Cancer-associated venous thrombosis in adults (second edition): A British Society for Haematology Guideline.

A shared decision on the most appropriate agent for the treatment of cancer-associated thrombosis should consider the following factors, which should be reassessed as patients continue along their cancer care pathway: risk of bleeding; tumour site; suitability of oral medications; potential for drug-drug interactions; and patient preference and values regarding choice of drug. Continuing anticoagulation beyond 6 months in patients with cancer-associated venous thromboembolism and active cancer is recommended.

Early Time Courses of Recurrent Venous Thromboembolism and Bleeding during Apixaban or Dalteparin Therapy for Patients with Cancer.

BACKGROUND: In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE. METHODS: The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding. RESULTS: In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group. CONCLUSION: The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE.

HIDDEN2: Study protocol for the hospital deep vein thrombosis detection study in patients with cancer receiving palliative care.

INTRODUCTION: Medical patients, admitted acutely to hospital, are at risk of venous thromboembolism (VTE). Clinical guidelines advise thromboprophylaxis prophylaxis for those at high risk of VTE. VTE is a common sequela of cancer, but guidelines take little consideration of cancer as an independent risk factor and their utility in palliative care patients is unclear. The hospice inpatient deep vein thrombosis (DVT) detection study (HIDDen) reported a 28% prevalence of asymptomatic iliofemoral DVT in hospice patients of poor performance status (PS) and prognosis, calling into question the utility of thromboprophylaxis in the palliative care setting. However, the majority of cancer inpatients receiving palliative care are admitted to hospital through the acute medical setting, yet their risk factors for VTE may differ from those admitted to hospices. OBJECTIVE: To better understand the prevalence and behaviours of VTE in patients with cancer receiving palliative care who are admitted as an acute medical emergency. DESIGN: Multicentre, observational cohort study. SETTING: Secondary care acute hospitals in South Wales, UK. PATIENTS: We plan to recruit 232 patients≥18 years old with a diagnosis of incurable cancer, and/or receiving palliative or best supportive care who are admitted acutely to hospital. Patients will be followed up for a maximum of 6 months following registration. PRIMARY OUTCOME: Presence of lower extremity DVT. SECONDARY OUTCOMES: Symptom burden attributed to DVT or pulmonary embolism, patient PS, patient demographics and development of new VTE within 90 days of registration. ANALYSIS: The study statistical analysis plan will document analysis, methodology and procedures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee, reference 22/WA/0037 (IRAS 306352)-the main trial results will be analysed as soon as practically possible and the publication shared with investigators and on sponsor website; applications to access trial data will be subject to sponsor review process.

A consensus viewpoint on the role of direct factor Xa inhibitors in the management of cancer-associated venous thromboembolism in the UK.

OBJECTIVE: Cancer patients are at high risk of venous thromboembolism (VTE), a significant cause of cancer-related death. Historically, low molecular weight heparins (LMWH) were the gold standard therapy for cancer-associated VTE, but recent evidence supports the use of direct factor Xa inhibitors in cancer-associated VTE and this is now reflected in many guidelines. However, uptake of direct factor Xa inhibitors varies and guidance on the use of direct factor Xa inhibitors in specific cancer sub-populations and clinical situations is lacking. This review presents consensus expert opinion alongside evaluation of evidence to support healthcare professionals in the use of direct factor Xa inhibitors in cancer-associated VTE. METHODS: Recent guidelines, meta-analyses, reviews and clinical studies on anticoagulation therapy for cancer-associated VTE were used to direct clinically relevant topics and evidence to be systematically discussed using nominal group technique. The consensus manuscript and recommendations were developed based on these discussions. RESULTS: Considerations when prescribing anticoagulant therapy for cancer-associated VTE include cancer site and stage, systemic anti-cancer therapy (including vascular access), drug-drug interactions, length of anticoagulation, quality of life and needs during palliative care. Treatment of patients with kidney or liver impairment, gastrointestinal disorders, extremes of bodyweight, elevated bleeding or recurrence risk, VTE recurrence and COVID-19 is discussed. CONCLUSION: Anticoagulant therapy for cancer-associated VTE patients should be carefully selected with consideration given to the relative benefits of specific drugs when individualizing care. Direct factor Xa inhibitors are typically the treatment of choice for preventing VTE recurrence in non-cancer patients and should also be considered as such for cancer-associated VTE in most situations.

Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update.

This is a collaboration between the British Society of Gastroenterology (BSG) and the European Society of Gastrointestinal Endoscopy (ESGE), and is a scheduled update of their 2016 guideline on endoscopy in patients on antiplatelet or anticoagulant therapy. The guideline development committee included representatives from the British Society of Haematology, the British Cardiovascular Intervention Society, and two patient representatives from the charities Anticoagulation UK and Thrombosis UK, as well as gastroenterologists. The process conformed to AGREE II principles and the quality of evidence and strength of recommendations were derived using GRADE methodology. Prior to submission for publication, consultation was made with all member societies of ESGE, including BSG. Evidence-based revisions have been made to the risk categories for endoscopic procedures, and to the categories for risks of thrombosis. In particular a more detailed risk analysis for atrial fibrillation has been employed, and the recommendations for direct oral anticoagulants have been strengthened in light of trial data published since the previous version. A section has been added on the management of patients presenting with acute GI haemorrhage. Important patient considerations are highlighted. Recommendations are based on the risk balance between thrombosis and haemorrhage in given situations.

Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update.

This is a collaboration between the British Society of Gastroenterology (BSG) and the European Society of Gastrointestinal Endoscopy (ESGE), and is a scheduled update of their 2016 guideline on endoscopy in patients on antiplatelet or anticoagulant therapy. The guideline development committee included representatives from the British Society of Haematology, the British Cardiovascular Intervention Society, and two patient representatives from the charities Anticoagulation UK and Thrombosis UK, as well as gastroenterologists. The process conformed to AGREE II principles, and the quality of evidence and strength of recommendations were derived using GRADE methodology. Prior to submission for publication, consultation was made with all member societies of ESGE, including BSG. Evidence-based revisions have been made to the risk categories for endoscopic procedures, and to the categories for risks of thrombosis. In particular a more detailed risk analysis for atrial fibrillation has been employed, and the recommendations for direct oral anticoagulants have been strengthened in light of trial data published since the previous version. A section has been added on the management of patients presenting with acute GI haemorrhage. Important patient considerations are highlighted. Recommendations are based on the risk balance between thrombosis and haemorrhage in given situations.

Suspected cancer symptoms and blood test results in primary care before a diagnosis of lung cancer: a case-control study.

Aim: To compare symptoms and blood test results prior to cancer diagnosis in individuals who developed lung cancer and those who did not. Patients & methods: Nested case-control study, lung cancer patients were matched to up four controls with no record of cancer. Differences in symptoms and blood test results were investigated in the 2-year period prior to diagnosis. Results: 26,379 lung cancer patients were matched to 92,125 controls. Elevated C-reactive protein (CRP) was independently predictive of lung cancer at every 2-month interval 12 months prior to diagnosis. Elevated CRP in conjunction with at least one symptom was associated with greater than fourfold higher odds of lung cancer. Conclusion: CRP may be a prediagnostic marker for lung cancer, and when present with other symptoms could facilitate the investigation of high-risk individuals.

Impact of blood group on survival following critical illness: a single-centre retrospective observational study.

