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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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Summary: Bleeding is the most concerning complication associated with anticoagulant therapy but poorly characterized and important for risk/benefit assessment. We developed a risk stratification score to predict vitamin K antagonist (VKA)‐associated bleeding in venous thromboembolism (VTE) using the UK Clinical Practice Research Datalink. Significant bleeding events in outpatients consisted of major bleeding and clinically relevant non‐major bleeding requiring hospitalisation (CRNMB‐H) within 90 days of VKA initiation. A scoring scheme for predicting bleeding was developed from subhazard ratios, validated using cross‐validation and expressed by the C‐statistic. The study cohort consisted of 10,010 patients with first VTE receiving initial VKA treatment, mean age 62·2 years. Between 2008 and 2016, 167 significant bleeding events were recorded (1·7%), i.e. incidence rate was 7·4/100 person‐years. Independent predictors for community‐acquired significant bleeding included active cancer, trauma/surgical procedure, male gender, dementia, liver disease, anaemia, history of bleeding, cerebrovascular, renal and chronic pulmonary disease, VTE presenting as pulmonary embolism and age over 75. The overall C‐statistic was 0·68 (95% CI, 0·60–0·76), 0·75 (0·60–0·88) for major bleeding and 0·65 (0·55–0·75) for CRNMB‐H, and higher than in other risk schemes applied to our study population. The developed risk score may identify patients having a significant bleeding risk, in particular major bleeding events, in outpatients. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the incidence of atrial fibrillation (AF) is static or rising in the UK.Design: Among the cohort of all individuals aged ≥45 years in the UK Clinical Practice Research Datalink (CPRD) (linked to hospital discharges) we identified incident non-valvular AF cases between 2001 and 2013. Overall and annual AF incidence rates were calculated and standardised to the UK population.Results: The cohort of 2.23 million individuals included 91,707 patients with incident AF. The overall standardised AF incidence rate was 6.7 (95% CI 6.7 to 6.8) per 1000 person-years, increasing exponentially with age and higher in men of all ages. There was a small increase in the standardised incidence of AF in the last decade from 5.9 (5.8 to 6.1)/1000 person-years in 2001 to 6.9 (6.8 to 7.1)/1000 person-years in 2013, mostly attributable to subjects aged >80 years with a non-primary hospital discharge diagnosis of AF. Standardised incidence rates of AF among white patients was 8.1 (8.1 to 8.2)/1000 person-years, compared with 5.4 (4.6 to 6.3) for Asians and 4.6 (4.0 to 5.3) for black patients. AF diagnosis was first made in general practice in 39% of incident AF.Conclusions: The incidence of AF in the UK has increased gradually in the last decade, with more than 200 000 first-ever non-valvular AF cases expected in 2015. This increase is only partly due to population ageing, though the principal increase has been in the elderly hospitalised for a reason other than AF. [ABSTRACT FROM AUTHOR]

The article offers information related to the risk assessment tool for venous thromboembolism (VTE) prophylaxis developed by the National Institute for Healthcare and Clinical Excellence (NICE), Great Britain. Topics discussed include rapid dissemination of the tool due to incorporation of the tool in the National Health Service (NHS) Commissioning for Quality and Innovation (CQUIN) program, evidence of thrombotic risk cited in the NICE publication and the NICE VTE risk assessment score.

