Journals Library Programme Grants for Applied Research Volume 8 • Issue 5 • May 2020 ISSN 2050-4322 Prevention and treatment of venous thromboembolism in hospital and the community: a research programme including the ExACT RCT David Fitzmaurice, Kate Fletcher, Sheila Greenfield, Sue Jowett, Alison Ward, Carl Heneghan, Eve Knight, Chris Gardiner, Andrea Roalfe, Yongzhong Sun, Pollyanna Hardy, Deborah McCahon, Gail Heritage, Helen Shackleford and FD Richard Hobbs DOI 10.3310/pgfar08050 Prevention and treatment of venous thromboembolism in hospital and the community: a research programme including the ExACT RCT David Fitzmaurice ,1* Kate Fletcher ,2 Sheila Greenfield,2 Sue Jowett ,2 Alison Ward ,3 Carl Heneghan ,3 Eve Knight,4 Chris Gardiner ,5 Andrea Roalfe ,2 Yongzhong Sun,2 Pollyanna Hardy ,2 Deborah McCahon ,6 Gail Heritage ,2 Helen Shackleford2 and FD Richard Hobbs 3 1Unit of Academic Primary Care, Warwick Medical School, University of Warwick, Coventry, UK 2Institute of Applied Health Research, University of Birmingham, Birmingham, UK 3Nuffield Department of Primary Care Health Sciences, Medical Sciences Division, University of Oxford, Oxford, UK 4Anticoagulation UK, Bromley, UK 5Haemostasis Research Unit, Department of Haematology, University College London, London, UK 6Centre for Academic Primary Care, Bristol Medical School, University of Bristol, Bristol, UK *Corresponding author Declared competing interests of authors: none Disclaimer: This report contains transcripts of interviews conducted in the course of the research and contains language that may offend some readers. Published May 2020 DOI: 10.3310/pgfar08050 This report should be referenced as follows: Fitzmaurice D, Fletcher K, Greenfield S, Jowett S, Ward A, Heneghan C, et al. Prevention and treatment of venous thromboembolism in hospital and the community: a research programme including the ExACT RCT. Programme Grants Appl Res 2020;8(5). Programme Grants for Applied Research ISSN 2050-4322 (Print) ISSN 2050-4330 (Online) This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (www.publicationethics.org/). Editorial contact: journals.library@nihr.ac.uk The full PGfAR archive is freely available to view online at www.journalslibrary.nihr.ac.uk/pgfar. Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: www.journalslibrary.nihr.ac.uk Criteria for inclusion in the Programme Grants for Applied Research journal Reports are published in Programme Grants for Applied Research (PGfAR) if (1) they have resulted from work for the PGfAR programme, and (2) they are of a sufficiently high scientific quality as assessed by the reviewers and editors. Programme Grants for Applied Research programme The Programme Grants for Applied Research (PGfAR) programme, part of the National Institute for Health Research (NIHR), was established in 2006 to fund collaborative, multidisciplinary programmes of applied research to solve health and social care challenges. Findings are expected to provide evidence that lead to clear and identifiable patient benefits, in the relatively near future. PGfAR is researcher led and does not specify topics for research; however, the research must be in an area of priority or need for the NHS and the social care sector of the Department of Health and Social Care, with particular emphasis on health and social care areas that cause significant burden, where other research funders may not be focused, or where insufficient funding is available. The programme is managed by the NIHR Central Commissioning Facility (CCF) with strategic input from the Programme Director. For more information about the PGfAR programme please visit the website: https://www.nihr.ac.uk/explore-nihr/funding-programmes/ programme-grants-for-applied-research.htm This report The research reported in this issue of the journal was funded by PGfAR as project number RP-PG-0608-10073. The contractual start date was in April 2010. The final report began editorial review in March 2018 and was accepted for publication in December 2019. As the funder, the PGfAR programme agreed the research questions and study designs in advance with the investigators. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The PGfAR editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report. This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, CCF, NETSCC, PGfAR or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the PGfAR programme or the Department of Health and Social Care. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Published by the NIHR Journals Library (www.journalslibrary.nihr.ac.uk), produced by Prepress Projects Ltd, Perth, Scotland (www.prepress-projects.co.uk). Editor-in-Chief of Programme Grants for Applied Research and NIHR Journals Library Professor Ken Stein Professor of Public Health, University of Exeter Medical School, UK NIHR Journals Library Editors Professor John Powell Chair of HTA and EME Editorial Board and Editor-in-Chief of HTA and EME journals. Consultant Clinical Adviser, National Institute for Health and Care Excellence (NICE), UK, and Senior Clinical Professor Andrée Le May Professor Matthias Beck Dr Tessa Crilly Dr Eugenia Cronin Senior Scientific Advisor, Wessex Institute, UK Dr Peter Davidson Ms Tara Lamont Dr Catriona McDaid Professor William McGuire Professor Geoffrey Meads Professor of Wellbeing Research, University of Winchester, UK Professor John Norrie Chair in Medical Statistics, University of Edinburgh, UK Professor James Raftery Dr Rob Riemsma Professor Helen Roberts Professor Jonathan Ross Professor Helen Snooks Professor of Health Services Research, Institute of Life Science, College of Medicine, Swansea University, UK Professor Ken Stein Professor of Public Health, University of Exeter Medical School, UK Professor Jim Thornton Professor Martin Underwood Please visit the website for a list of editors: Editorial contact: NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Abstract Prevention and treatment of venous thromboembolism in hospital and the community: a research programme including the ExACT RCT David Fitzmaurice ,1* Kate Fletcher ,2 Sheila Greenfield,2 Sue Jowett ,2 Alison Ward ,3 Carl Heneghan ,3 Eve Knight,4 Chris Gardiner ,5 Andrea Roalfe ,2 Yongzhong Sun,2 Pollyanna Hardy ,2 Deborah McCahon ,6 Gail Heritage ,2 Helen Shackleford2 and FD Richard Hobbs 3 1Unit of Academic Primary Care, Warwick Medical School, University of Warwick, Coventry, UK of Applied Health Research, University of Birmingham, Birmingham, UK 3Nuffield Department of Primary Care Health Sciences, Medical Sciences Division, University of Oxford, Oxford, UK 4Anticoagulation UK, Bromley, UK 5Haemostasis Research Unit, Department of Haematology, University College London, London, UK 6Centre for Academic Primary Care, Bristol Medical School, University of Bristol, Bristol, UK 2Institute *Corresponding author d.fitzmaurice@warwick.ac.uk Background: Deep-vein thrombosis and pulmonary embolism, collectively known as venous thromboembolism when clots are formed in the venous circulation, are common disorders that are often unprovoked (i.e. there is no obvious reason for the clot occurring). Some people, after having an unprovoked clot, are at a high risk of developing another, or at risk of developing a secondary clot, most importantly in the lungs. Furthermore, in the long term, some patients will develop circulation problems known as post-thrombotic syndrome. The aim of this programme was to improve the understanding of both the prevention and the treatment of thrombosis in people at the highest risk of recurrence. Objectives: To clarify if it is possible to identify those people at the highest risk of having a recurrent venous thromboembolism, and if it is possible to prevent this happening by giving anticoagulation treatment for longer. To clarify if it is possible to identify those people at the highest risk of developing post-thrombotic syndrome. To document the current knowledge level about prevention and treatment of venous thromboembolism. To find what the barriers are to implementing measures to prevent venous thromboembolism. To find the most cost-effective means of treating venous thromboembolism. Design: Mixed methods, comprising a randomised controlled trial, qualitative studies, cost-effectiveness analyses and questionnaire studies, including patient preferences. Setting: UK general practices and hospitals, predominantly from the Midlands and Shropshire. Participants: Adults attending participating anticoagulation clinics with a diagnosis of first unprovoked deep-vein thrombosis or pulmonary embolism, and health-care professionals, patients and other stakeholders who were involved in the prevention and treatment of venous thromboembolism. Intervention: Extended treatment with oral anticoagulation therapy (2 years) versus standard care (treatment with oral anticoagulation therapy for at least 3 months). © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. v ABSTRACT Results: Work package 1 demonstrated that extended anticoagulation for up to 2 years was clinically effective and cost-effective in reducing the incidence of recurrent venous thromboembolism, with a small increase in the risk of bleeding. There was no difference in post-thrombotic syndrome incidence or severity, or quality of life, between those undergoing the extended treatment and those receiving the standard care. Work package 2 identified five common themes with regard to the prevention of hospital-acquired thrombosis: communication, knowledge, role of primary care, education and training, and barriers to patient adherence. Work package 3 suggested that extended anticoagulation with novel oral anticoagulants was cost-effective only at the £20,000-per-quality-adjusted life-year level for a recurrence rate of between 17.5% and 22.5%, depending on drug acquisition costs, while identifying a strong patient preference for extended anticoagulation based on a fear of recurrent venous thromboembolism. Limitations: The major limitation was the failure to reach the planned recruitment target for work package 1. Conclusions: Extended anticoagulation with warfarin for a first unprovoked venous thromboembolism is clinically effective and cost-effective and is strongly preferred by patients to the alternative of not having treatment. There are significant barriers to the implementation of preventative measures for hospitalacquired thrombosis. Further research is required on identifying patients in whom it is safe to discontinue anticoagulation, and at what time point following a first unprovoked venous thromboembolism this should be done. Trial registration: Current Controlled Trials ISRCTN73819751 and EudraCT 2101-022119-20. