Adverse events of iron and/or erythropoiesis-stimulating agent therapy in preoperatively anaemic elective surgery patients: a systematic review

Abstract

Background. Iron supplementation and erythropoiesis-stimulating agent (ESA) administration represent the hallmark therapies in preoperative anaemia treatment, as reflected in a set of evidence-based treatment recommendations made during the 2018 International Consensus Conference on Patient Blood Management. However, little is known about the safety of these therapies. This systematic review investigated the occurrence of adverse events (AEs) during or after treatment with iron and/or ESAs. Methods. Five databases (The Cochrane Library, MEDLINE, Embase, Transfusion Evidence Library, Web of Science) and two trial registries (ClinicalTrials.gov, WHO ICTRP) were searched until November 6 2020. Randomized controlled trials (RCTs), cohort and case-control studies investigating any AE during or after iron and/or ESAs administration in adult elective surgery patients with preoperative anaemia were eligible for inclusion, and judged using the Cochrane Risk of Bias tools. The GRADE approach was used to assess the overall certainty of evidence. Results. 26 RCTs and 16 cohort studies involving a total of 6062 patients were included, providing data on 6 comparisons: (1) Intravenous (IV) versus oral iron, (2) IV iron versus usual care/no iron, (3) IV ferric carboxymaltose versus IV iron sucrose, (4) ESA+iron versus control (placebo and/or iron, no treatment), (5) ESA+IV iron versus ESA+oral iron, and (6) ESA+IV iron versus ESA+IV iron (different ESA dosing regimens). Most AE data concerned mortality/survival (n=24 studies), thromboembolic (n=22), infectious (n=20), cardiovascular (n=19) and gastrointestinal (n=14) AEs. Very low-certainty of evidence was assigned to all but one outcome category. This uncertainty results from both low quantity and quality of AE data due to high risk of bias caused by limitations in study design, data collection and reporting. Conclusions. It remains unclear if ESA and/or iron therapy is associated with AEs in preoperatively anaemic elective surgery patients. Future trial investigators should pay more attention to the systematic collection, measurement, documenting and reporting of AE data.