Macdougall IC, White C, Anker SD, Bhandari S, Farrington K, Kalra PA, McMurray JJV, Murray H, Tomson CRV, Wheeler DC, Winearls CG, and Ford I, for the PIVOTAL Investigators and Committees. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis. N Engl J Med 2019; 380:447-458.
Sang Hong Baek, Professor of Cardiology, Catholic University of Korea, Seoul
The PIVOTAL Trial
Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited.
The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial is a prospective, randomized, open-label, blinded end-point, controlled trial at 50 sites in the United Kingdom. The authors randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 μg/L or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0-400 mg monthly, with a ferritin concentration of <200 μg/L or a transferrin saturation of <20% being a trigger for iron administration).
A total of 2141 patients underwent randomization (1093 patients in the high-dose group and 1048 in the low-dose group). The median follow-up was 2.1 years. Patients in the high-dose group received a median monthly iron dose of 264 mg (interquartile range [25th to 75th percentile], 200 to 336), as compared with 145 mg (interquartile range, 100 to 190) in the low-dose group. The median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group (median difference, -7539 IU; 95% confidence interval [CI], -9485 to -5582). A total of 320 patients (29.3%) in the high-dose group had a primary end-point event, as compared with 338 (32.3%) in the low-dose group (hazard ratio, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). In an analysis that used a recurrent-events approach, there were 429 events in the high-dose group and 507 in the low-dose group (rate ratio, 0.77; 95% CI, 0.66 to 0.92). The infection rate was the same in the two groups.
- In contrast to the observational studies, the results of PIVOTAL trial showed that the use of a proactive high-dose intravenous iron regimen was superior to the use of a reactive low-dose intravenous iron regimen and was associated with a significant lower risk of death or major nonfatal cardiovascular events.
- The patients who received high-dose iron therapy had fewer blood transfusions and received significant lower doses of erythropoiesis-stimulating agents to maintain target hemoglobin levels than those in the low-dose group. And patients in the high-dose group also had a faster increase in the hemoglobin level.The absence of a greater risk of infection with the high-dose intravenous iron regimen is clinically important.
- The strengths of PIVOTAL trial include its sample size and 2.1-year long term follow-up study. And the limited exclusion criteria that allowed for the enrollment of a cohort of patients representative of those seen in a real world routine clinical practice.
- Limitations of the trial include a single country study, the generalizability of this new clinical trial informations to dialysis populations worldwide is unclear. The open-label nature of the trial may have potentially biased the rates of blood transfusion. And, the safety of this proactive high-dose iron regimen cannot be confirmed beyond the duration of the current clinical trial.