Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial

Abstract

Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.

Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9-10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5-9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.

Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.

Trial registration: ClinicalTrials.gov (identifier: NCT03369210 ).

Keywords: Red blood cell transfusion; anaemia; elderly patients; surgery.

Conflict of interest statement

Ethics approval and consent to participate

Study protocol V3.0 (EudraCT-Nr 2016–004446-29), patient information, and informed consent were approved by the Ethics Committee of the University of Frankfurt (Ref: 139/17F) and of all participating centres. At the same time the study documents have been approved by the responsible federal authority (Paul-Ehrlich-Institute) according to the requirements of GCP-V § 7. Each patient must give written informed consent to participate in the study.

Consent for publication

Not applicable.

Competing interests

M.M and E.S. work for the German Red Cross, deliver RBC units and may have a financial competing interest. All other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Schedule of Assessments and Procedures. X: assessments for all registered patients / •: additional assessments for randomised patients. 1 Randomisation: as soon as haemoglobin ≤9 g/dl during surgery (=day 0) or day 1, 2, or 3 after surgery, registered consenting patients will be randomised. Re-evaluation of inclusion−/exclusion criteria before randomisation only refers to obvious occurrence of any component of the composite endpoint and any allogeneic blood transfusion after registration (chapter 4.2.2.). No specified diagnostics are scheduled. 2a Haemoglobin levels will be determined from blood samples (primarily BGA measurement mainly as part of the patient’s usual care) at least daily before randomisation. 2b Mild drop of haemoglobin < 9 g/dl due to induction of anaesthesia before skin incision is permitted and not an exclusion criteria. 2c Haemoglobin levels will be determined from blood samples (primarily BGA measurement mainly as part of the patient’s usual care) at any time during or after randomisation until hospital discharge (up to 30 days after surgery; at least every 3 days), and after each transfused unit. Creatinine levels will be determined as part of the patient’s usual care at any time during or after randomisation until hospital discharge (or up to 30 days after surgery; at least every 7 days). 3 Intra-/Postoperative Intervention: Duration of intervention per patient: from intra−/postoperative randomisation until hospital discharge or 30 days after surgery, whichever occurs first. Physicians will be instructed to transfuse RBC units each time haemoglobin is lower than the randomised threshold and as soon as possible. The randomised target post-transfusion Hb level needs to be reached each time within 24 h upon receipt of lab result at the latest

Fig. 2

Study intervention. Hb levels will be determined from blood samples (*) mainly as part of the patient’s usual care at any time during or after surgery (up to 30 days after surgery; at least every 3 days), and after each transfused unit. Consenting patients will be registered (Step I) and will be randomised as soon as Hb falls ≤9 g/dl during surgery (=day 0) or day 1, 2, or 3 after surgery. Physicians will be instructed to transfuse RBC units each time Hb is lower the defined threshold and as soon as possible. The target post-transfusion Hb level needs to be reached within 24 h upon receipt of lab result at latest. The intervention per patient will be followed until hospital discharge or up to 30 days, whichever occurred first, comparable to recent large trials [–7, 15]. In case of any massive or life-threatening bleeding, the single-unit policy should be paused