0.90 g/dL, 95% CI 0.44 to 1.37); ferritin (24 studies, 1751 patients: MD 243.25 μg/L, 95% CI 188.74 to 297.75); and transferrin saturation (18 studies, 1457 patients: MD 10.20%, 95% CI 5.56 to 14.83) were significantly increased by IV iron compared with oral iron. There was a significant reduction in erythropoiesis-stimulating agent (ESA) dose in patients receiving dialysis who were treated with IV iron (9 studies, 487 patients: SMD -0.76, 95% CI -1.22 to -0.30). There was a high level of heterogeneity in all analyses. Mortality and cardiovascular morbidity did not differ significantly, but were reported in few studies. Gastrointestinal side effects were more common with oral iron, but hypotensive and allergic reactions were more common with IV iron. Authors' conclusions The included studies provide strong evidence for increased ferritin and transferrin saturation levels, together with a small increase in haemoglobin, in patients with CKD who were treated with IV iron compared with oral iron. From a limited body of evidence, we identified a significant reduction in ESA requirements in patients treated with IV iron, and found no significant difference in mortality. Adverse effects were reported in only 50% of included studies. We therefore suggest that further studies that focus on patient-centred outcomes are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse effects.

150 citations

Frequently Asked Questions (1)
Q1. What are the contributions in "Parenteral versus oral iron therapy for adults and children with chronic kidney disease" ?

