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BACKGROUND: Clinical evidence surrounding edoxaban use in patients weighing <50 kg and >120 kg is lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee suggests avoiding edoxaban in patients >120 kg. Additionally, concerns exist regarding decreased efficacy in patients prescribed edoxaban for atrial fibrillation with a creatinine clearance (CrCl) >95 ml/min, a finding of the ENGAGE AF-TIMI 48 trial when edoxaban was compared to warfarin. OBJECTIVE: To derive a population pharmacokinetic (PopPK) model using clinical practice data, to understand the impact of bodyweight and renal function on edoxaban pharmacokinetics. METHOD: Edoxaban plasma concentrations and patient characteristics were collated from King's College Hospital anticoagulation clinics between 11/2016 and 08/2022. A PopPK model was developed using non-linear mixed effects modelling and used to simulate edoxaban concentrations at the extremes of bodyweight and with varying renal function. RESULTS: Data from 409 patients (46 < 50 kg, 34 > 120 kg and 123 with a CrCl > 95 ml/min) provided 455 edoxaban plasma concentrations. A one-compartment model with between-subject variability on clearance with a proportional error model best described the data. The most significant covariates impacting on edoxaban exposure were CrCl and bodyweight. Our work suggests that edoxaban exposure in patients weighing up to 140 kg is comparable to those weighing 75 kg. Edoxaban exposure is reduced in patients weighing <50 kg due to the recommended dose reductions. There is also a reduction in AUCss when CrCl > 95 ml/min compared to CrCl 80 ml/min. CONCLUSIONS: Our population PK model for edoxaban suggests that renal function is a key driver for overall edoxaban exposure. Further clinical outcome data is required to understand clinical effectiveness and adverse outcomes.
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The optimal pharmacological prophylaxis for venous thromboembolism (VTE) after hip or knee arthroplasty is uncertain. We conducted a systematic review and network meta-analysis to compare the efficacy and safety of various medications. We searched multiple databases for randomized clinical trials (RCTs) comparing medications (including factor Xa inhibitors, factor IIa inhibitor, warfarin, unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], aspirin, pentasaccharide) for VTE prophylaxis post-arthroplasty. Outcomes included any postoperative VTE identified with screening, major bleeding, and death. We used LMWH as the main comparator for analysis and performed trial sequential analysis (TSA) for each pairwise comparison. Certainty of evidence was assessed using GRADE (Grading of Recommendations, Assessments, Developments and Evaluations). We analyzed 70 RCTs (55,841 participants). Factor Xa inhibitors decreased postoperative VTE significantly compared with LMWH (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.44-0.68, high certainty). Pentasaccharides probably reduce VTE (OR: 0.61, 95% CI: 0.36-1.02, moderate certainty), while the factor IIa inhibitor dabigatran may reduce VTE (OR: 0.75, 95% CI: 0.40-1.42, low certainty). UFH probably increases VTE compared with LMWH (OR: 1.31, 95% CI: 0.91-1.89, moderate certainty), and other agents like warfarin, aspirin, placebo, and usual care without thromboprophylaxis increase VTE (high certainty). Factor Xa inhibitors may not significantly affect major bleeding compared with LMWH (OR: 1.06, 95% CI: 0.81-1.39, low certainty). No medications had a notable effect on mortality compared with LMWH (very low certainty). TSA suggests sufficient evidence for the benefit of factor Xa inhibitors over LMWH for VTE prevention. Compared with LMWH and aspirin, factor Xa inhibitors are associated with reduced VTE after hip or knee arthroplasty, without an increase in bleeding and likely no impact on mortality.
