Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial

Abstract

Background: Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis.

Methods: Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter).

Results: We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so via a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes.

Conclusions: The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.

Keywords: chronic kidney disease; hemodialysis; infections; intravenous iron; randomized controlled trial.

Graphical abstract

Figure 1.

Schematic representation of the methodology used in the analysis of the association between a recent infection and risk of a first cardiovascular event. Infection in the previous 30 days was used as a time-varying covariate in a Cox regression model adjusted for treatment group and baseline stratification variables (diabetes status, time on dialysis, and vascular access status). Scenarios for four different patients shown. CV, cardiovascular; Pt, patient.

Figure 2.

Comparison of number and percentage of events (expressed as HR) and number of recurrent events per 100 patient years (PY; expressed as rate ratio) for “all infections” and “hospitalization for infection” as well as number and percentage of fatal infections (expressed as HR) between the high-dose intravenous (IV) iron group and the low-dose IV iron group. *Expressed as HR; ^†expressed as rate ratio. For all endpoints there were near-identical rates of infection for the proactive high-dose and reactive low-dose groups in the study.

Figure 3.

Comparison of cumulative event curves between the high-dose intravenous iron group and the low-dose intravenous iron group for “all infections,” “hospitalization for infection,” and “death from infection.” For all three endpoints there were near-identical event curves for the proactive high-dose and reactive low-dose groups in the study.

Figure 4.

Comparison of cumulative event curves between patients dialyzing on a fistula only for the whole study versus those dialyzing on a catheter only for “all infections,” “hospitalization for infection,” and “death from infection.” Patients dialyzing on a catheter had a higher incidence of having any infection, a hospitalization for infection, and a fatal infection compared to those dialyzing on a fistula.

Figure 5.

Comparison of cumulative event curves between patients dialyzing on a fistula only for the whole study versus those dialyzing on a catheter only for “all infections,” “hospitalization for infection,” and “death from infection” shown separately for the high-dose group versus the low-dose group. For both groups, patients dialyzing on a catheter had a higher incidence of having any infection, a hospitalization for infection, and a fatal infection compared to those dialyzing on a fistula, but there was no effect of the treatment assignment arm.

Figure 6.

Forest plot showing HRs and interaction P values for “all infections” and “hospitalization for infection” for all subjects in the trial as well as separated according to patients dialyzing on a fistula only for the whole study versus those dialyzing on a catheter only. Data are adjusted for stratification variables (vascular access, diabetic status, and time on dialysis).

Figure 7.

Proportion of causal infectious organisms for all patients randomized in the PIVOTAL trial where an infectious agent was identified. Similar proportions of gram-positive organisms, gram-negative organisms, and viral agents were seen.