This is an update of a review first published in 2012. The authors searched the Cochrane Kidney and Transplant Register of Studies up to 7 December 2018 through contact with the Information Specialist using search terms relevant to this review. The included studies provide low certainty evidence that IV iron compared with oral iron increases haemoglobin, ferritin and transferrin levels in CKD participants, increases the number of participants who achieve target haemoglobin and reduces ESA requirements. The authors therefore suggest that further studies that focus on patient-centred outcomes with longer follow-up periods are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse eKects. The authors reviewed 39 studies ( 3852 participants ) which compared IV iron supplements with oral iron in participants with chronic kidney disease. The authors did not find suKicient evidence to determine whether IV iron compared with oral iron improved quality of life, altered overall death rate or death due to heart disease. Although the results suggest that IV iron compared with oral iron may be more eKective in raising iron and haemoglobin levels, the authors found insuKicient data to determine if the benefits of IV iron are justified by improved quality of life or mortality despite the small risk of potentially serious allergic eKects in some patients given IV iron. Controversies remain about the most eKective and safe way to provide iron supplementation in patients with CKD ( Fishbane 2007 ; Macdougall 2016 ). Why it is important to do this review Only half of the studies reported on adverse events. The authors felt it was important to update this review to ensure that patient focused adverse events were analysed as well as providing up to date evidence on the eKicacy and safety of IV iron. In this review, the authors aimed to explore all possible causes of heterogeneity of study results in detail by subgroup analysis and to further investigate the eKects of IV iron in patients with CKD who were not on dialysis. The review aimed to examine the eKects of these interventions on patient centred outcomes including death, requirements for transfusion, hospitalisation, cardiac function, quality of life and change in eGFR as well as iron parameters, achieving target levels of Hb, reducing doses of ESA required, and to determine adverse eKects of the therapies. M E T H O D S Criteria for considering studies for this review Types of studies The authors examined diKerent IV iron supplements ( including iron sucrose, dextran, ferric gluconate, ferric carboxymaltose, ferumoxytol ) and oral iron preparations ( including oral iron preparations which contain folic acid, vitamin C or both ). The authors included studies using diKerent doses and durations of IV iron compared with oral iron preparations provided that the control group received oral iron supplements only. The authors searched the Cochrane Kidney and Transplant Register of Studies up to 7 December 2018 through contact with the Parenteral versus oral iron therapy for adults and children with chronic kidney disease ( Review ) Copyright © 2019 The Cochrane Collaboration. Cochrane Database of Systematic Reviews Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources. See Appendix 1 for search terms used in strategies for this review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable. Data extraction and management Data extraction and assessment of the risk of bias were performed independently by the same authors using standardised data extraction forms. Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review. The following items were assessed independently by two authors using the risk of bias assessment tool ( Higgins 2011 ) ( see Appendix 2 ). • Was knowledge of the allocated interventions adequately prevented during the study ? Are reports of the study free of suggestion of selective outcome reporting ( reporting bias ) ? • Was the study apparently free of other problems that could put it at a risk of bias ? When both measures are provided in a study, final levels were included. Therefore, only data from the first period of cross-over studies were included where these were reported separately, and included all or most patients who completed the first period, rather than only those who completed both treatment periods. Where necessary, the authors contacted triallists to request missing patient data due to loss to follow-up and exclusion from study analyses in an eKort to conduct intention-to-treat analyses. Where possible the authors imputed missing standard deviations and standard errors if data was presented alternatively, using methods stated in the Cochrane handbook ( Higgins 2011a ). When suKicient studies were available, the authors created funnel plots and calculated Eggers ' test to assess publication bias. However, all publications were reviewed to identify outcomes not reported in the index publication in an attempt to reduce outcome reporting bias. To explore clinical diKerences among studies that could influence the magnitude of the treatment eKect for the outcomes of diKerences in ferritin, TSAT and Hb, subgroup analyses and univariate meta-regression were performed using STATA soPware ( StataCorp LP, Texas, USA ) using restricted maximum-likelihood to estimate between study variance. The potential sources of variability were defined a priori and were related to study rationale ( CKD stage, whether aiming to increase or maintain Hb, concurrent use of erythropoietin co-intervention, timing of initiation of erythropoietin co-intervention ), dose delivered and duration of IV and oral iron therapy, and study sponsorship. Where subgroup analysis findings suggested that more than one factor could influence the magnitude of observed diKerences, the authors planned to conduct multivariate meta-regression. Sensitivity analysis Sensitivity analyses were performed to test decisions where inclusion of a study, with a much higher MD in Hb, might have altered meta-analysis results. The authors presented the main results of the review in 'Summary of findings ' tables. These tables present key information concerning the quality of the evidence, the magnitude of the eKects of the interventions examined, and the sum of the available data for the main outcomes ( Schünemann 2011a ). The authors presented the following outcomes in the 'Summary of findings ' tables. The initial study resulted in a total of 522 study reports from the Cochrane Kidney and Transplant Specialised Register to March 2010, CENTRAL ( in The Cochrane Library Issue 1, 2010 ), MEDLINE ( to October week 5, 2008 ) and EMBASE ( to week 45, 2008 ). For the 2019 update of this review, a search of the Cochrane Kidney and Transplant Specialised Register identified 49 new reports. From these the authors identified 11 new included studies ( 31 reports ) ( Agarwal 2015 CKD ; FIND-CKD 2014 CKD ; Kalra 2016 CKD ; Lu 2010 CKD ; Mudge 2009 TX ; Nagaraju 2013 CKD ; NCT01155375 HD, PD, CKD ; Pisani 2014 CKD ; Ragab 2007 HD ; Tsuchida 2010 HD ; Winney 1977 HD ), three new excluded studies ( 4 reports ) and 14 additional reports of previously included studies.. The additional reports included the full publication of Qunibi 2011 CKD. The paediatric study ( NCT01155375 HD, PD, CKD ) was terminated because of challenges with enrolment with minimal data reported. Spinowitz 2008 CKD included all nine reports, which included data for one new included study ( Lu 2010 CKD ). This 2019 update contains 44 studies ( 101 reports ). The 11 new included studies ( 31 reports ) provided an additional 1754 participants bringing the total to 3852 participants. Of the 39 included studies, 38 ( 3832 participants ) were parallel group studies, and one ( 20 patients ) was a cross-over study ( Strickland 1977 HD ). The duration of follow-up ranged from 35 days to 26 months. The IV iron agent was not reported in Kotaki 1997 HD. ESA therapy was started at study commencement in six studies ( Aggarwal 2003 CKD ; Charytan 2005 CKD ; Hussain 1998 HD ; Lye 2000 HD ; Macdougall 1996 HD, PD, CKD ; Stoves 2001 CKD ) and before study commencement in 15 studies ( Broumand 1998 HD ; Erten 1998 HD ; Fishbane 1995 HD ; Kotaki 1997 HD ; Leehey 2005 CKD ; Li 2008 HD ; Li 2008 PD ; Macdougall 1999 HD, PD ; Michael 2007 HD ; Mudge 2009 TX ; Provenzano 2009 HD ; Ragab 2007 HD ; Svara 1996 HD ; Tsuchida 2010 HD ; Warady 2002 HD ). The outcomes reported in 38 studies are presented in Figure 1. From the 2012 review, twenty-three reports were excluded based on titles and abstracts ; one study was not an RCT and the remainder involved ineligible interventions. There is insuKicient evidence to suggest that IV iron compared with oral iron makes any diKerence to death ( all causes ) ( 11 studies, 1952 participants: RR 1. 12, 95 % CI 0. 64, 1. 94 ) ( absolute eKect: 33 participants per 1000 with IV iron versus 31 per 1000 with oral iron ), the number of participants needing to start dialysis ( 4 studies, 743 participants: RR 0. 81, 95 % CI 0. 41, 1. 61 ) or the number needing blood transfusions ( 5 studies, 774 participants: RR 0. 86, 95 % CI 0. 55, 1. 34 ) ( absolute eKect: 87 per 1,000 with IV iron versus 101 per 1,000 with oral iron ). The most recent guidelines ( KDIGO 2012 ) suggest that the Hb in adult CKD patients should not exceed 11. The majority of the literature to date supports these associations although the most recent cohort study of nearly 23,000 HD patients suggested no diKerence in length of stay, death or readmission for infection in those who received IV iron during admission and those who did not ( Ishida 2015 ). Furthermore there is increasing evidence that free iron plays a role in direct injury to kidney tissue, which could result in more rapid deterioration in kidney function ( Shah 2011 ). The search strategy described was used to obtain titles and abstracts of studies that were potentially relevant to the review. One new report contained further information on two already included studies ( Li 2008 HD ; Li 2008 PD ).