Background: Predicting patient outcomes following critical illness is challenging. Recent evidence has suggested that patients with blood group AB are more likely to survive following major cardiac surgery, and this is associated with a reduced number of blood transfusions. However, there are no current data to indicate whether a patient's blood group affects general intensive care outcomes. Objective: The objective of this study was to determine if ABO blood group affects survival in intensive care. The primary outcome measure was 90-day mortality with a secondary outcome measure of the percentage of patients receiving a blood transfusion. Design: Retrospective analysis of electronically collected intensive care data, blood group and transfusion data. Setting: General intensive care unit (ICU) of a major tertiary hospital with both medical and surgical patients. Patients: All patients admitted to ICU between 2006 and 2016 who had blood group data available. Intervention: None. Measurements and main results: 7340 patients were included in the study, blood group AB accounted for 3% (221), A 41% (3008), B 10.6% (775) and O 45.4% (3336). These values are similar to UK averages. Baseline characteristics between the groups were similar. Blood group AB had the greatest survival benefit (blood group AB 90-day survival estimate 76.75, 95% CI 72.89 to 80.61 with the overall estimate 72.07, 95% CI 71.31 to 72.82) (log-rank χ2 16.128, p=0.001). Transfusion requirements were similar in all groups with no significant difference between the percentages of patients transfused (AB 23.1%, A 21.5%, B 18.7%, O 19.9%, Pearson χ2 5.060 p=0.167). Conclusion: Although this is primarily a hypothesis generating study, intensive care patients with blood group AB appeared to have a higher 90-day survival compared with other blood groups. There was no correlation between blood group and percentage of patients receiving transfusion.

Renal function and oral anticoagulant treatment of incident non-valvular atrial fibrillation: a retrospective study.

Aim: To describe the renal function of individuals newly diagnosed with non-valvular atrial fibrillation in England, and describe how oral anticoagulant (OAC) treatment varies according to renal function. Patients & methods: We identified a cohort of individuals with non-valvular atrial fibrillation (n = 18,419) and described their renal function at diagnosis and the prevalence of OAC treatment initiation by renal function. Results: 79% of individuals had some evidence of renal dysfunction with 12% having a glomerular filtration rate <30 ml/min/1.73 m2. OAC treatment initiation in the 6 months following diagnosis was lower in individuals with severe renal dysfunction than in those with normal renal function. Conclusion: The high prevalence of renal dysfunction and low OAC treatment prevalence highlights the need for additional evidence regarding OACs in individuals with severe renal dysfunction.

Can we use biomarkers of coagulation to predict which patients with foot and ankle injury will develop deep vein thrombosis?

BACKGROUND: Our aim was to determine whether plasma levels of Tissue Factor (TF), Vascular Cell Adhesion Molecule 1 (VCAM-1), Interleukin 6 (IL-6) or D-dimer after foot and ankle injury could predict which patients would develop deep vein thrombosis (DVT). METHODS: Patients aged 18-60 years with acute foot and ankle injury had venous blood sample to measure TF, VCAM-1, IL-6 and D-dimer within 3 days of injury. Patients had bilateral lower limb venous ultrasound to assess for DVT on discharge from clinic. RESULTS: 21 of 77 patients were found to have DVT (27%). There was no statistically significant association between levels of TF, VCAM-1, IL-6 or D-dimer and subsequent development of DVT. CONCLUSION: Tissue Factor (TF), Vascular Cell Adhesion Molecule-1 (VCAM-1), Interleukin-6 (IL-6) and D-dimer levels were not associated with development deep vein thrombosis in patients with acute foot and ankle injury.

Does thromboprophylaxis reduce symptomatic venous thromboembolism in patients with below knee cast treatment for foot and ankle trauma? A systematic review and meta-analysis.

BACKGROUND: Our aim was to determine the evidence for thromboprophylaxis for prevention of symptomatic venous thromboembolism (VTE) in adults with foot or ankle trauma treated with below knee cast or splint. Our secondary aim was to report major bleeding events. METHODS: MEDLINE and EMBASE databases were searched for randomized controlled trials from inception to 1st June 2015. RESULTS: Seven studies were included. All focused on low molecular weight heparin (LMWH). None found a statistically significant symptomatic DVT reduction individually. At meta-analysis LMWH was protective against symptomatic DVT (OR 0.29, 95% CI 0.09-0.95). Symptomatic pulmonary embolism affected 3/692 (0.43%). None were fatal. 86 patients required LMWH thromboprophylaxis to prevent one symptomatic DVT event. The overall incidence of major bleeding was 1 in 886 (0.11%). CONCLUSIONS: Low molecular weight heparin reduces the incidence of symptomatic VTE in adult patients with foot or ankle trauma treated with below knee cast or splint.

