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Meta-Analysis
. 2019 Dec 20;12(12):CD013084.
doi: 10.1002/14651858.CD013084.pub2.

Intravenous iron therapy for non-anaemic, iron-deficient adults

Lachlan F Miles  1 , Edward Litton  2 , Georgina Imberger  3 , David Story  4
Affiliations
Meta-Analysis

Intravenous iron therapy for non-anaemic, iron-deficient adults

Lachlan F Miles et al. Cochrane Database Syst Rev. .

Abstract

Background: Iron deficiency is one of the most common nutritional deficiencies, and has a number of physiological manifestations. Early, or non-anaemic iron deficiency can result in fatigue and diminished exercise capacity. Oral iron preparations have a high incidence of intolerable side effects, and are ineffective in certain forms of iron deficiency. Consequently, intravenous iron preparations are increasingly used in the treatment of non-anaemic iron deficiency. The newer, more stable iron preparations in particular purport to have a lower incidence of side effects, and are now used across a range of different patient populations.

Objectives: To assess the effects of intravenous iron therapy in the treatment of adults with non-anaemic iron deficiency.

Search methods: On 18 October 2019 we electronically searched CENTRAL, MEDLINE, Embase, two further databases and two trials registries 2019. We handsearched the references of full-text extracted studies, and contacted relevant study authors for additional data.

Selection criteria: We included randomised controlled trials that compared any intravenous iron preparation to placebo in adults. We excluded other forms of comparison such as oral iron versus placebo, intramuscular iron versus placebo, or intravenous iron studies where other iron preparations were used as the comparator. We also excluded studies involving erythropoietin therapy or obstetric populations.

Data collection and analysis: Two review authors screened references for eligibility, extracted data and assessed risk of bias. We resolved differences in opinion through discussion and consensus, and where necessary, involved a third review author to adjudicate disputes. We contacted study authors to request additional data where appropriate. The primary outcome measures were haemoglobin concentration at the end of follow-up, and quality-of-life scores at end of follow-up. Secondary outcome measures were serum ferritin, peak oxygen consumption (as measured by cardiopulmonary exercise testing), adverse effects (graded as mild to moderate and severe) and bacterial infection. We pooled data for continuous outcomes, which we then reported as mean differences (MDs) with 95% confidence intervals (CIs). We reported quality-of-life metrics as standardised mean difference (SMD), and then converted them back into a more familiar measure, the Piper Fatigue Scale. We analysed dichotomous outcomes as risk ratios (RRs). Given an expected degree of heterogeneity, we used a random-effects model for all outcomes. We performed the analysis with the software package Review Manager 5.

Main results: This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I2 = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I2 = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI -0.89 to 6.43; I2 = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size.

Authors' conclusions: Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.

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Conflict of interest statement

LFM: the institution of the author has received in‐kind and unrestricted financial support for two currently running studies from Vifor Pharma Pty Ltd. The author has not personally received any honoraria or speaking fees from any company. No other conflicts of interest.

EL: the institution of the author has received in‐kind support for a study from Vifor Pharma Pty Ltd (Litton 2016). The author has not personally received any honoraria or speaking fees from any company. No other conflicts of interest.

GI: none known

DS: the institution of the author has received in‐kind and unrestricted financial support for two currently running studies from Vifor Pharma Pty Ltd. The author has not personally received any honoraria or speaking fees from any company. No other conflicts of interest.

Figures

1
1
Flow diagram of studies included in the systematic review
2
2
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
3
3
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Intravenous iron versus placebo (population), Outcome 1 Haemoglobin concentration taken at the end of follow‐up.
1.2
1.2. Analysis
Comparison 1 Intravenous iron versus placebo (population), Outcome 2 Overall quality of life measured at the end of follow‐up.
1.3
1.3. Analysis
Comparison 1 Intravenous iron versus placebo (population), Outcome 3 Ferritin concentration taken at the end of follow‐up.
1.4
1.4. Analysis
Comparison 1 Intravenous iron versus placebo (population), Outcome 4 Peak oxygen consumption taken at the end of follow‐up.
1.5
1.5. Analysis
Comparison 1 Intravenous iron versus placebo (population), Outcome 5 Mild adverse effects.
2.1
2.1. Analysis
Comparison 2 Intravenous iron versus placebo (time to end of follow‐up), Outcome 1 Haemoglobin concentration taken at the end of follow‐up.
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References to other published versions of this review

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