Rachel Cm Brierley

A multi-centre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and healthcare resource use following cardiac surgery: study protocol.

Thresholds for red blood cell transfusion following cardiac surgery vary by hospital and surgeon. The TITRe2 multi-centre randomised controlled trial aims to randomise 2000 patients from 17 United Kingdom centres, and tests the hypothesis that a restrictive transfusion threshold will reduce postoperative morbidity and health service costs compared to a liberal threshold. Patients consent to take part in the study pre-operatively but are only randomised if their haemoglobin falls below 9 g/dL during their post-operative hospital stay. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first three months after randomisation. Many challenges have been encountered in the set-up and running of the study.

A multicentre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and health-care resource use following cardiac surgery (TITRe2).

BACKGROUND Uncertainty about optimal red blood cell transfusion thresholds in cardiac surgery is reflected in widely varying transfusion rates between surgeons and cardiac centres. OBJECTIVE To test the hypothesis that a restrictive compared with a liberal threshold for red blood cell transfusion after cardiac surgery reduces post-operative morbidity and health-care costs. DESIGN Multicentre, parallel randomised controlled trial and within-trial cost-utility analysis from a UK NHS and Personal Social Services perspective. We could not blind health-care staff but tried to blind participants. Random allocations were generated by computer and minimised by centre and operation. SETTING Seventeen specialist cardiac surgery centres in UK NHS hospitals. PARTICIPANTS Patients aged > 16 years undergoing non-emergency cardiac surgery with post-operative haemoglobin < 9 g/dl. Exclusion criteria were: unwilling to have transfusion owing to beliefs; platelet, red blood cell or clotting disorder; ongoing or recurrent sepsis; and critical limb ischaemia. INTERVENTIONS Participants in the liberal group were eligible for transfusion immediately after randomisation (post-operative haemoglobin < 9 g/dl); participants in the restrictive group were eligible for transfusion if their post-operative haemoglobin fell to < 7.5 g/dl during the index hospital stay. MAIN OUTCOME MEASURES The primary outcome was a composite outcome of any serious infectious (sepsis or wound infection) or ischaemic event (permanent stroke, myocardial infarction, gut infarction or acute kidney injury) during the 3 months after randomisation. Events were verified or adjudicated by blinded personnel. Secondary outcomes included blood products transfused; infectious events; ischaemic events; quality of life (European Quality of Life-5 Dimensions); duration of intensive care or high-dependency unit stay; duration of hospital stay; significant pulmonary morbidity; all-cause mortality; resource use, costs and cost-effectiveness. RESULTS We randomised 2007 participants between 15 July 2009 and 18 February 2013; four withdrew, leaving 1000 and 1003 in the restrictive and liberal groups, respectively. Transfusion rates after randomisation were 53.4% (534/1000) and 92.2% (925/1003). The primary outcome occurred in 35.1% (331/944) and 33.0% (317/962) of participants in the restrictive and liberal groups [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.91 to 1.34; p = 0.30], respectively. There were no subgroup effects for the primary outcome, although some sensitivity analyses substantially altered the estimated OR. There were no differences for secondary clinical outcomes except for mortality, with more deaths in the restrictive group (4.2%, 42/1000 vs. 2.6%, 26/1003; hazard ratio 1.64, 95% CI 1.00 to 2.67; p = 0.045). Serious post-operative complications excluding primary outcome events occurred in 35.7% (354/991) and 34.2% (339/991) of participants in the restrictive and liberal groups, respectively. The total cost per participant from surgery to 3 months postoperatively differed little by group, just £182 less (standard error £488) in the restrictive group, largely owing to the difference in red blood cells cost. In the base-case cost-effectiveness results, the point estimate suggested that the restrictive threshold was cost-effective; however, this result was very uncertain partly owing to the negligible difference in quality-adjusted life-years gained. CONCLUSIONS A restrictive transfusion threshold is not superior to a liberal threshold after cardiac surgery. This finding supports restrictive transfusion due to reduced consumption and costs of red blood cells. However, secondary findings create uncertainty about recommending restrictive transfusion and prompt a new hypothesis that liberal transfusion may be superior after cardiac surgery. Reanalyses of existing trial datasets, excluding all participants who did not breach the liberal threshold, followed by a meta-analysis of the reanalysed results are the most obvious research steps to address the new hypothesis about the possible harm of red blood cell transfusion. TRIAL REGISTRATION Current Controlled Trials ISRCTN70923932. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 60. See the NIHR Journals Library website for further project information.

Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial

Objective To assess the incremental cost and cost-effectiveness of a restrictive versus a liberal red blood cell transfusion threshold after cardiac surgery. Design A within-trial cost-effectiveness analysis with a 3-month time horizon, based on a multicentre superiority randomised controlled trial from the perspective of the National Health Service (NHS) and personal social services in the UK. Setting 17 specialist cardiac surgery centres in UK NHS hospitals. Participants 2003 patients aged >16 years undergoing non-emergency cardiac surgery with a postoperative haemoglobin of <9 g/dL. Interventions Restrictive (transfuse if haemoglobin <7.5 g/dL) or liberal (transfuse if haemoglobin <9 g/dL) threshold during hospitalisation after surgery. Main outcome measures Health-related quality of life measured using the EQ-5D-3L to calculate quality-adjusted life years (QALYs). Results The total costs from surgery up to 3 months were £17 945 and £18 127 in the restrictive and liberal groups (mean difference is −£182, 95% CI −£1108 to £744). The cost difference was largely attributable to the difference in the cost of red blood cells. Mean QALYs to 3 months were 0.18 in both groups (restrictive minus liberal difference is 0.0004, 95% CI −0.0037 to 0.0045). The point estimate for the base-case cost-effectiveness analysis suggested that the restrictive group was slightly more effective and slightly less costly than the liberal group and, therefore, cost-effective. However, there is great uncertainty around these results partly due to the negligible differences in QALYs gained. Conclusions We conclude that there is no clear difference in the cost-effectiveness of restrictive and liberal thresholds for red blood cell transfusion after cardiac surgery. Trial registration number ISRCTN70923932; Results.

Adherence in a randomised controlled trial comparing liberal and restrictive red blood cell (RBC) transfusion protocols after cardiac surgery (TITRe2)

Objectives The TITRe2 trial is comparing two haemoglobin (Hb) thresholds for RBC transfusion after cardiac surgery, Hb<9.0g/dl (liberal) vs. Hb<7.5g/dl (restrictive). Based on historic data, and with complete adherence, transfusion rates should be 100% in the liberal and 30% in the restrictive group. Convergence of these rates due to non-adherence severely threatens the power of the trial; there is also concern about differential non-adherence, with transfusion being delayed or withheld in the liberal group when Hb remains close to the 9.0g/dl threshold.

Formal consensus to identify clinically important changes in management resulting from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway

Objective To define important changes in management arising from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. Design Formal consensus study using literature review and cardiologist expert opinion to formulate consensus statements and setting up a consensus panel to review the statements (by completing a web-based survey, attending a face-to-face meeting to discuss survey results and modify the survey to reflect group discussion and completing the modified survey to determine which statements were in consensus). Participants Formulation of consensus statements: four cardiologists (two CMR and two interventional) and six non-clinical researchers. Formal consensus: seven cardiologists (two CMR and three interventional, one echocardiography and one heart failure). Forty-nine additional cardiologists completed the modified survey. Results Thirty-seven draft statements describing changes in management following CMR were generated; these were condensed into 12 statements and reviewed through the formal consensus process. Three of 12 statements were classified in consensus in the first survey; these related to the role of CMR in identifying the cause of out-of-hospital cardiac arrest, providing a definitive diagnosis in patients found to have unobstructed arteries on angiography and identifying patients with left ventricular thrombus. Two additional statements were in consensus in the modified survey, relating to the ability of CMR to identify patients who have a poor prognosis after PPCI and assess ischaemia and viability in patients with multivessel disease. Conclusion There was consensus that CMR leads to clinically important changes in management in five subgroups of patients who activate the PPCI pathway.