A three-year prospective study of the presentation and clinical outcomes of major bleeding episodes associated with oral anticoagulant use in the UK (ORANGE study).

The outcomes of patients developing major bleeding while on oral anticoagulants remain largely unquantified. The objectives of this study were to: (i) describe the burden of major hemorrhage associated with all available oral anticoagulants in terms of proportion of bleeds which are intracranial hemorrhages, in-hospital mortality and duration of hospitalization following major bleeding; (ii) identify risk factors for mortality; and (iii) compare the characteristics of major hemorrhage between cases treated with warfarin and direct oral anticoagulants for the subgroups of patients with atrial fibrillation or venous thromboembolism. This was a multicenter, 3-year prospective cohort study of patients aged ≥18 years on oral anticoagulants who developed major hemorrhage leading to hospitalization. The patients were followed up for 30 days or until discharge or death, whichever occurred first. In total 2,192 patients (47% female, 81% on warfarin, median age 80 years) were reported between October 2013 and August 2016 from 32 hospitals in the UK. Bleeding sites were intracranial (44%), gastrointestinal (33%), and other (24%). The in-hospital mortality was 21% (95% CI: 19%-23%) overall, and 33% (95% CI: 30%-36%) for patients with intracranial hemorrhage. Intracranial hemorrhage, advanced age, spontaneous bleeding, liver failure and cancer were risk factors for death. Compared to warfarin-treated patients, patients treated with direct oral anticoagulants were older and had lower odds of subdural/epidural, subarachnoid and intracerebral bleeding. The mortality rate due to major bleeding was not different between patients being treated with warfarin or direct oral anticoagulants. Major bleeding while on oral anticoagulant therapy leads to considerable hospital stays and short-term mortality.

The effect of active toe movement (AToM) on calf pump function and deep vein thrombosis in patients with acute foot and ankle trauma treated with cast - A prospective randomized study.

BACKGROUND: Patients with foot and ankle trauma treated with cast are advised to perform toe movements to prevent venous thromboembolism (VTE). Our aim was to determine the effect of active toe movement on asymptomatic deep vein thrombosis (DVT) and venous calf pump function. METHODS: Patients aged 18-60 years with acute foot and ankle trauma requiring below knee non weight bearing cast were randomized to intervention (regular active toe movement) or control groups (n=100). Patients had bilateral lower limb venous ultrasound to assess for DVT on discharge from clinic. Patients requiring chemical thromboprophylaxis were excluded. RESULTS: 78 completed the study. 27% sustained asymptomatic DVT, with no statistically significant difference in calf pump function or DVT incidence between groups. All DVT's occurred in the injured lower limb. CONCLUSION: Active toe movement is not a viable strategy for thromboprophylaxis in patients with acute foot and ankle trauma treated with cast.

Impact of a dedicated cancer-associated thrombosis service on clinical outcomes: a mixed-methods evaluation of a clinical improvement exercise.

