High-dose intravenous iron reduces myocardial infarction in patients on haemodialysis.

AIMS: To investigate the effect of high-dose iron vs. low-dose intravenous (IV) iron on myocardial infarction (MI) in patients on maintenance haemodialysis. METHODS AND RESULTS: This was a pre-specified analysis of secondary endpoints of the Proactive IV Iron Therapy in Hemodialysis Patients trial (PIVOTAL) randomized, controlled clinical trial. Adults who had started haemodialysis within the previous year, who had a ferritin concentration <400 µg per litre and a transferrin saturation <30% were randomized to high-dose or low-dose IV iron. The main outcome measure for this analysis was fatal or non-fatal MI. Over a median of 2.1 years of follow-up, 8.4% experienced a MI. Rates of type 1 MIs (3.2/100 patient-years) were 2.5 times higher than type 2 MIs (1.3/100 patient-years). Non-ST-elevation MIs (3.3/100 patient-years) were 6 times more common than ST-elevation MIs (0.5/100 patient-years). Mortality was high after non-fatal MI (1- and 2-year mortality of 40% and 60%, respectively). In time-to-first event analyses, proactive high-dose IV iron reduced the composite endpoint of non-fatal and fatal MI [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.52-0.93, P = 0.01] and non-fatal MI (HR 0.69, 95% CI 0.51-0.93; P = 0.01) when compared with reactive low-dose IV iron. There was less effect of high-dose IV iron on recurrent MI events than on the time-to-first event analysis. CONCLUSION: In total, 8.4% of patients on maintenance haemodialysis had an MI over 2 years. High-dose compared to low-dose IV iron reduced MI in patients receiving haemodialysis. EUDRACT REGISTRATION NUMBER: 2013-002267-25.

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy.

OBJECTIVES: This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients. BACKGROUND: Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat. METHODS: The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial. RESULTS: Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event. CONCLUSIONS: Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).

Stroke in Hemodialysis Patients Randomized to Different Intravenous Iron Strategies: A Prespecified Analysis from the PIVOTAL Trial.

Background: People with kidney failure treated with hemodialysis (HD) are at increased risk of stroke compared with similarly aged people with normal kidney function. One concern is that treatment of renal anemia might increase stroke risk. We studied risk factors for stroke in a prespecified secondary analysis of a randomized, controlled trial of intravenous iron treatment strategies in HD. Methods: We analyzed data from the Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial, focusing on variables associated with risk of stroke. The trial randomized 2141 adults who had started HD <12 months earlier and who were receiving an erythropoiesis-stimulating agent (ESA) to high-dose IV iron administered proactively or low-dose IV iron administered reactively in a 1:1 ratio. Possible stroke events were independently adjudicated. We performed analyses to identify variables associated with stroke during follow-up and assessed survival following stroke. Results: During a median 2.1 years of follow-up, 69 (3.2%) patients experienced a first postrandomization stroke. Fifty-seven (82.6%) were ischemic strokes, and 12 (17.4%) were hemorrhagic strokes. There were 34 postrandomization strokes in the proactive arm and 35 postrandomization strokes in the reactive arm (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.44; P=0.66). In multivariable models, women, diabetes, history of prior stroke at baseline, higher baseline systolic BP, lower serum albumin, and higher C-reactive protein were independently associated with stroke events during follow-up. Hemoglobin, total iron, and ESA dose were not associated with risk of stroke. Fifty-eight percent of patients with a stroke event died during follow-up compared with 23% without a stroke. Conclusions: In patients on HD, stroke risk is broadly associated with risk factors previously described to increase cardiovascular risk in this population. Proactive intravenous iron does not increase stroke risk.Clinical Trial registry name and registration number: Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL), 2013-002267-25.

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

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.

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND: Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited. METHODS: In a multicenter, open-label trial with blinded end-point evaluation, we 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 per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 µg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25. RESULTS: A total of 2141 patients underwent randomization (1093 patients to the high-dose group and 1048 to 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. CONCLUSIONS: Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered. (Funded by Kidney Research UK; PIVOTAL EudraCT number, 2013-002267-25 .).

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

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.