Developing a UK registry to investigate the role of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway: a multicentre, feasibility study linking routinely collected electronic patient data

Objectives To determine whether it is feasible to set up a national registry, linking routinely collected data from hospital information systems (HIS), to investigate the role of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. Design Feasibility prospective cohort study, to establish whether: (1) consent can be implemented; (2) data linkage and extraction from multiple HIS can be achieved for >90% of consented patients; (3) local data can be successfully linked with hospital episode data (Hospital Episode Statistics, HES; Patient Episode Database for Wales, PEDW) for >90% of consented patients and (4) the proportion of patients activating the PPCI pathway who get a CMR scan is ≥10% in hospitals with dedicated CMR facilities. Participants Patients from four 24/7 PPCI hospitals in England and Wales (two with and two without a dedicated CMR facility) who activated the PPCI pathway and underwent an emergency coronary angiogram. Results Consent was successfully implemented at all hospitals (consent rates ranged from 59% to 74%) and 1670 participants were recruited. Data submission was variable: all hospitals submitted clinical data (for ≥82% of patients); only three hospitals submitted biochemistry data (for ≥98% of patients) and echocardiography data (for 34%–87% of patients); only one hospital submitted medications data (for 97% of patients). At the two CMR centres, 14% and 20% of patients received a CMR scan. Data submitted by hospitals were linked with HES and PEDW for 99% of all consented patients. Conclusion We successfully consented patients but obtaining individual, opt-in consent would not be feasible for a national registry. Linkage of data from HIS with hospital episode data was feasible. However, data from HIS are not uniformly available/exportable and, in centres with a dedicated CMR facility, some referrals for CMR were for research rather than clinical purposes.

Adherence to transfusion strategies in a randomized controlled trial: experiences from the TITRe2 trial

United Kingdom National Institute for Health Research Health Technology Assessment programme. Grant Number: 06/402/94 NIHR Bristol Biomedical Research Unit in Cardiovascular Disease

P103 Benefit to Patients and the NHS of Cardiac Magnetic Resonance Imaging after Primary Percutaneous Coronary Intervention: Data challenges within a Routine Data Registry

Background Cardiac magnetic resonance imaging (CMR) is a medical imaging technology for the non-invasive assessment of heart structure and function. Although the long term prognostic value of CMR is uncertain for some disease indications, uptake has been rapid among cardiologists with a 44% increase in the number of CMR scans in the UK between 2008 and 2010 (Antony et al. J Cardiovasc Magn Reson. 2011). A study was conducted to test the feasibility of setting up a UK registry using routinely collected NHS data to document CMR use in patients with suspected heart attack who activate the primary percutaneous coronary intervention (PPCI) pathway and compare outcomes between those who do/do not receive CMR. Methods Consecutive eligible patients who presented to a “24/7” PPCI centre in four UK hospitals (two with CMR facilities in England and two without in Wales) between May 2013 and August 2014 were invited to participate. Routinely collected clinical, biochemistry and radiology data were requested on all patients from all sites. Resource use data (Hospital Episode Statistics, HES, England; and Patient Episode Database Wales, PEDW) were also requested. Anonymised datasets of non-consenting patients were requested for comparative purposes. Results Of 2500 eligible patients, 1670 (66.8%) provided consent. Anonymised data were provided for 705/830 (84.9%) patients who did not consent, who were broadly similar to those who did. The proportion having CMR within ten weeks of the event was 18.1% (187/1035). Extracting routine data from different hospital databases was challenging; two sites could not easily provide biochemistry data and three could not provide details on medications on discharge. Bedside echocardiograms were not routinely recorded electronically. Other essential data fields were incomplete, clinical data were unavailable for 7.0% of patients and CMR information was recorded as free text, preventing simple electronic extraction of key data. HES data are not yet available for the two English sites but PEDW data have been obtained for the Welsh sites. Linkage of Welsh hospital data with PEDW admission data resulted in a date-match for the index event for 88.0% (559/635), with congruent documentation of PPCI and diagnosis of acute coronary syndrome for 73.2% (465/635). Conclusion Many required electronic data were not available routinely or promptly. Due to challenges with data extraction, collation and accuracy we concluded that it is not currently feasible to set up a registry using routinely collected data in this population.

Formal consensus method for the development of a primary outcome measure to assess the clinical and cost-effectiveness of cardiac magnetic resonance imaging after primary percutaneous coronary intervention pathway activation (PIPA feasibility study)

Background PIPA is designed to determine the feasibility of a prospective, multi-centre cohort study to assess the clinical and cost-effectiveness of cardiac magnetic resonance imaging (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. A key PIPA objective is to define a primary composite outcome that represents a clinically important change in management (proxy outcome for reduction in the future risk of a major adverse cardiovascular event (MACE)) as a result of an eligible patient having had CMR. A formal consensus method based on the modified nominal group technique [1] is being used to define this outcome.