OBJECTIVES: Cancer-associated thrombosis (CAT) complex condition, which may present to any healthcare professional and at any point during the cancer journey. As such, patients may be managed by a number of specialties, resulting in inconsistent practice and suboptimal care. We describe the development of a dedicated CAT service and its evaluation. SETTING: Specialist cancer centre, district general hospital and primary care. PARTICIPANTS: Patients with CAT and their referring clinicians. INTERVENTION: A cross specialty team developed a dedicated CAT service , including clear referral pathways, consistent access to medicines, patient's information and a specialist clinic. PRIMARY AND SECONDARY OUTCOME MEASURES: The service was evaluated using a mixed-methods evaluation , including audits of clinical practice, clinical outcomes, staff surveys and qualitative interviewing of patients and healthcare professionals. RESULTS: Data from 457 consecutive referrals over an 18-month period were evaluated. The CAT service has led to an 88% increase in safe and consistent community prescribing of low-molecular-weight heparin, with improved access to specialist advice and information. Patients reported improved understanding of their condition, enabling better self-management as well as better access to support and information. Referring clinicians reported better care standards for their patients with improved access to expertise and appropriate management. CONCLUSIONS: A dedicated CAT service improves overall standards of care and is viewed positively by patients and clinicians alike. Further health economic evaluation would enhance the case for establishing this as the standard model of care.

Venous thromboembolism occurring during adolescence.

OBJECTIVE: Risk assessment for venous thromboembolism (VTE) and thromboprophylaxis in those with risk factors is established in adult practice. Evidence to support efficacy and safety of this approach in adolescents is lacking. We aimed to describe thrombotic risk factors and to determine the proportion of potentially preventable events in a retrospective cohort study of adolescents with VTE. DESIGN, SETTING AND PATIENTS: Data were collected between 2008 and 2014 from eight tertiary UK centres. Qualifying events were radiologically confirmed VTE in subjects aged 12-17 years. Central venous line-related upper venous system events were excluded. RESULTS: 76 cases were identified, 41 males, median age 15 years. Frequent risk factors were: reduced mobility, 45%; thrombophilia, 24%; malignancy, 20%; surgery, 18%; combined oral contraceptive pill, 12%; congenital venous anomaly, 5%. 28 (37%) had no significant underlying diagnosis and no provoking event/hospitalisation, presenting as outpatients with VTE which was considered 'unpreventable'. Of 48 where there had been opportunity for risk assessment, chemical thromboprophylaxis was not indicated in 26 and was contraindicated in 8. 14/76 (18%) had an indication to consider thromboprophylaxis and no contraindication. Of these, four had cerebral palsy, five malignancy and two inflammatory bowel disease. All had reduced mobility with recent surgery in eight. Four received chemical thromboprophylaxis prior to presentation. CONCLUSIONS: Among a cohort of adolescents with VTE, a small proportion (13%) had an indication to consider chemical thromboprophylaxis but did not receive it. VTE risk assessment and prevention should focus on adolescents with immobility or surgery, particularly in those with malignancy.

Superficial vein thrombosis: a current approach to management.

Superficial vein thrombosis (SVT) was considered to be a benign and self-limiting condition. However, it is now appreciated that a significant proportion of those presenting with SVT will have concomitant deep vein thrombosis or pulmonary embolism, or are at significant risk of developing deep venous thromboembolism. Potential therapeutic options include topical preparations, compression therapy (stockings, bandages), medication such as non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants (therapeutic or prophylactic doses) and surgery, ligation or stripping, of superficial veins. The treatment of choice is therapeutic/intermediate dose low molecular weight heparin or prophylactic dose fondaparinux administered for 4-6 weeks. The cost-effectiveness of treatment is a concern and more targeted therapy is required.

The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran.

Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not 'routine'. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s).

Catheter-related thrombosis in cancer patients.

Central venous catheters are commonly used in haematology departments for the administration of chemotherapy, blood products and parenteral nutrition in patients with haematological malignancy. Thrombosis is a recognized complication of such devices especially in oncology patients. Catheter-related thrombi (CRT) may lead to pulmonary embolism and infection, as well as catheter failure and potential delays in treatment. The vast majority of CRT are asymptomatic, thus a high index of suspicion is required in making the diagnosis. Doppler ultrasound or venography may be employed to identify CRT. Once confirmed, the initiation of treatment is a balance between the risks of anticoagulation against potential complications of CRT. A number of risk factors for CRT are discussed along with an overview of catheter types, their appropriate choice and intravascular positioning.