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Tromboembolia Venosa , Humanos , Medição de Risco/métodos , Doença Aguda , Masculino , Fatores de Risco , FemininoRESUMO
OBJECTIVES: Venous thromboembolism (VTE) is a major cause of morbidity and mortality globally, with hospital-associated thrombosis (HAT) accounting for at least half of VTE. We set out to understand more about deaths from HAT in England, to focus improvement efforts where they are needed most. DESIGN: A retrospective cohort combining death certification and hospital activity data to identify people with an inpatient or day case hospitalisation where no VTE diagnosis was recorded, and who died from VTE in a hospital or within 90 days of discharge, between April 2017 and March 2020. SETTING: All deaths occurring in England and all National Health Service-funded hospital care in England. PARTICIPANTS: After 0.1% of cases were excluded due to duplicate but conflicting records, a cohort of 13 995 deaths remained; 54% were women, and 26% were aged under 70 years. OUTCOME MEASURES: Analysis of age, gender, primary diagnosis, type of admission, specialties and (for day cases) procedure types were preplanned. RESULTS: Only 5% of these deaths followed planned inpatient admissions. Day case admissions preceded 7% of VTE deaths. Emergency inpatient admissions, medical specialties and infection-related primary diagnoses predominated in people who died from VTE after hospitalisation where no VTE diagnosis was recorded. Most deaths occurred in a hospital or within 30 days of discharge. CONCLUSIONS: International efforts to reduce HAT historically focused on planned inpatient admissions. Further initiatives and research to prevent deaths from VTE after hospitalisation should focus on the emergency care pathway where most deaths occurred, with people undergoing day case procedures an important additional focus.
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Hospitalização , Tromboembolia Venosa , Humanos , Inglaterra/epidemiologia , Feminino , Masculino , Tromboembolia Venosa/mortalidade , Tromboembolia Venosa/epidemiologia , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , Adulto , Idoso de 80 Anos ou mais , Mortalidade Hospitalar , Adulto Jovem , AdolescenteRESUMO
Hospital-associated venous thromboembolism (VTE) is defined as any case of VTE occurring during hospital admission and for up to 90 days post discharge. It accounts for over 50% of all cases of VTE internationally; indeed, there are an estimated 10 million cases of hospital-associated VTE annually. Over the last decade, there has been increasing interest in improving VTE risk assessment and thromboprophylaxis. This review summarises all the recent and ongoing major research studies and future challenges in the different areas, including medical, surgical and obstetric patients, as well as special areas such as lower limb immobilisation. We include sections on both pharmacological and mechanical thromboprophylaxis.
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Tromboembolia Venosa , Humanos , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/etiologia , Anticoagulantes/uso terapêutico , Hospitalização , Feminino , GravidezRESUMO
Venous thromboembolism is the third most common cause of cardiovascular death globally and many diagnoses are preventable. The UK NHS has led international efforts to reduce VTE, particularly hospital-associated VTE, through coordinated national policy action and world-leading research. Despite this, VTE remains an important cause of morbidity and mortality in the UK, as underlined by the recent COVID-19 pandemic. Future reductions in VTE incidence/deaths will require progress on several fronts: a better understanding of case mix; revisiting VTE risk assessment, focussing on thromboprophylaxis failure and improving awareness of VTE amongst clinicians and the public. Changes to healthcare delivery, with care increasingly delivered outside of hospital, alongside changing disease patterns, including the rise in obesity, have huge implications for VTE and will dramatically alter prevention. The UK, with its nationalised healthcare model and long history of policy action on VTE, provides a unique lens through which to study past successes and future priorities for VTE prevention.
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The present study aimed to identify rates of venous thromboembolism (VTE) amongst patients treated in inpatient mental health units using linked primary care and mental health care records. Patients resident in the London Borough of Lambeth admitted to mental health units in Southeast London between January 2008 and March 2019 were included, as well as a control group of patients being treated in the community for mental illness. The primary outcome measure was a diagnosis of VTE being recorded in GP records during or within 3 months of an admission to a mental health unit. For 7,198 psychiatric inpatient admissions, 11 episodes of VTE (1.5/1,000 admissions) were identified, with no VTE cases identified in 4,561 patients being treated in the community for mental illness during an equivalent window. This finding indicates that VTE rates following psychiatric inpatient admission might be similar to those following unselected acute medical admission. Larger scale studies are required to confirm the estimated incidence of VTE in patients with mental health conditions and the contribution of acute psychiatry hospitalisation to VTE risk.
