Are We Recruiting an Army for Magneto? Optimizing Iron Utilization in Hemodialysis

Proactive IV Iron Therapy for Hemodialysis Patients (PIVOTAL)

None (this is a European trial)

2013-002267-25.

King's College Hospital NHS Foundation Trust

Multicenter, prospective, open-label, randomized controlled trial

2,080

50 clinics in the United Kingdom

2,080

PIVOTAL is a multicenter, prospective, open-label, randomized controlled trial investigating the effects of two different doses of intravenous (IV) iron in patients with chronic kidney disease on hemodialysis. The primary study endpoint is to compare the effect of a proactive high-dose IV iron regimen with a reactive low-dose IV iron regimen on all-cause mortality and the incidence of nonfatal cardiovascular events (myocardial infarction, stroke, and hospitalization for heart failure) in patients on hemodialysis. Secondary endpoints include the comparison of the two regimens on erythropoiesis-stimulating agent (ESA) dose requirements, red blood cell transfusion requirements, complications of hemodialysis treatment, and patient quality of life. Safety concerns of IV iron will be analyzed by incidence of vascular access thrombosis, hospitalization for infection, and infectious episodes. Researchers will recruit and randomly assign 2,080 hemodialysis patients from 50 clinics to one of two treatment arms. Patients assigned to the proactive arm will receive 400 mg/month IV iron sucrose, unless their ferritin is >700 µg/L and transferrin saturation (TSAT) is greater than 40 percent. Patients assigned to the reactive arm will receive low-dose IV iron sucrose only if the ferritin is <200 μg/L and TSAT is <20 percent. Eligible patients are at least 18 years old and newly established (<12 months duration) on hemodialysis for end-stage renal failure receiving an ESA for anemia, and with a ferritin level less than 400 μg/L and TSAT lower than 30 percent. Patients with limited life expectancy or awaiting a renal transplant within the next 12 months are excluded from the study.

IV iron utilization has increased and ESA utilization has decreased in the United States’ hemodialysis patient population in recent years. A number of factors are associated with these trends. Several trials raised concerns about the safety of ESA dosing in those with renal failure.^1-4  These studies led to labeling revisions; concurrently, the U.S. Centers for Medicare and Medicaid Services introduced a bundled payment methodology for dialysis services, including ESA and IV iron, which were previously separately billable (providing incentives to reduce utilization of high-cost items such as ESAs). IV iron treatment, even with high levels of serum ferritin, results in increased hemoglobin levels and reduced ESA dose requirements and cost of care.⁵  Prior observational studies confirming the safety of IV iron in this setting have produced conflicting results, and moreover, have largely studied outcomes in patients treated at a time when lower cumulative iron doses were used.^6,7  Large randomized clinical trials of various doses of IV iron confirming the safety of this more aggressive IV iron repletion and improvement in patient-centered outcomes such as mortality, hospitalization, infectious risk, and quality of life, are lacking. Additionally, IV iron has been implicated in potentially causing oxidative stress and inflammation, as well as endothelial and immune dysfunction. The Dialysis Outcomes and Practice Patterns Study, a recent observational study using data obtained as part of the international prospective cohort study of hemodialysis patients 18 years or older, found all-cause mortality elevated among patients receiving IV iron doses higher than 300 mg/month with hemoglobin levels measured 10 g/dL or greater.⁸  In light of these uncertainties and associations, well-designed clinical trials are needed to evaluate the safety of different IV iron dosing strategies in hemodialysis patients.

IV iron utilization in hemodialysis patients has increased over time, and higher iron utilization is associated with higher iron stores. The mean serum ferritin of U.S. patients on hemodialysis increased from 300 to 600 ng/mL from 1993 to 2010 and to 799 ng/mL in 2014.⁹  One large study of hemodialysis patients receiving ESAs and intravenous iron dosed in keeping within current guidelines, demonstrated hepatic iron overload on MRI in the majority of patients.¹⁰  Despite this pattern of increased iron utilization, neither the risks nor the benefits of IV iron treatment in hemodialysis patients receiving ESAs are understood sufficiently. The PIVOTAL study will begin to address this fundamental gap in knowledge and should help inform practice not only in the United Kingdom, but also in the United States and elsewhere.