Background: Venous thromboembolism (VTE, including deep vein thrombosis [DVT] and pulmonary embolism [PE]) has an annual incidence rate of 104–183 per 100,000 person-years. After a VTE episode, the two-year recurrence rate is about 17%. Consequently, effective and safe anticoagulation is paramount. Edoxaban is a direct oral anticoagulant (DOAC) approved VTE treatment. Current safety and efficacy data are derived from clinical trials, and information about treatment durations beyond 12 months are not available. Methods: ETNA-VTE-Europe is an 18-month prospective, single-arm, non-interventional, multinational post-authorisation safety study. Approximately 310 sites across eight European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Switzerland and the United Kingdom) will participate in the study, with the intention to represent the regional distributions of centres, healthcare settings and specialties. An estimated cohort of 2700 patients will be recruited, the only enrolment criteria being acute symptomatic VTE, no participation in an interventional study, and treating physician decision to prescribe edoxaban independently from the registry. Data from patient medical records and/or telephone interviews will be collected at baseline, 1, 3, 6, 12 and 18 months. The primary objective is to evaluate the 18-month rate of symptomatic VTE recurrence in patients with VTE treated with edoxaban outside a clinical trial. The co-primary objective is to evaluate the real-world rates of bleeding and adverse drug reactions. Secondary outcomes include rates of other patient-relevant safety events, adherence to and discontinuation of edoxaban. Furthermore, 12-month ETNA-VTE-Europe data will be considered in the context of those for patients receiving different anticoagulants in the PREFER in VTE registry and Hokusai-VTE clinical trial. Conclusions: ETNA-VTE-Europe will allow the safety and effectiveness of edoxaban to be evaluated over an extended period in acute symptomatic VTE patients encountered in routine clinical practice. Findings will be informative for European practitioners prescribing edoxaban as part of real-world VTE treatment/prevention. Trial registration: ClinicalTrials.gov Identifier: NCT02943993. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is associated with an increased risk of stroke, enhanced stroke severity, and other comorbidities. However, AF is often asymptomatic, and frequently remains undiagnosed until complications occur. Current screening approaches for AF lack either cost-effectiveness or diagnostic sensitivity; thus, there is interest in tools that could be used for population screening. An AF risk prediction algorithm, developed using machine learning from a UK dataset of 2,994,837 patients, was found to be more effective than existing models at identifying patients at risk of AF. Therefore, the aim of the trial is to assess the effectiveness of this risk prediction algorithm combined with diagnostic testing for the identification of AF in a real-world primary care setting. Eligible participants (aged ≥30 years and without an existing AF diagnosis) registered at participating UK general practices will be randomised into intervention and control arms. Intervention arm participants identified at highest risk of developing AF (algorithm risk score ≥ 7.4%) will be invited for a 12‑lead electrocardiogram (ECG) followed by two-weeks of home-based ECG monitoring with a KardiaMobile device. Control arm participants will be used for comparison and will be managed routinely. The primary outcome is the number of AF diagnoses in the intervention arm compared with the control arm during the research window. If the trial is successful, there is potential for the risk prediction algorithm to be implemented throughout primary care for narrowing the population considered at highest risk for AF who could benefit from more intensive screening for AF. Trial Registration: NCT04045639 [ABSTRACT FROM AUTHOR]

Introduction: Purpose: To develop a risk score for community-acquired bleeding events from a large inception cohort with venous thromboembolism (VTE). Methods: The study cohort was derived from the primary care UK Clinical Practice Research Datalink with linked hospital and mortality data between Jan 2008 and Mar 2016. The cohort consisted of patients with a first VTE, deep vein thrombosis or pulmonary embolism, and vitamin K antagonist (VKA) use within 30 days. Potential community-acquired significant bleeding, defined as acute major bleeding or acute clinically relevant non-major bleeding requiring hospitalization (CRNMB-H) within 90 days of VKA initiation, were manually reviewed. The scoring scheme for the prediction of bleeding events was developed from the sub-hazard ratios estimated from Fine and Gray models. The derived score for prediction of bleeding during VKA treatment were validated using cross validation expressed by C-statistics. Results: The study cohort of patients with first VTE and initial VKA treatment consisted of 10,169 patients (deep vein thrombosis 57.1%, pulmonary embolism 42.9%), mean age 62.2, 49.8% males. Within 90 days of VKA initiation and during ~2300 person-years of observation 165 community-acquired significant bleeding events occurred, 43 major bleeding events (27.9% fatal) and 122 CRNMB-H events. According to their score weighting, predictors for community acquired significant bleeding were active cancer, male gender, trauma/surgical procedure, history of major bleeding or of CRNMB, dementia, VTE presenting as pulmonary embolism, body mass index below 25 or over 30, liver disease, anemia, renal disease, cerebrovascular disease and chronic pulmonary disease. Our prediction score had a moderately high C-statistic of 0.68 overall and was higher for major bleeding events (0.76) than for CRNMB-H (0.65). Conclusions: Our risk score was effective in quantifying the risk of VKA-associated bleeding in a large community-based cohort of patients with VTE, and highly effective for predicting major bleeding events. [ABSTRACT FROM AUTHOR]

Background Asymptomatic proximal deep vein thrombosis (DVT) is an end point frequently used to evaluate the efficacy of anticoagulant thromboprophylaxis in medical patients. Recently, the clinical relevance of asymptomatic DVT has been challenged. Methods and Results The objective of this study was to evaluate the relationship between asymptomatic proximal DVT and all-cause mortality (ACM) using a cohort analysis of a randomized trial for the prevention of venous thromboembolism (VTE) in acutely ill medical patients. Patients who received at least 1 dose of study drug and had an adequate compression ultrasound examination of the legs on either day 10 or day 35 were categorized into 1 of 3 cohorts: no VTE, asymptomatic proximal DVT, or symptomatic DVT. Cox proportional hazards model, with adjustment for significant independent predictors of mortality, were used to compare the incidences of ACM. Of the 7036 patients, 6776 had no VTE, 236 had asymptomatic DVT, and 24 had symptomatic VTE. The incidence of ACM was 4.8% in patients without VTE. Both asymptomatic proximal DVT (mortality, 11.4%; hazard ratio [HR], 2.31; 95% CI, 1.52-3.51; P <0.0001) and symptomatic VTE (mortality, 29.2%; HR, 9.42; 95% CI, 4.18-21.20; P <0.0001) were independently associated with significant increases in ACM. The analysis was post hoc, and ultrasound results were not available for all patients. Adjustment for baseline variables significantly associated with ACM may not fully compensate for differences. Conclusions Asymptomatic proximal DVT is associated with higher ACM than no VTE and remains a relevant end point to evaluate the efficacy of anticoagulant thromboprophylaxis in medical patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00571649.

