Improving outcomes for hospital patients with critical bleeding requiring massive transfusion: The Australian and New Zealand Massive Transfusion Registry study methodology

Background: The Australian and New Zealand (ANZ) Massive Transfusion (MT) Registry (MTR) has been established to improve the quality of care of patients with critical bleeding (CB) requiring MT (≥ 5 units red blood cells (RBC) over 4 h). The MTR is providing data to: (1) improve the evidence base for transfusion practice by systematically collecting data on transfusion practice and clinical outcomes; (2) monitor variations in practice and provide an opportunity for benchmarking, and feedback on practice/blood product use; (3) inform blood supply planning, inventory management and development of future clinical trials; and (4) measure and enhance translation of evidence into policy and patient blood management guidelines. The MTR commenced in 2011. At each participating site, all eligible patients aged ≥18 years with CB from any clinical context receiving MT are included using a waived consent model. Patient information and clinical coding, transfusion history, and laboratory test results are extracted for each patient’s hospital admission at the episode level. Results: Thirty-two hospitals have enrolled and 3566 MT patients have been identified across Australia and New Zealand between 2011 and 2015. The majority of CB contexts are surgical, followed by trauma and gastrointestinal haemorrhage. Validation studies have verified that the definition of MT used in the registry correctly identifies 94 % of CB events, and that the median time of transfusion for the majority of fresh products is the ‘product event issue time’ from the hospital blood bank plus 20 min. Data linkage between the MTR and mortality databases in Australia and New Zealand will allow comparisons of risk-adjusted mortality estimates across different bleeding contexts, and between countries. Data extracts will be examined to determine if there are differences in patient outcomes according to transfusion practice. The ratios of blood components (e.g. FFP:RBC) used in different types of critical bleeding will also be investigated. Conclusions: The MTR is generating data with the potential to have an impact on management and policy decision-making in CB and MT and provide benchmarking and monitoring tools for immediate application

Design and development of the Australian and New Zealand (ANZ) myeloma and related diseases registry

© 2016 The Author(s). Background: Plasma cell dyscrasias (PCD) are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ) for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR) was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process. Methods: The MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources. Results: More than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and 'real world' outcome data, to support the conduction of high quality studies. In addition, the Myeloma 1000 sub-study is establishing a repository of paired peripheral blood specimens from registry patients to study mechanisms underlying disease progression. Conclusion: Establishment of the MRDR has been challenging, but it is a valuable investment that will provide a platform for coordinated national and international collaboration for clinical research in PCD in ANZ

A multicentred study to validate a consensus bleeding assessment tool developed by the biomedical excellence for safer transfusion collaborative for use in patients with haematological malignancy

Background There continues to be uncertainty about the optimal approach to documenting bleeding data in platelet transfusion trials, with a desire to apply a common assessment tool across all trials. With this in mind, a consensus bleeding assessment tool (BAT) has been developed by the Biomedical Excellence for Safer Transfusion (BEST) collaborative, based on review of data collection forms used in published randomized trials and following content validation with a range of healthcare professionals at seven haematology centres through BEST members. This study aimed to evaluate reliability and reproducibility of the consensus BAT. Methods Replicated clinical assessments of bleeding were undertaken by participants with haematological malignancies recruited at four haematology centres in an international, multicentred, observational study. Concordance of repeat assessments was calculated for agreement in site and grade of bleeding observed. Results Forty patients consented to participate, and 13 trained bleeding assessors collected these data. Bleeding assessments were carried out on 113 separate days. Of all 225 bleeding assessments, 204 were compared for grade concordance, and 160 were compared for site concordance. There was very good grade concordance (83%, 95% confidence interval 74–93%) and good bleeding site concordance (69%, 95% confidence interval 57–79%) in observations of bleeding. Discordance was primarily in relation to assessing skin bleeding. Conclusions Alongside a structured training programme, levels of concordance for a consensus BAT were high. Researchers using assessment tools for bleeding need to balance comprehensive data collection against potential loss of accuracy for some types of bleeding, such as skin findings

Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude.

TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Descriptive characteristics and in-hospital mortality of critically bleeding patients requiring massive transfusion: Results from the Australian and New Zealand Massive Transfusion Registry

Background and Objectives Critically bleeding patients requiring massive transfusion (MT) are clinically challenging, and limited data exist to support management decisions. This study describes patient characteristics, transfusion support and clinical outcomes from the Australian and New Zealand (NZ) Massive Transfusion Registry (ANZ‐MTR). Materials and Methods Retrospective, cohort study of all adult patients receiving MT (≥5 units red blood cells [RBC] in 4 h) at participating ANZ‐MTR hospitals, 2011–2015. Mortality information was collected from the Australian National Death Index and NZ Ministry of Health. Associations between patient characteristics and outcomes were modelled using logistic regression. Results A total of 3560 MT cases were identified. For in‐hospital deaths, cardiothoracic surgery was the most frequent bleeding context (24·5%) followed by trauma (18·3%). Age (OR = 1·03; 95% CI: 1·02–1·04), more comorbidities (OR = 1·14; 95% CI: 1·09–1·21), larger volume of RBC in first 24 h from MT onset (OR = 1·04; 95% CI: 1·02–1·06), higher platelet to RBC ratio at 4 h (OR = 2·76; 95% CI: 1·14–6·65) and higher activated partial thromboplastin time (OR = 1·02; 95% CI: 1·01–1·03) were associated with in‐hospital mortality. Conclusion Patients with more comorbidities, older age, traumatic or surgical bleeding or requiring more blood components had higher in‐hospital mortality. These findings provide a basis to evaluate and monitor practice relating to optimal use of blood products, variation in transfusion practices and patient outcomes, and also enable benchmarking of hospital performance for management of MT in specific patient groups

Evaluation of clinical coding data to determine causes of critical bleeding in patients receiving massive transfusion: a bi-national, multicentre, cross-sectional study

Objectives: To evaluate the use of routinely collected data to determine the cause(s) of critical bleeding in patients who receive massive transfusion (MT). Background: Routinely collected data are increasingly being used to describe and evaluate transfusion practice. Materials/methods: Chart reviews were undertaken on 10 randomly selected MT patients at 48 hospitals across Australia and New Zealand to determine the cause(s) of critical bleeding. Diagnosis-related group (DRG) and International Classification of Diseases (ICD) codes were extracted separately and used to assign each patient a cause of critical bleeding. These were compared against chart review using percentage agreement and kappa statistics. Results: A total of 427 MT patients were included with complete ICD and DRG data for 427 (100%) and 396 (93%), respectively. Good overall agreement was found between chart review and ICD codes (78·3%; κ = 0·74, 95% CI 0·70–0·79) and only fair overall agreement with DRG (51%; κ = 0·45, 95% CI 0·40–0·50). Both ICD and DRG were sensitive and accurate for classifying obstetric haemorrhage patients (98% sensitivity and κ > 0·94). However, compared with the ICD algorithm, DRGs were less sensitive and accurate in classifying bleeding as a result of gastrointestinal haemorrhage (74% vs 8%; κ = 0·75 vs 0·1), trauma (92% vs 62%; κ = 0·78 vs 0·67), cardiac (80% vs 57%; κ = 0·79 vs 0·60) and vascular surgery (64% vs 56%; κ = 0·69 vs 0·65). Conclusion: Algorithms using ICD codes can determine the cause of critical bleeding in patients requiring MT with good to excellent agreement with clinical history. DRG are less suitable to determine critical bleeding causes