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BACKGROUND: The risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis. OBJECTIVES: To develop and validate a prediction model for 90-day VTE risk. METHODS: A multinational cohort study was performed. For model development, records were used from the Oxford Royal College of General Practitioners Research and Surveillance Centre linked to Hospital Episode Statistics and Office of National Statistics UK routine data. For external validation, data were used from the Danish Hip and Knee Arthroplasty Registry, the National Patient Registry, and the National Prescription Registry. Binary multivariable logistic regression techniques were used for development. RESULTS: In the UK data set, 64 032 THA/TKA procedures were performed and 1.4% developed VTE. The prediction model consisted of age, body mass index, sex, cystitis within 1 year before surgery, history of phlebitis, history of VTE, presence of varicose veins, presence of asthma, history of transient ischemic attack, history of myocardial infarction, presence of hypertension and THA or TKA. The area under the curve of the model was 0.65 (95% CI, 0.63-0.67). Furthermore, 36 169 procedures were performed in the Danish cohort, of whom 1.0% developed VTE. Here, the area under the curve was 0.64 (95% CI, 0.61-0.67). The calibration slope was 0.92 in the validation study and 1.00 in the development study. CONCLUSION: This clinical prediction model for 90-day VTE risk following THA and TKA performed well in both development and validation data. This model can be used to estimate an individual's risk for VTE following THA/TKA.
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Artroplastia de Quadril , Artroplastia do Joelho , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Anticoagulantes/uso terapêutico , Artroplastia do Joelho/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/tratamento farmacológico , Estudos de Coortes , Modelos Estatísticos , Prognóstico , Artroplastia de Quadril/efeitos adversos , Fatores de RiscoRESUMO
Whole-body vibration (WBV) and resistive vibration exercise (RVE) are utilized as countermeasures against bone loss, muscle wasting, and physical deconditioning. The safety of the interventions, in terms of the risk of inducing undesired blood clotting and venous thrombosis, is not clear. We therefore performed the present systematic review of the available scientific literature on the issue. The review was conducted following the guidelines by the Space Biomedicine Systematic Review Group, based on Cochrane review guidelines. The relevant context or environment of the studies was "ground-based environment"; space analogs or diseased conditions were not included. The search retrieved 801 studies; 77 articles were selected for further consideration after an initial screening. Thirty-three studies met the inclusion criteria. The main variables related to blood markers involved angiogenic and endothelial factors, fibrinolysis and coagulation markers, cytokine levels, inflammatory and plasma oxidative stress markers. Functional and hemodynamic markers involved blood pressure measurements, systemic vascular resistance, blood flow and microvascular and endothelial functions. The available evidence suggests neutral or potentially positive effects of short- and long-term interventions with WBV and RVE on variables related to blood coagulation, fibrinolysis, inflammatory status, oxidative stress, cardiovascular, microvascular and endothelial functions. No significant warning signs towards an increased risk of undesired clotting and venous thrombosis were identified. If confirmed by further studies, WBV and RVE could be part of the countermeasures aimed at preventing or attenuating the muscular and cardiovascular deconditioning associated with spaceflights, permanence on planetary habitats and ground-based simulations of microgravity.
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Citrate is widely used as an anticoagulant for platelet function tests (PFTs). Due to an intrinsic inhibitory effect of citrate on platelet function, hirudin is used as an alternative. However, studies comparing the effect of these anticoagulants on rotational thromboelastometry (ROTEM) platelet whole blood impedance aggregometry in thrombocytopenic patients are scant. Cross-sectional study was done in 105 patients who entered the critical phase of Dengue hemorrhagic fever with plasma leakage and severe thrombocytopenia (<100 × 109/L). Samples were collected on two consecutive days and considered as a combined data set for analysis, out of which 200 have been included in the data analysis. Platelet count was used from routine full blood count. ROTEM platelet used TRAPTEM assay, which was performed with 3.2% sodium citrate and 525 ATU/ml hirudin anticoagulated blood. Means of all the TRAPTEM parameters were significantly higher in hirudin, compared to citrate samples (p < .05). Significantly higher overall platelet aggregation was observed in hirudinized samples with a significant mean difference (p < .05) compared to citrate in each quartile of platelet count. Higher platelet aggregation was observed with hirudin compared to citrate in ROTEM platelet whole blood impedance aggregometry in thrombocytopenic patients elaborating the importance of using hirudin anticoagulation in PFTs, particularly in patients with severe thrombocytopenia.