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 8, No. 5. See the NIHR Journals Library website for further project information. vi NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Contents List of tables ix List of figures xi List of boxes xiii List of supplementary material xv List of abbreviations xvii Plain English summary xix Scientific summary xxi SYNOPSIS Background Prevention of venous thromboembolism Patient and public involvement 1 1 2 4 Work package 1: randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism and post-thrombotic syndrome in patients being treated for a first episode of unprovoked venous thromboembolism (the ExACT trial) Overview Methods Aim Objectives Sample size calculation Summary of changes to the protocol (version 2.11) Results Participant recruitment Baseline characteristics Primary outcome Secondary outcomes Discussion Limitations Summary 5 5 5 5 5 6 6 6 6 7 11 14 16 17 17 Work package 2: Exploring Prevention and Knowledge of venous Thromboembolism (ExPeKT) – surveys Overview Objectives Methods and analysis Ethics and dissemination Setting Participants 19 19 19 19 20 20 20 © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii CONTENTS Work package 2: surveys and interviews with patients and health-care professionals regarding prevention of venous thromboembolism Background Objectives Methods Surveys Patient survey Primary care survey Interviews General practitioner interviews Interviews with other health-care professionals and relevant organisations Patient interviews Results Summary 21 21 22 22 22 22 23 23 23 24 24 25 44 Work package 3: health economics and patient preferences Within-trial health economic analysis (work package 3) Methods Quality of life Cost-effectiveness analysis Results Costs Outcomes Base-case analysis Discussion Health economic modelling study to evaluate the cost-effectiveness of extended anticoagulation (work package 3) Methods Results Discussion A patient preference study of extended oral anticoagulation for first unprovoked venous thromboembolism (work package 3) Methods for data collection and analysis Results Discussion Health economic modelling of extended anticoagulation for treatment and prevention of recurrent venous thromboembolism using a decision rule (work package 3) Methods Results Discussion Summary of the venous thromboembolism programme Limitations Implications Recommendations for future research 45 45 45 46 46 46 46 46 46 47 Acknowledgements 57 References 61 Appendix 1 Methods for work package 1 (the ExACT trial) 67 Appendix 2 Work package 3 79 viii NIHR Journals Library www.journalslibrary.nihr.ac.uk 47 47 50 50 51 51 51 52 52 52 53 53 53 55 55 55 DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 List of tables TABLE 1 Summary of work packages 1 TABLE 2 Baseline characteristics 8 TABLE 3 Primary and secondary outcomes 11 TABLE 4 Subgroup analysis of primary and secondary outcomes 14 TABLE 5 Association of baseline D-dimer level and risk of VTE recurrence 15 TABLE 6 The therapeutic range for the intervention group (group E) by the recurrence of VTE (18 participants with zero therapeutic range were excluded) 15 TABLE 7 Secondary outcomes (continuous) 15 TABLE 8 Mean per-patient costs over 24 months by trial arm (£) 46 TABLE 9 Base-case cost–utility analysis (imputed analysis) 47 TABLE 10 Unit costs of anticoagulation 79 TABLE 11 Mean resource use for PTS 80 TABLE 12 Post-thrombotic syndrome unit costs 80 TABLE 13 Unit costs of adverse events 81 TABLE 14 Unit costs of consultations and visits 82 TABLE 15 Mean per-patient costs over 24 months by trial arm (£) 83 TABLE 16 Mean outcomes by trial arm 83 TABLE 17 Base-case cost–utility analysis (imputed analysis) 83 TABLE 18 Model clinical parameters 87 TABLE 19 Model unit costs 89 TABLE 20 Utility values for health states 90 TABLE 21 Cost-effectiveness of extended vs. discontinued anticoagulation (lifetime time horizon) 90 TABLE 22 Cost-effectiveness of extended vs. discontinued anticoagulation: sensitivity analysis 91 TABLE 23 Response rate by patient characteristic 94 © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ix LIST OF TABLES TABLE 24 Preference for warfarin by patient characteristic 95 TABLE 25 Model parameters 98 TABLE 26 Model unit costs 99 TABLE 27 Utility values for health states 99 TABLE 28 Cost-effectiveness of using each decision rule sorted by increasing effectiveness (lifetime time horizon): warfarin 100 TABLE 29 Cost-effectiveness of using each decision rule sorted by increasing effectiveness (lifetime time horizon): apixaban 100 TABLE 30 Cost-effectiveness of using each decision rule sorted by increasing effectiveness (lifetime time horizon): dabigatran 101 TABLE 31 Cost-effectiveness of using each decision rule sorted by increasing effectiveness (lifetime time horizon): rivaroxaban 101 TABLE 32 Sensitivity analysis: higher risk of death from PE 102 TABLE 33 Sensitivity analysis: all patients with index PE event 102 x NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 List of figures FIGURE 1 Patient flow diagram 7 FIGURE 2 Patient flow diagram following randomisation 8 FIGURE 3 Cumulative risk of the primary outcome of time to first recurrent VTE (a) and of the secondary outcomes of time to first major bleeding (b), and time to first clinically relevant non-major bleeding event (c) between discontinued AT and extended AT 12 FIGURE 4 Model patient pathways 48 FIGURE 5 Eligibility 70 FIGURE 6 Cost-effectiveness plane of extended AT vs. discontinued AT 84 FIGURE 7 The CEAC of extended AT vs. discontinued AT 84 FIGURE 8 Model patient pathways 86 FIGURE 9 Model patient pathways 89 FIGURE 10 Cost-effectiveness plane of extended AT vs. discontinued AT 91 FIGURE 11 The CEAC of extended AT vs. discontinued AT 92 © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xi DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 List of boxes BOX 1 Baseline data collection 71 BOX 2 Follow-up data collection 73 © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 List of supplementary material Report Supplementary Material 1 Patient preferences for extended warfarin Supplementary material can be found on the NIHR Journals Library report page (https://doi.org/10.3310/pgfar08050). Supplementary material has been provided by the authors to support the report and any files provided at submission will have been seen by peer reviewers, but not extensively reviewed. Any supplementary material provided at a later stage in the process may not have been peer reviewed. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xv DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 List of abbreviations A&E accident and emergency HCP health-care professional AIDS acquired immune deficiency syndrome ICER incremental cost-effectiveness ratio APPTG All-Party Parliamentary Thrombosis Group INR international normalised ratio IQR interquartile range AT anticoagulation therapy NICE CEAC cost-effectiveness acceptability curve National Institute for Health and Care Excellence OAT oral anticoagulation therapy CQUIN Commissioning for Quality and Innovation PE pulmonary embolism CI confidence interval PSA probabilistic sensitivity analysis DOAC direct oral anticoagulant PSS Personal Social Services DODS D-dimer optimal duration study PTS post-thrombotic syndrome DVT deep-vein thrombosis QALY quality-adjusted life-year EQ-5D-3L EuroQol-5 Dimensions, three-level version RCT randomised controlled trial SD standard deviation SPSS Statistical Product and Service Solutions ExACT Extended Anticoagulation ExPeKT Exploration of Patient Knowledge and expectation GP general practitioner HAT hospital-acquired thrombosis HCHS Hospital and Community Health Services VEINES-QOL Venous Insufficiency Epidemiological and Economic study – Quality of Life VTE venous thromboembolism WP work package © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Plain English summary B lood clots often occur in the legs and the lungs, with up to 25,000 deaths every year in the UK from clots following a stay in hospital, with immobility, surgery and general ill health thought to be some of the reasons why these clots occur. Some people are at a very high risk of having a second clot, and the risk is highest in those people for whom no obvious cause for the clot can be found. Patients can develop problems with circulation, known as post-thrombotic syndrome. We do not know how to identify those people who will go on to have a further clot, and treatment of the first clot with bloodthinning drugs is usually stopped after 3 to 6 months. One reason why treatment is not continued is that the blood-thinning drugs can cause problems with bleeding. This research looked at different ways to prevent and treat clots in patients in whom there is no obvious cause for the clot. The first work package looked at whether or not it is possible to stop further blood clots by increasing the duration of treatment with blood-thinning drugs. This work package also aimed to find out if we could identify those at the highest risk of developing post-thrombotic syndrome, experiencing swelling of the legs and, at worst, developing leg ulcers. We found that, by extending treatment with blood thinners for 2 years, it is possible to reduce the number of patients developing further clots, with a small increase in bleeding. The longer treatment did not prevent development of post-thrombotic syndrome. Patients preferred to be treated for longer. The second work package aimed to understand what patients and health-care professionals know and understand about providing treatment to prevent blood clots, and whether or not there are any barriers to implementing this treatment. We identified five areas where improvements could be made: communication, knowledge, role of primary care, education and training, and barriers to patient adherence. The third work package identified the most cost-effective ways of treating clots and stopping further clots. We concluded that extending treatment is cost-effective and results in better patient outcomes. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xix DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Scientific summary Background The venous thromboembolism prevention and treatment programme (RP-PG-0608-10073) was designed to provide an evidence base to improve the prevention and treatment of venous thromboembolism in the NHS by addressing some of the existing gaps in the evidence. The programme consists of a series of studies, including a randomised controlled trial; a survey of stakeholders; qualitative interviews with patients, doctors, nurses and other stakeholders; cost-effectiveness analyses; a patient preference survey; and a number of economic modelling studies. The three interconnecting work packages were: 1. a randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism and post-thrombotic syndrome [the ExACT (Extended Anticoagulation) trial] 2. a qualitative study to explore existing knowledge and barriers, across the spectrum of health care from patients to health-care professionals [the ExPeKT (Exploration of Patient knowledge and expectation) study] 3. a health economic modelling study to evaluate the most cost-effective methods of treating and preventing recurrence of venous thromboembolism. Objectives Work package 1 l l l To determine the protective effect of prolonged anticoagulation therapy on recurrent events of deep-vein thrombosis or pulmonary embolism. To establish the performance characteristics of D-dimer testing while still on treatment as a prediction tool for recurrence of venous thromboembolism in patients with a first unprovoked proximal deep-vein thrombosis or pulmonary embolism. To establish factors that contribute to the recurrence of venous thromboembolism in patients with a first unprovoked proximal deep-vein thrombosis or pulmonary embolism. Work package 2 l l l l l l To assess the level of existing knowledge of venous thromboembolism risk among a wide range of primary health-care professionals and patients. To assess current practice and the perceived role of primary care in thromboprophylaxis among primary health-care professionals and patients. To explore the interface between primary and secondary care in terms of thromboprophylaxis and the perceived role of primary care among acute trusts and other relevant organisations. To identify local organisations’ perceived and actual clinical barriers to implementation of thromboprophylaxis for high-risk patients. To explore potential care pathways for high-risk patients prior to hospital admission in terms of assessment for thromboprophylaxis. To design effective education initiatives to ensure public and primary care engagement in venous thromboembolism preventative measures outside the hospital setting. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxi SCIENTIFIC SUMMARY Work package 3 l l l l To determine the costs and cost-effectiveness of different approaches to delivery of care and treatment for suspected thromboembolism. To determine patient preferences for extended versus standard treatment. To determine the cost-effectiveness of the measurement of levels of D-dimer and subsequent extended treatment with anticoagulation. To determine patient preferences and utilities with regard to extended anticoagulation treatment. Methods Work package 1 A prospective, multicentre, randomised controlled trial. Setting Patients were identified from anticoagulation clinics in hospitals and general practices across the Midlands, UK. Recruitment and follow-up took place in both hospital and primary care settings. Participants Patients aged ≥ 18 years with a first unprovoked deep-vein thrombosis or pulmonary embolism. Work package 2 A two-stage, mixed-methods study that included a survey study and a qualitative interview study. Participants Primary health-care professionals, patients, acute trusts and other key stakeholders. Work package 3 Analysis and decision model for alternative treatment pathways, and a patient preference study. Results Work package 1 A total of 281 patients were recruited, of whom 141 were randomly allocated to the intervention arm (group E) and 140 were randomly allocated to the control arm (group D) of the study. There were 32 recurrent venous thromboembolisms in 31 patients (13.54 events per 100 person-years) in the control group (group D) compared with seven events in seven patients (2.75 events per 100 personyears) in the intervention group (group E). This gave an adjusted hazard ratio of 0.2 (95% confidence interval 0.09 to 0.46; p < 0.001), meaning that patients who received extended anticoagulation therapy were 80% less likely to suffer a recurrent event than those patients who discontinued anticoagulation therapy. Age did not affect the rate of recurrence in either group, but males had numerically more recurrences of venous thromboembolisms off treatment than females. There were three major bleeding events (1.18 events per 100 person-years) in the control group (group D) and nine major bleeding events (3.54 events per 100 person-years) in the intervention group (group E), which gave an adjusted hazard ratio of 2.99 (95% confidence interval 0.81 to 11.05; p = 0.10). There were 19 clinically relevant non-major bleeding events (8.13 events per 100 personyears) in the control group (group D) and 28 clinically relevant non-major bleeding events (12.50 events per 100 person-years) in the intervention group (group E), which gave an adjusted hazard ratio of 1.51 (95% confidence interval 0.84 to 2.71; p = 0.165). These differences were not statistically significant. In both groups, more people aged > 65 years experienced bleeding xxii NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 The D-dimer levels pre-randomisation showed no difference in terms of risk of recurrence, but a higher percentage of those patients with venous thromboembolism recurrence had a baseline D-dimer level above 0.5 µg/l; this was not statistically significant. Similarly, there was no significant difference in the time in the therapeutic range for patients on extended treatment between those with and those without recurrence (84% vs. 76%), but the numbers are small. In terms of the quality of life and post-thrombotic syndrome outcomes, there were no differences between the groups. Work package 2 Using a combination of questionnaire surveys and face-to-face qualitative interviews with patients, health-care professionals and other stakeholders identified five key areas that remain barriers to the effective implementation of preventative strategies for hospital-acquired thrombosis: communication, knowledge, role of primary care, education and training, and barriers to patient adherence. Work package 3 The health economic model suggested that extended treatment with oral anticoagulants was only cost-effective at the £20,000-per-quality-adjusted life-year level if the annual venous thromboembolism recurrence rate was between 17.5% and 22.5%, depending on the drug acquisition costs. A patient preference study demonstrated a strong patient preference for extended treatment with anticoagulants based on a fear of recurrent venous thromboembolism over the risk of bleeding. Limitations Work package 1 did not achieve its recruitment target, which made it difficult to draw strong conclusions on the generalisability of these data. There are two similar studies currently being undertaken, one in Canada [DODS (the D-dimer Optimal Duration Study)] and the other in the Netherlands [the Venous thrombolISm: Tailoring Anticoagulant therapy duration (VISTA) study], and we have an agreement with those triallists to combine data. Another weakness of this study was that there was no blinding for some of the end-point adjudication, particularly the evaluation of post-thrombotic syndrome. However, in terms of thrombosis and bleeding, an independent end-point adjudication committee was established. Conclusions This programme of work has added to the growing evidence that patients suffering a first unprovoked venous thromboembolism could be treated for longer than the standard 3–6 months, with a significant reduction in recurrence and only a small increase in major bleeding. Patients expressed a strong preference for extended treatment. The within-trial economic analysis and the model that extrapolated beyond the trial suggested that the extended strategy was cost-effective; however, further health economic modelling utilising a previously derived prognostic model suggested cost-effectiveness with novel oral anticoagulants only if the risk threshold for annual recurrence was between 17.5% and 22.5%. There was no effect on the rate or severity of post-thrombotic syndrome. Significant barriers were identified to the successful implementation of thromboprophylaxis of hospital-acquired thrombosis, particularly at a primary care level. Future research should focus on better identifying patients in whom it is safe to stop anticoagulation therapy early following a first unprovoked venous thromboembolism, on improving communication © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxiii SCIENTIFIC SUMMARY and knowledge of hospital-acquired thrombosis (particularly at the primary care level), and the health economic model can be utilised with future data to better elucidate the cost-effectiveness of prolonged anticoagulation. Trial registration This trial is registered as ISRCTN73819751 and EudraCT 2101-022119-20. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 8, No. 5. See the NIHR Journals Library website for further project information. xxiv NIHR Journals Library www.journalslibrary.nihr.ac.uk Programme Grants for Applied Research 2020 Vol. 8 No. 5 DOI: 10.3310/pgfar08050 SYNOPSIS T his programme of work comprises three interconnecting work packages: 1. a RCT of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome (PTS) [the ExACT (Extended Anticoagulation) trial] 2. a qualitative study to explore existing knowledge and barriers, across the spectrum of health care from patients to health-care professionals (HCPs) [the ExPeKT (Exploration of Patient knowledge and expectation) study] 3. a health economic modelling study to evaluate the most cost-effective methods of treating and preventing recurrence of VTE. Protocols for the ExACT trial [work package (WP) 1]1 and the ExPeKT study (WP2)2 have been published. These WPs are summarised in Table 1 and detailed in subsequent pages of the report. Background Venous thromboembolism, defined as deep-vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disorder, after myocardial infarction and stroke. DVT is common (i.e. an incidence of approximately 1 per 1000 people per annum) and is associated with mortality and serious morbidity, particularly PE and PTS. The largest attributable risk for acquiring VTE is hospital admission for either medical or surgical conditions. Most hospitalised patients have one or more risk factors for VTE,3 with mortality from hospital-acquired thrombosis (HAT) greater than the combined total number of deaths from breast cancer, acquired immune deficiency syndrome (AIDS) and road traffic accidents each year in the UK. There is evidence to show that around 60% of people undergoing hip or knee replacement will suffer a DVT if they receive no preventative intervention, and that the mortality rate is around 30% if this is left untreated.4 TABLE 1 Summary of work packages Year Work package 2011 WP1: the ExACT RCT First patient recruited July 2011 WP2: the ExPeKT studies 2012 2013 2014 2015 Last patient recruited February 2015 2016 2017 2018 Last patient follow-up February 2017 HCP interviews Patient interviews WP3: health economic analysis Data collection Modelling June 2017 to February 2018 RCT, randomised controlled trial. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 1 SYNOPSIS Venous thromboembolism is therefore a substantial health-care problem that is associated with significant mortality, morbidity and economic cost. In 2005, there was an estimated cost to the NHS of £640M for the management of VTE.5 Some people suffer an unprovoked DVT, where no identifiable reason for the DVT can be found. These unprovoked DVTs are treated with oral anticoagulation therapy (OAT), which generally continues for between 6 weeks and 6 months. However, the optimal duration of treatment is still uncertain.6 When OAT is discontinued, there is an annual recurrence rate of approximately 10% in the first year and around 5% thereafter, irrespective of the duration of treatment. Prevention of venous thromboembolism Hospital-acquired thrombosis The largest risk for acquiring VTEs is hospital admission.4 Current UK guidelines for preventing HAT recommend using the Department of Health and Social Care’s risk assessment tool to assess appropriate thromboprophylaxis for individuals.7 Thromboprophylaxis has been shown to reduce the risk of VTE by 75% in surgical patients and 50% in medical patients. In 2010, Commissioning for Quality and Innovation (CQUIN) agreements were introduced that required all UK acute trusts to assess risk for VTEs for at least 90% of patients, or risk financial penalties.8 However, an All-Party Parliamentary Thrombosis Group (APPTG) survey found that implementation of risk assessment was poor,9 and only 58% of trusts carry out a regular clinical audit of thromboprophylaxis. Furthermore, HAT can occur up to 90 days post discharge, but there is little or no understanding of the role that primary care can play in the process; there is also no evidence of the use of care plans for community VTE prophylaxis. Unprovoked deep-vein thrombosis The risk of recurrence among patients with unprovoked thrombosis is higher than for those with identifiable risk factors, such as surgery or long-haul travel. The cumulative rate of recurrence for those with unprovoked VTE is about 25% at 5 years and 30% at 10 years. The risk varies with time, with the highest risk evident during the first 6–12 months; the risk never reaches zero. Furthermore, these recurrent events are fatal in about 5–9% of people. Most recurrences can be prevented by appropriate antithrombotic therapy, but there is a concern in terms of the duration of treatment owing to the increased risk of bleeding from prolonged OAT. Several studies have investigated the optimal duration of OAT, with the British Committee for Standards in Haematology recommending between 6 weeks and 6 months, depending on the aetiology.6 However, the optimal duration of OAT for patients with a first unprovoked DVT remains uncertain, with randomised controlled trials (RCTs) suggesting that the duration has little effect on the rate of recurrence.10 Research to address the most appropriate approach to preventing recurrences is still required. Identification of patients at the highest risk of recurrence Given the balance of risks and benefits of anticoagulation therapy (AT) described above, it may be beneficial to identify those at the highest risk of recurrence. It may be possible to stratify individual risk based on a variety of clinical factors, including sex or comorbidities, or to measure laboratory markers such as coagulation factors. Alternatively, risk prediction models can be used, such as the Vienna Prediction Model, although this is most accurate in people already at low risk of recurrence.11 There is evidence that normal D-dimer levels, measured around 4 weeks after cessation of OAT, are associated with lower risk of recurrence.12 2 NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 D-dimer is a fibrin degradation product present in the blood after a blood clot is degraded by fibrinolysis; levels of D-dimer can be tested using laboratory and point-of-care testing devices. The primary clinical use of levels of D-dimer has been in conjunction with probability scores to determine whether or not further investigation is required for the diagnosis of VTE. More recently, interest has been shown in studies that have investigated whether or not the levels of D-dimer can be utilised as a guide for determining who is at risk of recurrent VTE following treatment of the initial acute episode. Some small studies have suggested that the levels of D-dimer could act as a useful predictor of recurrent VTE in patients whose OAT is discontinued.13 There are limited data on the utility of levels of D-dimer as a predictor in patients still on therapy, but Rodgers et al.14 have shown that the levels of D-dimer can be used to predict recurrence in low-risk female patients. Two systematic reviews of D-dimer testing after cessation of treatment for VTE (seven studies with total of 1888 patients) concluded that ‘additional research is needed to establish the optimal interval between stopping anticoagulation and performing D-dimer testing, (and) to identify the optimum cut-off point that predicts recurrence’.14 No studies to date have investigated the utility of D-dimer testing while a patient is still undergoing therapy, and there are no studies that have investigated the utility of D-dimer testing in conjunction with clinical algorithms to prevent recurrence of DVT. Post-thrombotic syndrome Post-thrombotic syndrome is a frequent and costly complication of DVT that can lead to chronic venous insufficiency and ulceration, and reduced quality of life for patients. Prevalence of PTS in one study was found to be 37% after 2.2 years, with 4% of people having severe PTS.15 PTS has a cumulative incidence after 2 years of around 25%, and it has been postulated that prolonged treatment with OAT could prevent the development of PTS.16 However, the only randomised data available suggested no association between long-term low-dose warfarin treatment and the development of PTS,15 and there are no data available for patients treated with long-term therapeutic warfarin. Barriers to implementation of thromboprophylaxis For the reasons discussed above, the prevention of VTE and appropriate management of the risk of recurrence is important. However, despite the introduction of guidelines8 and CQUIN agreements, it seems that the guidelines and recommendations are not universally implemented. It is known that there is little knowledge about VTE in the public arena,4 which is perhaps unsurprising, as it is apparent that HCPs also underestimate the extent and impact of the problem. The APPTG report highlighted the role that primary care could play in improving the management of VTE.17 General practitioners (GPs) are in a good position to deliver education to patients, and to improve the management of patients post hospital discharge. However, there is little evidence to date of the use of care plans for community VTE prophylaxis. When considering patient barriers, diabetes studies have shown the desire to avoid injectable drugs, so low-molecular-weight heparin therapy may, therefore, introduce concordance issues.18 Patients were educated about the risk of heparin-induced thrombocytopenia, a life-threatening, immune-mediated prothrombotic adverse drug effect. Patients appreciated the information about the potential adverse reactions to the drug; the information given did not lead to a treatment refusal, with all patients choosing treatment.19 The lack of public awareness could be addressed through public education programmes, as improving understanding will empower patients with the knowledge to request a risk assessment on admission to hospital.20 However, we do not know patients’ attitudes to education and information in this area. Furthermore, we do not know how best to deliver this information; no educational measures have been developed. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 3 SYNOPSIS The HCP barriers to initiating VTE prophylaxis may be manifold. There is some evidence that non-adherence to guidelines is an issue for clinicians but barriers to implementation are unclear. Knowledge to practice translational issues are extremely important for the successful integration of thromboprophylaxis into the community and clarity around processes is necessary. The guidelines stipulate a supporting role for GPs, based on notification that a patient has been discharged from hospital and the treatment prescribed. However, communication between care settings is known to be problematic, leading to the role performed by primary care being unclear. If primary care is to contribute more effectively to the prevention of HAT, then a better understanding of its role and of the factors that influence the role is required. Summary The VTE prevention and treatment programme was designed to provide an evidence base to improve the prevention and treatment of VTE in the NHS, through addressing some of the existing gaps in the evidence, as discussed above. The programme consists of a series of studies including a RCT; a survey of stakeholders; qualitative interviews with patients, doctors, nurses and other stakeholders; cost-effectiveness analyses; patient preference survey; and a number of economic modelling studies. Each work package is detailed below. Patient and public involvement Mrs Eve Knight, Director of Anticoagulation Europe, a patient-based charitable organisation, was involved in this programme from its conception and continued to provide input throughout the lifetime of the programme as a member of the Programme Board. She approved all patient-facing material and also contributed to the develoment of the interview schedule for WP2. The charity was not involved in the identification of patients for the programme. The programme of work was reviewed and edited by the two public representatives on the Primary Care Research Network, Central England (PCRN-CE) Management Group. 4 NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Work package 1: randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism and post-thrombotic syndrome in patients being treated for a first episode of unprovoked venous thromboembolism (the ExACT trial) Overview The background section described the existing evidence around the most appropriate treatment to prevent recurrent clots in people who have had a first unprovoked VTE, and the identification of people likely to be at the highest risk of recurrence. Uncertainty remains about the optimum duration of anticoagulation treatment following a first unprovoked VTE, and there is no clear guidance to help clinicians identify those at a high risk of recurrence. There is also a lack of data available around the use of anticoagulation treatment to prevent the development of PTS. This work package aimed to address these gaps in the knowledge. This section reports on the ExACT trial. The cost analysis and patient preference study are presented in subsequent sections. The ExACT trial was approved by Trent Research Ethics Committee on 21 October 2010. Methods The ExACT trial was a non-blinded, prospective, multicentre RCT. The full methods of the ExACT trial have been published.1,21 The methods are further described in Appendix 1. Aim The aim of the ExACT trial was to investigate the effect of extending treatment with oral anticoagulation for those patients with first unprovoked proximal DVT or PE prior to discontinuing treatment, in terms of reduction in incidence of VTE and PTS. Objectives l l l l To determine the protective effect of prolonged AT on recurrent events of DVT or PE. To determine the protective effect of prolonged AT on the severity of PTS. To establish the performance characteristics of D-dimer testing while still on treatment as a prediction tool for recurrence of VTE in patients with first unprovoked proximal DVT or PE. To establish factors that contribute to the recurrence of VTE in patients with a first unprovoked proximal DVT or PE. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 5 WORK PACKAGE 1 l l To determine the cost-effectiveness of extended treatment with anticoagulation (described in WP3). To determine patient preferences and utilities with regard to extended anticoagulation treatment (described in WP3). Sample size calculation The study was designed to compare 2-year VTE recurrence rates between participants in the extended versus discontinued AT arms, and also to compare these rates for a group of participants with a baseline raised levels of D-dimer. A sample size of 352 (176 per arm) would be sufficient to detect a clinically important difference between the arms with minimum 86% power, two-sided alpha = 0.05, assuming recurrence rates between 1.4% and 4.3% for the extended AT arm and 14.2% in the discontinued AT arm. Recruitment was lower than expected and, at the request of the Trial Steering Committee, the power calculation was re-estimated, as a result of which it was determined that a sample of 270 participants (allowing for 10% loss to follow-up) would provide at least 80% power to detect the planned effect sizes. Summary of changes to the protocol (version 2.11) l l l We listed an additional objective (to determine the protective effect of prolonged AT on the severity of PTS) that was included as a planned secondary outcome in the protocol but was not detailed in the objectives. We clarified that VTE and bleeding events are time-to-event outcomes. We excluded the second analysis outlined in section 4.1 of protocol version 2.11 (number of recurrent thrombotic events between those with a raised level of D-dimer who were randomly allocated to the no-treatment arm and those with normal levels of D-dimer who were randomly allocated to the no-treatment arm), as the first analysis listed in this section is the only subgroup analysis required to investigate the cut-off point analysis. Results Participant recruitment The first patient was randomised in July 2011 and the last patient was randomised in February 2015. The records of 8422 patients presenting to the recruiting sites with a suspected DVT/PE were screened to identify potentially eligible patients who met the inclusion criteria. Following application of the criteria, 5034 patients were identified as ineligible for invitation to participate. Invitations to participate in the trial in the form of postcards and participant information sheets were provided to 3388 potentially eligible patients. Responses were received from 1361 out of 3388 (40%) potentially eligible patients, with 993 out of 1361 (73%) notifying the research team that they were interested in participating in the study and providing their permission for the research team to contact their GP to confirm their eligibility to participate. Overall, 368 out of 3388 (11%) patients responded stating that they did not wish to participate. Responses to the invitation were not returned by 2027 out of 3388 (60%) patients (Figure 1). The GPs of the 993 potentially eligible patients were contacted to confirm patient eligibility to take part. GPs confirmed eligibility for 393 out of 993 (40%) patients, and 499 out of 993 (50%) were ineligible. GPs did not complete the eligibility checks for 101 out of 993 (10%) patients. The main reasons for exclusion were that the patient had recently stopped oral anticoagulation (20%), they had an indication for long-term OAT (15%) and they had a provoked DVT or PE (14%). The reasons for ineligibility were not reported for 112 out of 499 (22%) patients. A total of 281 patients provided written informed consent to participate and were randomised: 141 were randomly allocated to the intervention arm of the study (group E) and 140 to the control arm (group D) of the study. All 281 trial participants attended visit 1, 273 (97%) attended visit 2, 263 (94%) 6 NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Screening of patients with suspected DVT or PE attending the recruitment site (n = 8422a) Excluded following screening (n = 5034) Potentially eligible patients provided with an invitation to participate (n = 3388) No response to invitation [n = 2027 (60%, 2027/3388)] Potentially eligible patients responded to the invitation (n = 1361) Declined invitation to participate [n = 368 (27%, 368/1361)] Accepted invitation to participate and consented to GP screening of eligibility [n = 993 (73%, 993/1361)] Incomplete GP eligibility check [n = 101 (10%, 101/993)] Ineligible following GP eligibility screen [n = 499 (50%, 499/993)] Patients fulfilled trial eligibility criteria [n = 393 (40%, 393/993)] Reason for ineligibility • No reason reported, n = 110 (22%) • No longer receiving OAT, n = 100 (20%) • Long-term OAT, n = 76 (15%) • Provoked DVT/PE, n = 70 (14%) • Distal/another site DVT, n = 46 (9%) • Recurrent DVT/PE, n = 39 (8%) • GP discretion, n = 23 (5%) • High bleeding risk, n = 16 (3%) • Housebound, n = 10 (2%) • Active cancer, n = 8 (2%) • Pregnancy, n = 1 (0.2%) Did not commit to baseline research clinic [n = 112 (28%, 112/393)] Committed to baseline research clinic, consented and randomised [n = 281 (72%, 281/393)] FIGURE 1 Patient flow diagram. a, Data for suspected DVT or PE are taken from site screening logs and are therefore only estimates of the total number with DVT or PE. attended visit 3 and 260 attended (93%) visit 4 (Figure 2). Post oral anticoagulation cessation visits were completed by 182 out of 281 (65%) participants. Baseline characteristics No differences were found in baseline characteristics between the intervention and control groups (Table 2). The mean age of participants was around 63 years, with a roughly even split between DVT and PE, and approximately two-thirds of participants were male. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 7 WORK PACKAGE 1 Randomised (n = 281) Discontinued anticoagulation therapy (group D) (n = 140) Extended anticoagulation therapy (group E) (n = 141) Withdrawn (n = 6a) Withdrawn (n = 2b) Data available for analysis of primary outcome (time to the first recurrent VTE since randomisation up to 24 months’ follow-up) (n = 134) Data available for analysis of primary outcome (time to the first recurrent VTE since randomisation up to 24 months’ follow-up) (n = 139c) Excluded from analysis (n = 6) Excluded from analysis (n = 2) • Consent to use data withdrawn, n = 4 • Participant with antiphospholipid syndrome, n = 0 • Participant with protein C and/or protein S or antithrombin deficiency, n = 2 • Consent to use data withdrawn, n = 1 • Participant with antiphospholipid syndrome, n = 1 • Participant with protein C and/or protein S or antithrombin deficiency, n = 0 FIGURE 2 Patient flow diagram following randomisation. a, Includes four participants who withdrew consent to use their data; b, includes one participant who withdrew consent to use their data; and c, includes two patients receiving rivaroxaban (Xarelto; Bayer AG, Leverkusen, Germany) therapy. TABLE 2 Baseline characteristics Trial group Control (group D) (N = 134) Characteristic Intervention (group E) (N = 139) Total (N = 273) Age at time of randomisation (years) Mean (SD) 63.3 (12.7) 62.2 (13.0) 62.7 (12.8) Median (IQR) 64.5 (55.6–74.0) 64.4 (53.3–72.4) 64.4 (54.4–72.7) Sex, n (%) Female 44 (32.8) 45 (32.4) 89 (32.6) 90 (67.2) 94 (67.6) 184 (67.4) Unprovoked DVT 69 (51.5) 70 (50.4) 139 (50.9) Unprovoked PE 65 (48.5) 69 (49.6) 134 (49.1) Male a Diagnosis (DVT/PE), n (%) 8 NIHR Journals Library www.journalslibrary.nihr.ac.uk Programme Grants for Applied Research 2020 Vol. 8 No. 5 DOI: 10.3310/pgfar08050 TABLE 2 Baseline characteristics (continued ) Trial group Control (group D) (N = 134) Intervention (group E) (N = 139) Total (N = 273) White 131 (97.8) 131 (94.2) 262 (96.0) Mixed 1 (0.8) 0 (0.0) 1 (0.4) Asian or Asian British 0 (0.0) 3 (2.2) 3 (1.1) Black or black British 2 (1.5) 5 (3.6) 7 (2.6) Other ethnic groups 0 (0.0) 0 (0.0) 0 (0.0) Non-smoker 63 (47.0) 60 (43.2) 123 (45.1) Ex-smoker 48 (35.8) 60 (43.2) 108 (39.6) Current smoker 19 (14.2) 18 (13.0) 37 (13.6) 4 (3.0) 1 (0.7) 5 (1.8) No 44 (32.8) 51 (36.7) 95 (34.8) Yes 90 (67.2) 88 (63.3) 178 (65.2) 2 (1.5) 0 (0.0) 2 (0.7) Characteristic Ethnicity, n (%) Smoking status, n (%) Smokes occasionally Alcohol consumption, n (%) BMI classification (kg/m2), n (%) Underweight (< 18.5) Normal range (18.5–24.99) 47 (35.1) 47 (33.8) 94 (34.4) Overweight (25–29.99) 51 (38.1) 53 (38.1) 104 (38.1) Obese (≥ 30) 33 (24.6) 37 (26.6) 70 (25.6) 1 (0.8) 2 (1.4) 3 (1.1) No 102 (76.1) 102 (73.4) 204 (74.7) Yes 32 (23.9) 37 (26.6) 69 (25.3) No 130 (97.0) 136 (97.8) 266 (97.4) Yes 4 (3.0) 3 (2.2) 7 (2.6) No 129 (96.3) 138 (99.3) 267 (97.8) Yes 5 (3.7) 1 (0.7) 6 (2.2) No 129 (96.3) 136 (97.8) 265 (97.1) Yes 5 (3.7) 3 (2.2) 8 (2.9) No 133 (99.3) 134 (96.4) 267 (97.8) Yes 1 (0.8) 5 (3.6) 6 (2.2) No 130 (97.0) 136 (97.8) 266 (97.4) Yes 4 (3.0) 3 (2.2) 7 (2.6) Missing Family history of VTE, n (%) Medical history Stroke, n (%) Transient ischaemic attack, n (%) Angina, n (%) Myocardial infarction, n (%) Ischaemic heart disease, n (%) continued © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 9 WORK PACKAGE 1 TABLE 2 Baseline characteristics (continued ) Trial group Control (group D) (N = 134) Intervention (group E) (N = 139) Total (N = 273) No 134 (100.0) 134 (96.4) 268 (98.2) Yes 0 (0.0) 5 (3.6) 5 (1.8) No PTS 70 (52.2) 66 (47.5) 136 (49.8) Mild PTS 42 (31.3) 51 (36.7) 93 (34.1) Moderate PTS 15 (11.2) 18 (13.0) 33 (12.1) Severe PTS 5 (3.7) 2 (1.4) 7 (2.6) Missing 2 (1.5) 2 (1.4) 4 (1.5) Mean (SD) 5.2 (4.2) 5.1 (3.8) 5.2 (4.0) Median (IQR) 4.0 (2.0–7.5) 5.0 (2.0–8.0) 4.0 (2.0–8.0) Missing 2 2 4 0.8 (0.2) 0.8 (0.3) 0.8 (0.3) Characteristic Peripheral vascular disease, n (%) PTS score (categorical), n (%) PTS score EQ-5D-3L Mean (SD) Median (IQR) 0.8 (0.7–1.0) 0.8 (0.7–1.0) 0.8 (0.7–1.0) Missing 0 4 4 VEINES-QOL score Mean (SD) 48.2 (10.7) 49.6 (9.9) 48.9 (10.3) Median (IQR) 51.1 (41.1–57.6) 53.0 (44.6–56.7) 52.1 (43.3–57.5) Missing 0 2 2 Health-care utilisation because of PTS Patient receiving primary care treatment, n (%) No 124 (92.5) 128 (92.1) 252 (92.3) Yes 9 (6.7) 11 (7.9) 20 (7.3) Missing 1 (0.8) 0 (0.0) 1 (0.4) Type of nurse patients were seen by, n (%) Practice 2 (1.5) 1 (0.7) 3 (1.1) District 0 (0.0) 0 (0.0) 0 (0.0) HCA 0 (0.0) 0 (0.0) 0 (0.0) None 59 (44.0) 70 (50.4) 129 (47.3) Other 0 (0.0) 0 (0.0) 0 (0.0) 73 (54.5) 68 (48.9) 141 (51.7) Missing Patient receiving treatment for a leg ulcer, n (%) No 66 (49.3) 71 (51.1) 137 (50.2) Yes 1 (0.8) 2 (1.4) 3 (1.1) 67 (50.0) 66 (47.5) 133 (48.7) Missing 10 NIHR Journals Library www.journalslibrary.nihr.ac.uk Programme Grants for Applied Research 2020 Vol. 8 No. 5 DOI: 10.3310/pgfar08050 TABLE 2 Baseline characteristics (continued ) Trial group Characteristic Control (group D) (N = 134) Intervention (group E) (N = 139) Total (N = 273) Patient receiving secondary care treatment, n (%) No 131 (97.8) 135 (97.1) 266 (97.4) Yes 1 (0.8) 4 (2.9) 5 (1.8) Missing 2 (1.5) 0 (0.0) 2 (0.7) BMI, body mass index; EQ-5D-3L, EuroQol-5 Dimensions, three-level version; HCA, health-care assistant; IQR, interquartile range; SD, standard deviation; VEINES-QOL, Venous Insufficiency Epidemiological and Economic study – Quality of Life. a Minimisation variable. Primary outcome In terms of the primary outcome, there were 32 recurrent VTEs in 31 patients (13.54 events per 100 person-years) within the control group (group D) compared with seven events in seven patients (2.75 events per 100 person-years) in the intervention group (group E). This gave an adjusted hazard ratio of 0.2 [95% confidence interval (CI) 0.09 to 0.46; p < 0.001], meaning that patients receiving extended AT were 80% less likely to suffer a recurrent event than those patients who discontinued AT (Table 3 and Figure 3). Age did not affect the rate of recurrence in either group, but males had numerically more recurrences off treatment than females. The intervention effect does not differ significantly between the two age groups (p = 0.267), but the intervention group (group E) had significantly reduced VTE recurrences than the control group (group D) in males (adjusted hazard ratio 0.11, 95% CI 0.03 to 0.38) but not in females (adjusted hazard ratio 0.48, 95% CI 0.14 to 1.59), even though the associated interaction effect is not significant at the 5% level (p = 0.099) (see Table 4). TABLE 3 Primary and secondary outcomes Trial group Control (group D) (N = 134) Intervention (group E) (N = 139) Adjusted hazard ratio (95% CI)a Number of participants with one or more events, n (%) 31 (23.1) 7 (5.0) 0.20 (0.09 to 0.46) < 0.001 Number of eventsb 32 7 13.54 2.75 Number of participants with one or more events, n (%) 3 (2.2) 9 (6.5) 2.99 (0.81 to 11.05) 0.100 Number of events 3 9 1.18 3.54 Outcome p-value Primary outcome Recurrent VTE c Number of events per 100 person-years Secondary outcomes Major bleeding events c Number of events per 100 person-years continued © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 11 WORK PACKAGE 1 TABLE 3 Primary and secondary outcomes (continued ) Trial group Control (group D) (N = 134) Intervention (group E) (N = 139) Adjusted hazard ratio (95% CI)a Number of participants with one or more events and non-missing event dates,d n (%) 19 (14.2) 28 (20.1) 1.51 (0.84 to 2.71) Number of participants with one or more events,d n (%) 21 (15.7) 32 (23.0) Number of eventsd 25 43 Number of events per 100 person-yearsc 8.13 12.50 Outcome p-value Clinically relevant non-major bleeding events a b c d 0.165 Adjusting for baseline diagnosis (DVT/PE). One participant in the discontinued AT group had two thrombotic events within the 2-year follow-up period. Number of events per 100 person-years was calculated only for the first events with a non-missing event time. Among the 53 time to first events, six events (two in the discontinued AT group and four in the extended AT group) had their event time missing (all of which should have occurred before the end of the 2-year follow-up by checking the corresponding visit number); therefore, only 47 events contributed to the calculation of the adjusted hazard ratio. (a) Cumulative rate of events 0.30 AT 0.20 Discontinued Extended 0.10 0.00 0 200 400 600 800 100 123 0 0 Days of follow-up Number at risk Discontinued AT Extended AT 134 139 123 130 114 127 FIGURE 3 Cumulative risk of the primary outcome of time to first recurrent VTE (a) and of the secondary outcomes of time to first major bleeding (b), and time to first clinically relevant non-major bleeding event (c) between discontinued AT and extended AT. (continued ) 12 NIHR Journals Library www.journalslibrary.nihr.ac.uk Programme Grants for Applied Research 2020 Vol. 8 No. 5 DOI: 10.3310/pgfar08050 (b) Cumulative rate of events 0.08 0.06 AT Discontinued Extended 0.04 0.02 0.00 0 200 400 600 800 124 122 0 0 Days of follow-up Number at risk Discontinued AT Extended AT (c) 134 139 129 130 127 125 Cumulative rate of events 0.25 0.20 AT Discontinued Extended 0.15 0.10 0.05 0.00 0 200 400 600 800 110 101 0 0 Days of follow-up Number at risk Discontinued AT Extended AT 132 135 119 118 116 108 FIGURE 3 Cumulative risk of the primary outcome of time to first recurrent VTE (a) and of the secondary outcomes of time to first major bleeding (b), and time to first clinically relevant non-major bleeding event (c) between discontinued AT and extended AT. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 13 WORK PACKAGE 1 Secondary outcomes There were three major bleeding events (1.18 events per 100 person-years) in the control group (group D) and nine major bleeding events (3.54 events per 100 person-years) in the intervention group (group E), giving an adjusted hazard ratio of 2.99 (95% CI 0.81 to 11.05; p = 0.10). There were 19 clinically relevant non-major bleeding events (8.13 events per 100 person-years) in the control group (group D) and 28 clinically relevant non-major bleeding events (12.50 events per 100 person-years) in the intervention group (group E), giving an adjusted hazard ratio of 1.51 (95% CI 0.84 to 2.71; p = 0.165). These differences were not statistically significant (see Table 3 and Figure 3). In both groups, more people aged > 65 years experienced bleeding (Table 4). The D-dimer levels pre-randomisation showed no difference in terms of risk of recurrence. Although a higher percentage of those patients with VTE recurrence had a baseline D-dimer level > 0.5 µg/l, this was not statistically significant (Table 5). Further work is being done as part of an ongoing Doctor of Philosophy (PhD) project to investigate whether or not there is an alternative cut-off point for D-dimer levels while still on therapy, which might be predictive of further events. Similarly, there was no significant difference in time in therapeutic range for patients on extended treatment between those with or without recurrence, but the number of participants was small (Table 6). In terms of the quality of life and PTS outcomes, there were no differences between the groups (Table 7). TABLE 4 Subgroup analysis of primary and secondary outcomes Trial group Control (group D) (n = 134) Characteristic Number of events (%) Number of events per 100 person-years Intervention (group E) (n = 139) Number of events (%) Number of events per 100 person-years Hazard ratio (95% CI)a p-value for interaction Recurrent VTE Sex Male Female 0.099 23 (25.6) 15.26 3 (3.2) 1.75 0.11 (0.03 to 0.38) 8 (18.2) 10.23 4 (8.9) 4.83 0.48 (0.14 to 1.59) Age (years) 0.267 ≤ 65 17 (23.3) 13.77 2 (2.8) 1.52 0.11 (0.03 to 0.48) > 65 14 (23.0) 13.28 5 (7.5) 4.07 0.31 (0.11 to 0.85) Major bleeding events Sex 0.961 Male 2 (2.2) 1.18 6 (6.4) 3.57 2.92 (0.59 to 14.48) Female 1 (2.3) 1.18 3 (6.7) 3.49 3.13 (0.33 to 30.12) Age (years) 0.190 ≤ 65 2 (2.7) 1.45 2 (2.8) 1.50 1.01 (0.14 to 7.17) > 65 1 (1.6) 0.86 7 (10.5) 5.79 6.89 (0.85 to 56.03) a Adjusting for baseline diagnosis (DVT/PE), the interaction between treatment and each of the two covariates (age and sex), separately, together with their main effects. 14 NIHR Journals Library www.journalslibrary.nihr.ac.uk Programme Grants for Applied Research 2020 Vol. 8 No. 5 DOI: 10.3310/pgfar08050 TABLE 5 Association of baseline D-dimer level and risk of VTE recurrence Recurrence, n (%) D-dimer level at baseline No recurrence (n = 235) Recurrent VTE (n = 38) Total (n = 273), n (%) < 0.5 µg/l (%) 216 (91.91) 33 (86.84) 249 (91.21) ≥ 0.5 µg/l (%) 9 (3.83) 3 (7.89) 12 (4.40) 10 (4.26) 2 (5.26) 12 (4.40) Missing TABLE 6 The therapeutic range for the intervention group (group E) by the recurrence of VTE (18 participants with zero therapeutic range were excluded) Recurrence Therapeutic range No recurrence (n = 116) Recurrent VTE (n = 5)a Total (n = 121) Mean (SD) 76.27 (15.27) 83.93 (13.86) 76.59 (15.24) Median (IQR) 77.03 (67.81–86.53) 76.95 (75.22–97.63) 77.02 (68.21–86.66) IQR, interquartile range; SD, standard deviation. a Two patients excluded, one patient received rivaroxaban and one patient did not attend for international normalised ratio monitoring. TABLE 7 Secondary outcomes (continuous) AT Discontinued (n = 134) Outcome n Adjusted meana (95% CI) Extended (n = 139) n Adjusted meana (95% CI) VEINES-QOL p-value for time–treatment interaction 0.766 6 months 118 50.13 (48.98 to 51.29) 126 49.87 (48.74 to 51.00) 12 months 116 50.13 (48.97 to 51.29) 124 50.34 (49.20 to 51.48) 18 months 112 50.74 (49.57 to 51.91) 117 50.20 (49.04 to 51.35) 24 months 108 50.33 (49.14 to 51.51) 120 50.30 (49.16 to 51.45) EQ-5D-3L 0.908 6 months 118 0.80 (0.76 to 0.83) 126 0.81 (0.78 to 0.84) 12 months 117 0.81 (0.77 to 0.84) 124 0.81 (0.78 to 0.85) 18 months 113 0.82 (0.79 to 0.86) 117 0.82 (0.79 to 0.86) 108 0.82 (0.79 to 0.85) 120 0.81 (0.78 to 0.85) 24 months b 0.907 Severity of PTS 6 months 117 4.77 (4.24 to 5.30) 126 4.73 (4.22 to 5.25) 12 months 116 4.68 (4.14 to 5.21) 123 4.88 (4.36 to 5.40) 18 months 111 4.73 (4.19 to 5.28) 115 4.96 (4.43 to 5.49) 24 months 110 5.00 (4.45 to 5.54) 120 5.09 (4.57 to 5.62) continued © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 15 WORK PACKAGE 1 TABLE 7 Secondary outcomes (continuous) (continued ) AT Discontinued (n = 134) Extended (n = 139) n % n % None (0–4) 66 49.25 71 51.08 Mild (5–9) 42 31.34 36 25.90 Moderate (10–14) 7 5.22 15 10.79 Severe (≥ 15) 2 1.49 4 2.88 None (0–4) 67 50.00 71 51.08 Mild (5–9) 38 28.36 38 27.34 Moderate (10–14) 10 7.46 10 7.19 1 0.75 4 2.88 None (0–4) 63 47.01 63 45.32 Mild (5–9) 39 29.10 37 26.62 Moderate (10–14) 8 5.97 11 7.91 Severe (≥ 15) 1 0.75 4 2.88 None (0–4) 66 49.25 65 46.76 Mild (5–9) 29 21.64 37 26.62 Moderate (10–14) 11 8.21 12 8.63 4 2.99 6 4.32 Outcome p-value for time–treatment interaction Category of PTSb 6 months 12 months Severe (≥ 15) 18 months 24 months Severe (≥ 15) EQ-5D-3L, EuroQol-5 Dimensions, three-level version; VEINES-QOL, Venous Insufficiency Epidemiological and Economic study – Quality of Life. a A linear mixed model was fitted adjusting for the corresponding baseline response, baseline diagnosis (DVT/PE), treatment, the time of assessments and the interaction between treatment and time. b Worst score from both legs. Discussion Work package 1 adds to the accumulating evidence base that patients with a first unprovoked VTE, either DVT or PE, can benefit from prolonged anticoagulation in terms of reducing recurrence of VTE with no statistical increased risk of bleeding. Data that have been published subsequent to the start of WP1 have also demonstrated reduction in recurrence of VTE with no increase in bleeding using lower doses of alternative agents in RCTs.21 The previously published study used apixaban at two doses or placebo in a population who had already been treated for 6 or 12 months and in whom there remained clinical equipoise in terms of continuing or stopping the AT, with follow-up for 12 months. The event rates for recurrence were somewhat higher in the current study, at 8.8% for the placebo group in the apixaban study compared with 23.1% for the control group (group D) in the current study. In terms of 16 NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 the treated populations, the event rates in the apixaban study were 1.7% for both the 2.5-mg and the 5-mg group compared with 5% in the intervention group (group E) from WP1. Patients were, of course, followed up for 2 years in WP1. There were no differences found in the current study with regard to any of the other secondary outcomes, quality of life (including both disease-specific and generic measures) or the incidence or severity of PTS. The results of D-dimer levels at baseline, prior to cessation of AT, were not discriminatory in terms of predicting VTE recurrence. Limitations Work package 1 did not achieve its recruitment target, which made it difficult to draw strong conclusions on the generalisability of these data. Two similar studies are currently being undertaken in Canada [DODS (D-dimer Optimal Duration Study)22] and the Netherlands [the Venous thrombolISm: Tailoring Anticoagulant therapy duration (VISTA) study], and we have an agreement with those triallists to combine data. Another weakness of this study was that there was no blinding for some of the end-point adjudication, particularly the evaluation of PTS. However, in terms of thrombosis and bleeding, an independent end-point adjudication committee was established. The cost-effectiveness of the approach followed in WP1 will be explored in the subsequent sections. Summary Work package 1 has demonstrated that extended treatment with anticoagulation for up to 2 years following initial treatment of a first unprovoked VTE provides protection in terms of recurrent VTE with a non-significant increase in the risk of major and non-major clinically relevant bleeding. No protection was seen in terms of PTS and there was no difference on either of the quality-of-life measures. Finally, no evidence was seen in this study to support the use of measuring levels of D-dimers while the patient is still taking anticoagulant treatment in terms of predicting who will have a recurrent VTE event. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 17 DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Work package 2: Exploring Prevention and Knowledge of venous Thromboembolism (ExPeKT) – surveys I n previous sections, the findings from WP1 were described and summarised. This section reports on WP2, the qualitative element of the programme. The aim of this WP was to explore existing knowledge and barriers to implementing thromboprophylaxis pre and post hospital admission. We would like to acknowledge both the British Medical Journal23,24 and the British Journal of General Practice25 for their permission in reproducing text and data from previous publications. Some parts of this report have been reproduced with permission from McFarland et al.23 [This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/] and Apenteng et al.24 [This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/ licenses/by/4.0/]. Some parts have also been reproduced with permission from Litchfield et al.25 Overview Venous thromboembolism is a recognised risk following hospital admission. Most hospitalised patients have one or more risk factors for VTE. Around 60% of people undergoing hip or knee replacement will suffer a DVT without preventative intervention. Appropriate thromboprophylaxis reduces the risk of VTE by up to 70% for medical and surgical conditions. The introduction of the VTE Quality Standard [National Institute for Health and Care Excellence (NICE)26] and the CQUIN27 goal has led to improved VTE risk management in the hospitals. Objectives The objective of this series of studies was to explore the views of primary HCPs, patients and other relevant organisations on the potential role of primary care in hospital-acquired VTE risk management. Other objectives were to assess the level of existing