Infectious complications and mortality associated with the use of IV iron therapy: a systematic review and meta-analysis

Background: Parental iron is used to optimize hemoglobin and enhance erythropoiesis in end-stage renal disease along with erythropoietin-stimulating agents. Safety of iron has been debated extensively and there is no definite evidence whether parenteral iron increases the risk of infections and mortality. We performed this meta-analysis to evaluate the incidence of infectious complications, hospitalizations and mortality with use of parenteral iron.

Methods: Medical electronic databases [PubMed, EMBASE, Scopus, Web of Science, and cochrane central register for controlled clinical trials (CENTRAL)] were queried for studies that investigated the association between intravenous iron administration and infection in hemodialysis patients. 24 studies (8 Randomized control trials (RCTs) and 16 observational studies) were considered for qualitative and quantitative analysis.

Results: All-cause mortality Data from 6 RCTs show that high-dose IV iron conferred 17% less all-cause mortality compared to controls; however, this outcome was not statistically significant (OR = 0.83, CI [0.7, 1.01], p = 0.07). Nine observational studies were pooled under the random effects model due to significant heterogeneity (I² = 83%, p < 0.001). The overall HR showed increased risk of all-cause mortality in the high-dose group but was statistically non-significant (HR = 1.1, CI [1, 1.22], p = 0.06). Infections Four RCTs with no heterogeneity among their data (I² = 0%, p = 0.61). Under the fixed effect model, there was no difference in the infection rate between high-dose iron and control group (OR = 0.97, CI [0.82, 1.16], p = 0.77); eight observational studies with significant heterogeneity and utilizing random effects model. Summary HR showed increased yet non-significant risk of infection in the high-dose group (HR = 1.13, CI [0.99, 1.28], p = 0.07) Hospitalization 1 RCT and six observational studies provided data for the rate of all-cause hospitalization. There was marked heterogeneity among observational studies. RCT showed no significant difference between high-dose iron and controls in the rate of hospitalization (OR = 1.03, CI [0.87, 1.23], p = 0.71). Summary HR for observational data showed increased rate of hospitalization in the high-dose group; however, this effect was not statistically significant (HR = 1.11, CI [0.99, 1.24], p = 0.07). Cardiovascular events One RCT compared the rate of adverse cardiovascular events between high-dose and low-dose iron. No significant difference was observed between the two groups (22.3% vs 25.6%, p = 0.12). Six heterogeneous observational studies (I² = 65%, p < 0.001) reported on the rate of cardiovascular events. No significant difference was observed between high-dose iron and controls (HR = 1.18, CI [0.89, 1.57], p = 0.24).

Conclusion: High-dose parenteral iron does not seem to be associated with higher risk of infection, all-cause mortality, increased hospitalization or increased cardiovascular events on analysis of RCTs. Observational studies show increased risk for all-cause mortality, infections and hospitalizations that were not statistically significant and were associated with significant heterogeneity.