Safety of Dynamic Intravenous Iron Administration Strategies in Hemodialysis Patients

Abstract

Background and objectives: Intravenous iron therapy for chronic anemia management is largely driven by dosing protocols that differ in intensity with respect to dosing approach (i.e., dose, frequency, and duration). Little is known about the safety of these protocols.

Design, setting, participants, & measurements: Using clinical data from a large United States dialysis provider linked to health care utilization data from Medicare, we constructed a cohort of patients with ESKD aged ≥65 years who initiated and continued center-based hemodialysis for ≥90 days between 2009 and 2012, and initiated at least one of the five common intravenous iron administration strategies; ranked by intensity (the amount of iron given at moderate-to-high iron indices), the order of strategies was 3 (least intensive), 2 (less intensive), 1 (reference), 4 (more intensive), and 5 (most intensive). We estimated the effect of continuous exposure to these strategies on cumulative risks of mortality and infection-related events with dynamic Cox marginal structural models.

Results: Of 13,249 eligible patients, 1320 (10%) died and 1627 (12%) had one or more infection-related events during the 4-month follow-up. The most and least commonly initiated strategy was strategy 2 and 5, respectively. Compared with the reference strategy 1, more intensive strategies (4 and 5) demonstrated a higher risk of all-cause mortality (e.g., most intensive strategy 5: 60-day risk difference: 1.3%; 95% confidence interval [95% CI], 0.8% to 2.1%; 120-day risk difference: 3.1%; 95% CI, 1.0% to 5.6%). Similarly, higher risks were observed for infection-related morbidity and mortality among more intensive strategies (e.g., strategy 5: 60-day risk difference: 1.8%; 95% CI, 1.2% to 2.6%; 120-day risk difference: 4.3%; 95% CI, 2.2% to 6.8%). Less intensive strategies (2 and 3) demonstrated lower risks of all-cause mortality and infection-related events.

Conclusions: Among dialysis patients surviving 90 days, subsequent intravenous iron administration strategies promoting more intensive iron treatment at moderate-to-high iron indices levels are associated with higher risks of mortality and infection-related events.

Keywords: Administration, Intravenous; Confidence Intervals; Iron; Kidney Failure, Chronic; Medicare; Proportional Hazards Models; anemia; anemia management; comparative safety; dialysis; endstage kidney disease; hemodialysis patients; infections; intravenous iron administration strategies; mortality.

Graphical abstract

Figure 1.

Study design for assessing the effect of initiating and staying on a particular dynamic IV iron administration strategy. Patients are followed starting on the end of the first 14-day iron strategy assessment window (the gray block) for all-cause mortality or infection-related events. Those deviated from their index strategy are censored at the end of current assessment window.

Figure 2.

After adjustment for baseline confounding and strategy deviation in the follow-up, higher cumulative risks of all-cause mortality were associated with more intense strategies compared with the reference strategy 1 in the 4-month follow-up. These RDs represent differences in risks of all-cause mortality if strategy 1 users, contrary to fact, initiated and stayed on another intravenous iron strategy instead of initiating and staying on strategy 1 during the 120-day follow-up.

Figure 3.

After adjustment for baseline confounding and strategy deviation in the follow-up, higher cumulative risks of infection-related events were associated with more intense strategies compared with the reference strategy 1 in the 4-month follow-up. These RDs represent differences in risks of infection-related events if strategy 1 users, contrary to fact, initiated and stayed on another intravenous iron strategy instead of initiating and staying on strategy 1 during the 120-day follow-up.