Risk of Infection Associated With Administration of Intravenous Iron

Abstract

IMPORTANCEIntravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain. OBJECTIVE To examine the risk of infection associated with intravenous iron compared with oral iron or no iron. DATA SOURCES Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform. STUDY SELECTION Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility. DATA EXTRACTION AND SYNTHESIS Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection. MAIN OUTCOMES AND MEASURESThe primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences.RESULTS A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I 2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I 2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I 2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay. (continued) Key Points Question In patients who require treatment with intravenous iron, what is the evidence that this intervention increases the risk of developing a new infection? Findings In this systematic review and meta-analysis of 154 randomized clinical trials that included 32 920 participants, intravenous iron was associated with an increased risk of infection. Meaning The results of this study suggest that, despite broad advocacy in clinical guidelines, intravenous iron may increase the risk of infection, which must be balanced with the potential benefits of treating anemia and reducing blood transfusion requirements.

Rationale and design of a randomised trial of intravenous iron in patients with heart failure

“… 17 A meta-analysis of studies across a broad range of conditions found that intravenous iron was associated with an increased risk of infection (rate ratio (RR) 1.17; 95% CI 1.04 to 1.31). 8 This was not confirmed across heart failure studies. Most studies did not define infection a priori, and the authors note potential bias.…”

“…Labile (free) iron can result in the generation of reactive oxygen species, which could lead onto oxidative stress and cell damage 17. A meta-analysis of studies across a broad range of conditions found that intravenous iron was associated with an increased risk of infection (rate ratio (RR) 1.17; 95% CI 1.04 to 1.31) 8. This was not confirmed across heart failure studies.…”

“…Major gaps in our knowledge remain, including the long-term benefits and safety of repeated administration of intravenous iron. Although the rationale for benefit is clear, bypassing evolutionary systems that have evolved to prevent iron overload also poses theoretical risks, including increased oxidative stress, mitochondrial damage and infection 8. These theoretical risks should be confirmed or refuted by clinical evidence.…”

“…Although the rationale for benefit is clear, bypassing evolutionary systems that have evolved to prevent iron overload also poses theoretical risks, including increased oxidative stress, mitochondrial damage and infection. 8 These theoretical risks should be confirmed or refuted by clinical evidence. The Effectiveness of I nt r avenous ir on treat m ent versus standard care in p a tie n ts with heart failure and iron deficiency (IRONMAN) trial was designed and conducted in the UK to investigate the benefits and safety of repeated doses of intravenous ferric derisomaltose over an extended period, which should help inform clinical practice and international guidelines.…”

Errors in Data

“…In the Original Investigation titled “Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis,” 1 published November 12, 2021, the number of participants and the number of infection events in each group were incorrectly recorded. Once corrected, the overall point estimate for the risk of infection changed from a relative risk of 1.17 (95% CI, 1.04-1.13, I 2 = 37%) to 1.16 (95% CI, 1.03-1.29, I 2 = 36%).…”