title: Transfusion Indication Threshold Reduction (TITRe2) randomized controlled trial in cardiac surgery: statistical analysis plan.
abstract: BACKGROUND
  The Transfusion Indication Threshold Reduction (TITRe2) trial is the largest randomized controlled trial to date to compare red blood cell transfusion strategies following cardiac surgery. This update presents the statistical analysis plan, detailing how the study will be analyzed and presented. The statistical analysis plan has been written following recommendations from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, prior to database lock and the final analysis of trial data. Outlined analyses are in line with the Consolidated Standards of Reporting Trials (CONSORT).
  
  
  METHODS
  The study aims to randomize 2000 patients from 17 UK centres. Patients are randomized to either a restrictive (transfuse if haemoglobin concentration <7.5 g/dl) or liberal (transfuse if haemoglobin concentration <9 g/dl) transfusion strategy. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first 3 months following randomization. The statistical analysis plan details how non-adherence with the intervention, withdrawals from the study, and the study population will be derived and dealt with in the analysis. The planned analyses of the trial primary and secondary outcome measures are described in detail, including approaches taken to deal with multiple testing, model assumptions not being met and missing data. Details of planned subgroup and sensitivity analyses and pre-specified ancillary analyses are given, along with potential issues that have been identified with such analyses and possible approaches to overcome such issues.
  
  
  BACKGROUND
  ISRCTN70923932 .
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. katie.pike@bristol.ac.uk.
authors.forename: Katie
authors.initials: K
authors.lastname: Pike
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. rachel.nash@bristol.ac.uk.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Nash
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. gjm19@leicester.ac.uk.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Murphy
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. barney.reeves@bristol.ac.uk.
authors.forename: Barnaby C
authors.initials: BC
authors.lastname: Reeves
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. chris.rogers@bristol.ac.uk.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Rogers
mesh_terms: D006348:Cardiac Surgical Procedures; D003627:Data Interpretation, Statistical; D017707:Erythrocyte Transfusion; D019983:Guideline Adherence; D006801:Humans; D017063:Outcome Assessment, Health Care; D011446:Prospective Studies