knowledge of VTE risk among a range of primary HCPs and patients, to assess current practice and the perceived role of primary care in thromboprophylaxis among primary HCPs and patients; and to explore the interface between primary and secondary care in terms of thromboprophylaxis. Methods and analysis The studies were carried out using a two-stage, mixed-methods approach using surveys with primary HCPs and patients followed by interviews with primary HCPs, patients, acute trusts and other relevant organisations. Survey and qualitative interview data were used to examine the current practice of thromboprophylaxis, and the knowledge and experience of VTE prevention. Survey data were analysed using SPSS (Statistical Product and Service Solutions) version 20 (IBM Corporation, Armonk, NY, USA). Open-ended responses were analysed using qualitative thematic methods. The recorded and transcribed semistructured interview data were analysed using constant comparative methods. © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 19 WORK PACKAGE 2: EXPEKT SURVEYS Ethics and dissemination Ethics approval was provided by the National Research Ethics Committee (reference: 11/H0605/5), and site-specific research and development approval was granted by the relevant research and development departments in each NHS trust. Setting Two acute trusts in the UK, and Oxfordshire and South Birmingham PCTs. Participants l l l Patients were recruited from medical, surgical and orthopaedic wards from acute trusts in Oxfordshire and Birmingham. All of the GPs and practice nurses in Oxfordshire and South Birmingham PCTs took part. HCPs and personnel based in other organisations involved in supporting patients with thromboembolic disease contributed to the other elements of this WP. 20 NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Work package 2: surveys and interviews with patients and health-care professionals regarding prevention of venous thromboembolism Background In 2012, the APPTG (established in 2006 to promote awareness of VTE among parliamentarians) recommended that primary care should take an increasing role in the VTE prevention pathway including pre-assessments of VTE risk for elective hospital admissions. It also recommended that there should be an increasing role for informing patients about the risks of VTE and preventative treatment, and that a robust system be developed to ensure that primary care clinicians are informed when patients are discharged on extended VTE prophylaxis so that patients can be managed and supported effectively.3 Subsequent to these initiatives, NICE published guidance in 2018, but this was after this WP was undertaken.7 Venous thromboembolism is a major public health problem, with VTE-related deaths per annum estimated to be almost 550,000, more than double the 209,926 combined deaths due to AIDS, breast cancer, prostate cancer and road traffic accidents.28 Many of these events are hospital acquired and could be prevented, given the availability of effective VTE prophylaxis.5 One in every 100 patients undergoing total knee replacement and 1 in every 200 patients undergoing total hip replacement will experience a VTE event before hospital discharge.4 Without thromboprophylaxis, approximately 60% of patients undergoing major orthopaedic surgery, which includes total knee or hip replacement, will experience a confirmed DVT.29 Similarly, acute medical illness patients have a moderate (10–20%) risk of developing a DVT.30 The association between VTE and cancer is well established,31–33 and one in seven inpatients with cancer dies of PE.34 With appropriate thromboprophylaxis, the risk of VTE can be reduced by up to 70% for medical and surgical conditions,35 and clinical trials have shown that the use of anticoagulants reduces the risk of VTE in hospitalised acutely ill medical patients.5,6 However, VTE is highly relevant to the primary care context as a large proportion of postoperative VTEs happen in the community.35 One study showed that 36.8% of patients developed VTE within 3 months of hospital discharge.36 A further study of 3039 patients admitted to post-acute care after a medical condition or surgery showed that 2.4% of patients developed VTE within an average of 13 days.37 The average length of hospital stay for medical, surgical and critical care patients is 5.3 days.16 After discharge from hospital, these patients may discontinue thromboprophylaxis and will remain at risk of VTE for some time. Research suggests that the risk remains for up to 90 days after hospital discharge10 Extended thromboprophylaxis for at-risk medical and surgical patients that is easily administered in a community setting is essential for a reduction in VTE rates and could be cost-effective.8,9 Many patients do not receive appropriate VTE prophylaxis both as inpatients and post discharge,35,38–40 despite government guidelines (which recommend that all patients admitted to hospital be assessed for risk of developing DVT and be given preventative treatment) and the availability of effective thromboprophylaxis.41 Recent studies have shown that around 37% of all at-risk patients did not receive thromboprophylaxis in hospital,40 25% of medical or surgery patients at risk of VTE did not receive thromboprophylaxis in post-acute care settings, and only 54% of orthopaedic surgery © Queen’s Printer and Controller of HMSO 2020. This work was produced by Fitzmaurice et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 21 WORK PACKAGE 2: SURVEYS AND INTERVIEWS patients had a prescription for thromboprophylaxis dispensed 30 days after discharge.40,42 The need for daily injections of low-molecular-weight heparin may create problems with compliance in the outpatient setting.37 Objectives The aim of the research was to explore the potential role for primary care in hospital-acquired VTE risk management. The specific objectives were to: l l l l l assess the level of existing knowledge of VTE risk among a wide range of primary HCPs and patients assess current practice and the perceived role of primary care in thromboprophylaxis among primary HCPs and patients explore the interface between primary and secondary care in terms of thromboprophylaxis identify local organisations’ perceived and actual clinical barriers to the implementation of thromboprophylaxis for high-risk patients explore potential care pathways for high-risk patients prior to hospital admission in terms of assessment for thromboprophylaxis. Methods A mixed-methods approach was employed, which involved a postal survey of patients, GPs and practice nurses followed by interviews with a subset of survey respondents and other stakeholders. This approach was selected to obtain the views of a broad range of GPs, hospital clinicians, practice nurses and other stakeholders but also to further explore specific issues identified in the survey. Surveys Patient survey A postal survey of hospitalised patients who were assessed to be at a high risk of VTE was conducted. Patients were recruited from three hospital trusts in Oxfordshire and the West Midlands. A range of wards was recruited to ensure that orthopaedic, surgical and medical patients were represented in the sample. The specific wards included orthopaedic surgery, general surgery, cancer, upper gastrointestinal, lower gastrointestinal, cardiothoracic, renal and urology, and trauma. Patients were eligible for the study if they were admitted to the participating wards during the recruitment period and were assessed to be at a high risk of VTE (identified by screening VTE risk assessments in hospital records). Patients requiring prophylaxis during their admission only and those requiring extended prophylaxis post discharge were eligible to participate. Research nurses approached eligible patients on the wards and those agreeing to participate were asked to provide informed consent. Recruited patients were subsequently sent a study pack immediately after discharge or 1 month following discharge, if they required extended prophylaxis. The study pack contained a questionnaire, cover letter and freepost return envelope. A reminder pack was sent to non-responders after 1 month. The patient questionnaire was designed to explore patients’ experiences of VTE risk management prior to, during and post hospital admission. The main areas covered were knowledge and understanding of VTE risk and prevention, VTE information received and the format, and VTE prophylaxis received. The questionnaire employed multiple choice and open-response question formats and could be completed in 15 minutes. 22 NIHR Journals Library www.journalslibrary.nihr.ac.uk DOI: 10.3310/pgfar08050 Programme Grants for Applied Research 2020 Vol. 8 No. 5 Primary care survey A postal survey of all GPs (n = 817) and practice nurses (n = 583) within Oxfordshire and South Birmingham was conducted simultaneously. GPs were identified from the NHS choices register43 and practice nurses were identified from practice websites or by contacting practices directly. A copy of the questionnaire with enclosed consent form, participant information sheet, cover letter and freepost return envelope was included in the study packs. Respondents were asked to indicate on the survey whether or not they would be willing to participate in an individual interview. The GP and practice nurse questionnaires were developed using the NICE guidelines8 and the Department of Health and Social Care’s risk assessment tool.9 The main areas covered by the GP and practice nurse survey were knowledge of hospital-acquired VTE risk and appropriate management; training and current practice of VTE risk management; views of the potential role of primary care in VTE risk management; and the barriers that exist to its implementation. The survey employed multiple choice, Likert scale and open-response question formats and could be completed in 5–10 minutes. Data were double entered into SPSS software and analysed descriptively....
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