Citrate is the most commonly used anticoagulant for coagulation studies including rotational thromboelastometry (ROTEM).Hirudin is an alternative option to be used as an anticoagulant for PFTs because of the inhibitory effect of citrate on platelet function.One study (Nissen et al. (2020)) reported higher precision and platelet aggregation with hirudinized blood of healthy individuals, over citrate using ROTEM platelet.However, none of the studies were performed in patients in actual clinical context.We evaluated the potential benefit of using hirudin anticoagulated blood over citrate in thrombocytopenic patients due to Dengue hemorrhagic fever using ROTEM platelet.We observed higher platelet aggregation with hirudin compared to citrate suggesting the importance of using hirudin anticoagulation in PFTs, particularly in patients with severe thrombocytopenia.
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Anticoagulantes , Trombocitopenia , Humanos , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Ácido Cítrico/farmacologia , Ácido Cítrico/uso terapêutico , Hirudinas/farmacologia , Impedância Elétrica , Tromboelastografia , Estudos Transversais , Plaquetas , Citratos/farmacologia , Agregação Plaquetária , Trombocitopenia/tratamento farmacológicoRESUMO
Background: Although there is increased recognition that many menstruating women commenced on anticoagulants experience heavy menstrual bleeding, little research has been published describing what women go through and actually experience. Objectives: The aim of this study was to understand the "lived" experience of menstruating women commencing anticoagulants. Methods: We undertook a qualitative study using semistructured interviews. Women who had taken part in the parent PERIOD study and expressed an interest in an in-depth interview were recruited. Interviews were conducted online, and transcripts were generated through MS Teams. Data were analyzed using thematic analysis. Ethics committee approval: REC reference: 19/SW/0211. Results: A total of 15 participants were interviewed. The median age of the participants was 36 years (range, 20-49 years). The following 7 primary themes emerged from the interviews: (1) information received when commencing anticoagulation, (2) mood, (3) strategies used to manage heavy bleeding, (4) social/family life, (5) work life, (6) finances, and (7) multiple health issues-with saturation of themes achieved following 9 interviews. Women affected by heavy menstrual bleeding experienced a negative change in their work/social life and mood. Conclusion: Heavy menstrual bleeding experienced by women commencing anticoagulants has a significant impact on their lives. Recognized measures should be employed to support and minimize the problem for menstruating people.
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Background: There is increasing recognition that menstruating women prescribed anticoagulants experience heavy menstrual bleeding. Objectives: The aim of this study is to report the extent of bleeding in menstruating women after commencing anticoagulants and the impact it has on their quality of life. Methods: Women aged 18 to 50, initiated on anticoagulant therapy, were approached to take part in the study. In parallel, a control group of women was also recruited. Women were asked to complete the menstrual bleeding questionnaire and a pictorial blood assessment chart (PBAC) during their next 2 menstrual cycles. Differences between the control and anticoagulated group were compared. Significance was considered at < .05. Ethics committee approval: REC reference: 19/SW/0211. Results: Fifty-seven women in the anticoagulation and 109 women in the control group returned their questionnaires. Women in the anticoagulated group reported an increase in the median length of their menstrual cycle from 5 to 6 days after commencing anticoagulation, compared to 5 days for women in the control group (P < .05). Anticoagulated women reported significantly higher PBAC scores as compared to the control group (P < .05), with two-thirds of women in the anticoagulation group reporting heavy menstrual bleeding. Women in the anticoagulation group reported worsening quality of life scores following the initiation of anticoagulation, compared with women in the control group (P < .05). Conclusion: Heavy menstrual bleeding occurred in two-thirds of women commencing anticoagulants, who completed a PBAC, which had negative impact on their quality of life. Clinicians commencing anticoagulation therapy should be mindful of this, and recognized measures should be taken to help minimize this problem for menstruating individuals.
