Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data

Abstract

Background: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. Methods: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin < 400 µg/L and transferrin saturation (TSAT) levels < 30% receiving erythropoiesis-stimulating agents (ESA) were eligible. Enrolled patients were randomized to a proactive, high-dose IV iron arm (iron sucrose 400 mg/month unless ferritin > 700 µg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 µg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2–4 years. Results: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. Conclusions: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. Trial Registration: EudraCT number: 2013-002267-25.

Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases

“…Moreover, hardly any information from prospective trials is available regarding optimal therapeutic targets (e.g., hemoglobin or ferritin levels), which, however, may be different according to the underlying disease. One pioneering study (PIVOTAL for Proactive IV Iron Therapy in Hemodialysis Patients) addressed some of these end-points (risk of death, major adverse cardiovascular events, and infection) in patients undergoing hemodialysis and has just been published [149,150]. A high-dose regimen of i.v.…”

Protocol and Baseline Data of a Multicentre Prospective Double-Blinded Randomized Study of Intravenous Iron on Functional Status in Patients with Chronic Kidney Disease

“…Furthermore, 43% of patients with identified anaemia and 15% of those without anaemia from the total cohort had iron and/or folate deficiency and survival was worse in deficient patients [3]. Hence, iron may be an important substrate for optimal cardiac function and reduction in cardiac risk as noted in the recent PIVOTAL study [4].…”

Economic Evaluation of Ferric Carboxymaltose for the Management of Hemodialysis Patients with Iron Deficiency Anemia in Italy

“…The PIVOTAL trial [16], the largest prospective randomized study, recruiting 2171 HD patients, has recently provided important safety results. This study has demonstrated, for the first time, that the use of a liberal, proactive higher dose IS regimen [aimed at targeting higher ferritin and transferrin saturation (TSAT) values] was superior to the use of a low-dose, reactive IS regimen and was associated with a lower risk of major cardiovascular events (acute myocardial infarction, stroke, hospitalization for heart failure or mortality) and did not increase the risk of all-cause mortality.…”