Objectives: Venous thromboembolism (VTE) incurs substantial costs to the UK National Health Service (NHS). Betrixaban is approved in the US for VTE prophylaxis with a recommended 35-42 days of treatment. This analysis modeled the budget impact of introducing betrixaban for extended-duration VTE prophylaxis in nonsurgical patients with acute medical illness at risk of VTE in the UK, where it is not yet licensed., Methods: The 5-year budget impact of introducing betrixaban into current prophylaxis (low molecular weight heparin and fondaparinux) was estimated for the UK NHS. The Phase 3 APEX study provided primary event (VTE, myocardial infarction, ischemic stroke, and death; all-cause or VTE-related) and treatment complications data. Literature informed risk of recurrent events and long-term complications, population, market share, and costs for treatment and management of events. Network meta-analyses informed symptomatic DVT, pulmonary embolism and VTE-related death rates in fondaparinux patients. Deterministic sensitivity analyses explored uncertainty., Results: Introducing betrixaban accrued savings of £1,290,000-£23,000,000 in years 1-5. Savings were from reduced primary VTE events, which reduced recurrent events and future complications. All sensitivity analyses showed savings., Conclusion: Introducing extended-duration VTE prophylaxis with betrixaban in the UK would accrue substantial savings annually over the next 5 years compared to current prophylaxis. Clinical trial registration: www.clinicaltrials.gov identifier is NCT01583218.

Aims: Most reports estimating national incidence rates of coronary (CAD) and peripheral arterial disease (PAD) have focused on stable outpatients or acute or elective hospital admissions, but not on the overall burden of disease. In this study, we report the changing trends in the population-level incidence of CAD and PAD, respectively from 2006 to 2015, statin utilization for secondary prevention and survival outcomes using multiple nationally representative data sources from the UK (primary care encounters, hospital admissions, and procedure-level data)., Methods and Results: A nationally representative study of linked primary and secondary care electronic health records of 4.6 million individuals from the UK. We calculated crude and standardized annual incidence rates separately for CAD and PAD. Statin use for secondary prevention, trends in annual major vascular event rates, and mortality between 2006 and 2015, were estimated for CAD and PAD, respectively. We identified 160 376 and 70 753 patients with incident CAD and PAD, respectively. The age- and sex-standardized incidence of CAD was similar in 2006 (443 per 100 000 person-years) and 2015 [436 per 100 000 person-years; adjusted incidence rate ratio (IRR) 0.98, 95% confidence interval (CI) 0.96-1.00]. In contrast, there was a 15% decline in the standardized incidence of PAD (236 per 100 000 person-years in 2006 to 202 per 100 000 person-years in 2015; adjusted IRR 0.85, 95% CI 0.82-0.88). The proportion of incident CAD and PAD patients prescribed long-term statins, was only 66% and 55%, respectively and was less common amongst women, patients aged >70 years, with heart failure, chronic lung disease, or depression. Cardiovascular mortality declined by 43% for incident CAD (adjusted IRR 0.57, 95% CI 0.50-0.64) between 2006 and 2015 but did not decline for incident PAD (adjusted IRR 0.84, 95% CI 0.70-1.00)., Conclusion and Relevance: In the UK, the standardized incidence of CAD appears stable but mortality rates are falling, whereas the standardized incidence of PAD is falling but mortality rates are not., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background:  Venous thromboembolism (VTE) is a major cause of death in cancer patients. Although patients with cancer have numerous risk factors for VTE, the relative contribution of cancer treatments is unclear., Objective:  The objective of this study is to evaluate the association between cancer therapies and the risk of VTE., Methods:  From UK Clinical Practice Research Datalink, data on patients with first cancer diagnosis between 2008 and 2016 were extracted along with information on hospitalization, treatments, and cause of death. Primary outcome was active cancer-associated VTE. To establish the independent effects of risk factors, adjusted subhazard ratios (adj-SHR) were calculated using Fine and Gray regression analysis accounting for death as competing risk., Results:  Among 67,801 patients with a first cancer diagnosis, active cancer-associated VTE occurred in 1,473 (2.2%). During a median observation time of 1.2 years, chemotherapy, surgery, hormonal