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The recent incidental discovery of an asymptomatic venous thrombosis (VT) in the internal jugular vein of an astronaut on the International Space Station prompted a necessary, immediate response from the space medicine community. The European Space Agency formed a topical team to review the pathophysiology, risk and clinical presentation of venous thrombosis and the evaluation of its prevention, diagnosis, mitigation, and management strategies in spaceflight. In this article, we discuss the findings of the ESA VT Topical Team over its 2-year term, report the key gaps as we see them in the above areas which are hindering understanding VT in space. We provide research recommendations in a stepwise manner that build upon existing resources, and highlight the initial steps required to enable further evaluation of this newly identified pertinent medical risk.
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BACKGROUND: Hump-nosed vipers (HNV; Hypnale spp) are one of the medically important venomous snakes in Sri Lanka and South-Western regions of India. The haemostatic dysfunction due to HNV bites is poorly characterized by standard diagnostic tests performed to identify coagulopathy. We aimed to determine the usefulness of rotational thromboelastometry (ROTEM) parameters compared to 20-minute whole blood clotting test (WBCT20) and prothrombin time (PT) in understanding the coagulopathy of HNV bites. METHODS: Twenty-three HNV snakebite patients in a prospective study of 127 consecutive snakebites were recruited. After recording details of the clinical presentation, PT/international normalized ratio (INR), WBCT20 and ROTEM delta were performed at presentation. RESULTS: In this preliminary study, none of the patients had clinically apparent bleeding. Coagulopathy was detected by either WBCT20, INR or ROTEM in 13 HNV patients. Eleven had a coagulopathy detectable by ROTEM (either abnormal EXTEM-CT, INTEM-CT or FIBTEM-MCF) but with negative WBCT20. Of them, only two had prolonged INR values. Two patients had positive WBCT20 but with normal ROTEM and INR values. The remaining 10 patients did not show any coagulopathy either by INR, ROTEM or WBCT20. CONCLUSION: In this preliminary study with small number of sample size, ROTEM parameters appeared to be more sensitive to subtle changes in coagulation compared to WBCT20. The clinical utility of detecting these changes and their usefulness in managing snakebite should be explored further in a larger study.
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A national Venous Thromboembolism (VTE) Prevention Programme was introduced in England in 2010, with limited subsequent study of its impact. Whilst the National Outcomes Framework reports VTE deaths related to hospitalisation annually, there are little data regarding VTE prevention practice or non-fatal VTE associated with hospitalisation. We report the first national thrombosis survey undertaken in collaboration with Getting It Right First Time. 98 Trusts (103 sites, 67% of 144 invited) participated in at least one survey, contributing data regarding VTE prevention in 9553 patients. Anti-coagulant thromboprophylaxis was prescribed to 88% (when indicated), with 8.1% of patients missing doses. Written patient information was provided to 31%. Of 4595 episodes of hospital-associated VTE, 13% were considered potentially preventable. The survey highlights the success of the national programme and areas for improvement in delivery of thromboprophylaxis and patient information.
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Trombose , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Anticoagulantes/uso terapêutico , Trombose/tratamento farmacológico , Hospitais , Inglaterra/epidemiologiaRESUMO
Direct oral anticoagulants (DOACs) have been a welcome addition to clinical practice due to the practical advantages they confer over traditional anticoagulants. In many countries, DOACs are now used as first-line treatment for the management of venous thromboembolism (VTE). Traditional anticoagulants allow for a degree of individualization, either through monitoring the international normalized ratio in the case of vitamin-K antagonists or through dose titration according to bodyweight in the case of low-molecular-weight heparin. However, the use of fixed doses and removal of the need for routine monitoring has created uncertainty in prescribing DOACs for patients at the extremes of bodyweight, renal function, and patients with liver impairment, who were not well represented in the DOAC licensing clinical trials. The discipline of pharmacokinetics is concerned with the movement of drugs through the body. Although the extremes of bodyweight and renal and liver function will influence the pharmacokinetics of DOACs, are these changes significant enough to affect clinical outcomes of bleeding and thrombosis? In other words, can the fixed-dosing strategy of DOACs accommodate these differences in physiology? In this review, we recap key pharmacokinetic principles for drug dosing; review venous thromboembolism trial and real-world data on patients prescribed DOACs at the extremes of bodyweight, renal function, and liver function; relate this to the pharmacokinetic properties of DOACs; and summarize the state of the field and current unknowns.