title: Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial.
abstract: BACKGROUND
  Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding.
  
  
  METHODS
  In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532.
  
  
  RESULTS
  Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes.
  
  
  CONCLUSIONS
  A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding.
  
  
  BACKGROUND
  NHS Blood and Transplant Research and Development.
authors.affiliation: NHS Blood and Transplant, Oxford, UK; Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: vipul.jairath@nhsbt.nhs.uk.
authors.forename: Vipul
authors.initials: V
authors.lastname: Jairath
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Brennan C
authors.initials: BC
authors.lastname: Kahan
authors.affiliation: Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Gray
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Doré
authors.affiliation: NHS Blood and Transplant Clinical Trials Unit, Cambridge, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Mora
authors.affiliation: National Institute for Health Research Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Martin W
authors.initials: MW
authors.lastname: James
authors.affiliation: Gastrointestinal Unit, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Stanley
authors.affiliation: Department of Gastroenterology, St James's University Hospital, Leeds, UK.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Everett
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Bailey
authors.affiliation: Department of Gastroenterology, James Cook University Hospital, Middlesbrough, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Dallal
authors.affiliation: Department of Gastroenterology, James Cook University Hospital, Middlesbrough, UK.
authors.forename: John
authors.initials: J
authors.lastname: Greenaway
authors.affiliation: Department of Research and Education in Emergency Medicine, Acute Medicine and Trauma, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Le Jeune
authors.affiliation: Department of Emergency Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Darwent
authors.affiliation: Department of Gastroenterology, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Church
authors.affiliation: Department of Acute General Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Reckless
authors.affiliation: NHS Blood and Transplant Clinical Trials Unit, Cambridge, UK.
authors.forename: Renate
authors.initials: R
authors.lastname: Hodge
authors.affiliation: NHS Blood and Transplant Clinical Trials Unit, Cambridge, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Dyer
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Meredith
authors.affiliation: NHS Blood and Transplant Clinical Trials Unit, Cambridge, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Llewelyn
authors.affiliation: Western General Hospital, Edinburgh, UK.
authors.forename: Kelvin R
authors.initials: KR
authors.lastname: Palmer
authors.affiliation: National Institute for Health Research Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Logan
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Travis
authors.affiliation: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Walsh
authors.affiliation: NHS Blood and Transplant, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals, Oxford, UK.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Murphy
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017707:Erythrocyte Transfusion / Q000379:methods*; D005240:Feasibility Studies; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000097:blood / Q000628:therapy*; D019983:Guideline Adherence; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D012107:Research Design; D015983:Selection Bias
chemical_list: D006454:Hemoglobins