therapy, radiation therapy, and immunotherapy were given to 71.1, 37.2, 17.2, 17.5, and 1.4% of patients with VTE, respectively. The active cancers associated with the highest risk of VTE-as assessed by incidence rates-included pancreatic cancer, brain cancer, and metastatic cancer. Chemotherapy was associated with an increased risk of VTE (adj-SHR: 3.17, 95% confidence interval [CI]: 2.76-3.65) while immunotherapy with a not significant reduced risk (adj-SHR: 0.67, 95% CI: 0.30-1.52). There was no association between VTE and radiation therapy (adj-SHR: 0.91, 95% CI: 0.65-1.27) and hormonal therapies., Conclusion:  VTE risk varies with cancer type. Chemotherapy was associated with an increased VTE risk, whereas with radiation and immunotherapy therapy, an association was not confirmed., Competing Interests: A.T.C. reports receiving consulting fees and research funding from Bayer, Boehringer Ingelheim, BMS, Daiichi-Sankyo, Johnson and Johnson, Pfizer, Portola, Sanofi, and XO1. He is an advisor to the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health and the NHS on the prevention of VTE. He is also an advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity, the Coalition to Prevent VTE. J.I.W. receives support from research grant (significant): Bayer AG, Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer; Honoraria (significant): Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Portola, Pfizer. T.S.F. research supports from Bayer Canada (in-kind study medication); honoraria from Bayer Canada, Boehringer Ingelheim Canada, Pfizer-BMS, and Servier. A.K., C.M., and C.W. are employees of the Institute for Epidemiology, Statistics and Informatics GmbH. The Institute for Epidemiology, Statistics and Informatics GmbH has received grants from Bayer, Bristol-Myers Squibb, CSL Behring, and Merz Pharma outside the submitted work. M.G., A.C., S.S., and B.W. have nothing to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction:  Atrial fibrillation (AF) is associated with dementia. Anticoagulation may modify this relationship, but it is unclear if this is due to stroke reduction alone., Methods:  Age- and sex-matched individuals from the U.K. Clinical Practice Research Datalink (2008-2016) with and without an incident diagnosis of AF were followed for a new dementia diagnosis. We estimated adjusted hazard ratios (aHRs) for incident dementia diagnosis in the AF cohort, overall and stratified by anticoagulation status, using the matched non-AF cohorts as reference. We performed a sensitivity analysis excluding individuals with stroke/transient ischaemic attack (TIA) before the observation period., Results:  Over 193,082 person-years (mean follow-up 25.7 ± 0.1 months), 347/15,276 AF (2.3%) and 1,085/76,096 non-AF (1.4%) were newly diagnosed with dementia (aHR, 1.31, 95% confidence interval, 1.15-1.49). The AF group had more co-morbidity and higher rates of dementia, both with and without anticoagulation, than non-AF. When those with history of stroke/ TIA before the observation period were excluded and those with incident stroke/TIA during the observation period were censored, AF individuals not on anticoagulation had significantly higher rates of dementia compared with non-AF, aHR 1.30 (1.06-1.58)., Conclusion:  Our findings support the hypothesis that AF is a distinct risk factor for dementia, independent of stroke/TIA and other vascular risk factors. In those without stroke/TIA, risk of dementia is increased only in those who are not on anticoagulation, suggesting anticoagulation is protective presumably through reduction of sub-clinical embolic events. Further prospective research is needed to better ascertain the role of anticoagulation amongst targeted therapeutic strategies to reduce cognitive decline in AF., Competing Interests: T. Field: Research Grant (modest): Boehringer Ingelheim Canada, Bayer Canada; Other Research Support (modest): Bayer Canada; Honoraria (modest): Bayer Canada, Boehringer Ingelheim Canada, Pfizer-BMS, Servier. J. Weitz: Research Grant (significant): Bayer AG, Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer; Honoraria (significant): Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Portola, Pfizer. A. Cohen: Research Grant (significant): Daiichi-Sankyo Europe, Bristol-Myers Squibb, Pfizer; Honoraria (significant): Bayer AG, Daiichi-Sankyo Europe, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Johnson & Johnson, Ono Pharmaceuticals, Portola, Sanofi, Janssen. C. Martinez: Research Grant (significant): CSL Behring, Bayer Pharma AG, Bristol-Myers Squibb; Honoraria (modest): Boehringer Ingelheim., (Georg Thieme Verlag KG Stuttgart · New York.)