Impact of treating iron deficiency, diagnosed according to hepcidin quantification, on outcomes after a prolonged ICU stay compared to standard care: a multicenter, randomized, single-blinded trial

Abstract

Background Anemia is a significant problem in patients on ICU. Its commonest cause, iron deficiency (ID), is difficult to diagnose in the context of inflammation. Hepcidin is a new marker of ID. We aimed to assess whether hepcidin levels would accurately guide treatment of ID in critically ill anemic patients after a prolonged ICU stay and affect the post-ICU outcomes. Methods In a controlled, single-blinded, multicenter study, anemic (WHO definition) critically ill patients with an ICU stay ≥ 5 days were randomized when discharge was expected to either intervention by hepcidin treatment protocol or control. In the intervention arm, patients were treated with intravenous iron (1 g of ferric carboxymaltose) when hepcidin was < 20 μg/l and with intravenous iron and erythropoietin for 20 ≤ hepcidin < 41 μg/l. Control patients were treated according to standard care (hepcidin quantification remained blinded). Primary endpoint was the number of days spent in hospital 90 days after ICU discharge (post-ICU LOS). Secondary endpoints were day 15 anemia, day 30 fatigue, day 90 mortality and 1-year survival. Results Of 405 randomized patients, 399 were analyzed (201 in intervention and 198 in control arm). A total of 220 patients (55%) had ID at discharge (i.e., a hepcidin < 41 μg/l). Primary endpoint was not different (medians (IQR) post-ICU LOS 33(13;90) vs. 33(11;90) days for intervention and control, respectively, median difference − 1(− 3;1) days, p = 0.78). D90 mortality was significantly lower in intervention arm (16(8%) vs 33(16.6%) deaths, absolute risk difference − 8.7 (− 15.1 to − 2.3)%, p = 0.008, OR 95% IC, 0.46, 0.22–0.94, p = 0.035), and one-year survival was improved (p = 0.04). Conclusion Treatment of ID diagnosed according to hepcidin levels did not reduce the post-ICU LOS, but was associated with a significant reduction in D90 mortality and with improved 1-year survival in critically ill patients about to be discharged after a prolonged stay. Trial registration www.clinicaltrial.gov NCT02276690 (October 28, 2014; retrospectively registered)

Early Post-Hospitalization Hemoglobin Recovery and Clinical Outcomes in Survivors of Critical Illness: A Population-Based Cohort Study

“…One recent multicenter trial randomized approximately 400 patients with anemia during critical illness to receive intravenous iron therapy, with or without erythropoietin (EPO), at the time of ICU discharge versus standard care. 26 While there was no difference in the primary outcome of hospital length of stay, those in the intervention arm had a substantial reduction in 90-day mortality (8% vs. 17%). A similar trial of IV iron therapy delivered between ICU and hospital discharge is underway.…”

“…First, it is observational in design, and the presented associations do not represent causal relationships. To this end, impaired hemoglobin recovery after critical illness may be a marker of persistent chronic illness, and interventional trials, some of which have recently been completed or are ongoing, 26,27 are necessary to determine if anemia prevention, mitigation, or treatment strategies translate into improvement in post-hospitalization clinical outcomes. Second, 1-month hemoglobin data was not available in all critical illness survivors, which reflects the real-world experience of post-hospitalization follow-up; hence, our primary results are only applicable to those with available 1-month outpatient hemoglobin data.…”

Practical Anemia Bundle for Sustained Blood Recovery (PABST-BR) in critical illness: a protocol for a randomised controlled trial

“…5 Numerous clinical trials in critically ill patients have evaluated treatment of anaemia with iron and/or erythropoietin (EPO). [6][7][8][9][10][11] While these therapies have consistently augmented haemoglobin recovery, they have had inconsistent results on transfusion reductions and mortality and have not been widely adopted into clinical practice. However, there is increasing recognition that anaemia may contribute to persistent functional impairments after survival of hospitalisation.…”

“…Two recent trials suggest that intravenous iron, with or without EPO, may improve haemoglobin recovery after critical illness, with one trial showing lower 90-day mortality and the other showing reduced readmissions (secondary outcomes). 10 12 Importantly, anaemia treatments are typically delivered late in the disease process after anaemia has fully developed and are generally not targeted to the underlying aetiology of anaemia. Fortunately, there are strategies available that may prevent or attenuate the severity of anaemia development such as minimising iatrogenic blood loss via phlebotomy, 13 ensuring appropriate bleeding prophylaxis for high-risk patients and preventing haemodilution.…”

Targeted treatment of iron deficiency in prolonged critical illness: an opportunity to improve survival or not?

“…Lasocki et al recently reported the results of the Hepcidane randomized controlled trial (RCT), randomizing long-stay intensive care unit (ICU) patients to hepcidin-guided treatment of iron deficiency versus standard care [ 1 ]. Although the intervention had no impact on the primary endpoint—post-ICU length of stay (LOS)—it apparently improved survival, a secondary endpoint.…”