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Background: Cancer-associated venous thromboembolism (VTE) management guideline recommendations include continued therapeutic anticoagulation while active cancer persists. The Federal Drug Administration label for apixaban for secondary VTE prevention includes a dose reduction to 2.5 mg twice daily after 6 months of treatment., Objectives: The study's purpose was to determine whether this dose reduction is advisable for cancer-associated VTE., Methods: A randomized, double-blind trial compared apixaban 2.5 mg with 5 mg twice daily for 12 months among cancer patients with VTE who had completed 6 to 12 months of anticoagulation therapy. The primary outcome was combined major bleeding plus clinically relevant nonmajor bleeding., Results: Of 370 patients recruited, 360 were included in the intention-to-treat analyses. Major plus clinically relevant nonmajor bleeding occurred in 16 of 179 patients (8.9%) in the apixaban 2.5 mg group compared with 22 of 181 patients (12.2%) in the 5 mg group (hazard ratio [HR], 0.72; 95% CI, 0.38-1.37; P = .39). Major bleeding occurred in 2.8% of the apixaban 2.5 mg group and in 2.2% of the 5 mg group (HR, 1.26; 95% CI, 0.34-4.66; P = .73). Recurrent VTE or arterial thrombosis occurred in 9 of 179 patients (5.0%) in the apixaban 2.5 mg group and 9 of 181 patients (5.0%) in the 5 mg group (HR, 1.0; 95% CI, 0.40-2.53; P = 1.00). All-cause mortality rates were similar between groups, 13% vs 12% (HR, 1.14; 95% CI, 0.63-2.04; P = .67)., Conclusion: For secondary prevention of cancer-associated VTE, apixaban 2.5 mg compared with 5 mg twice daily did not lower combined bleeding events (EVE trial NCT03080883)., Competing Interests: Declaration of competing interests The authors declare no competing financial interests., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients., Objectives: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission., Methods: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM., Results: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race., Conclusion: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. All rights reserved.)

Purpose: Venous thromboembolism (VTE), especially pulmonary embolism (PE) and lower extremity deep vein thrombosis (LE-DVT), is a serious and potentially preventable complication for patients with cancer undergoing systemic therapy., Methods: Using retrospective data from patients diagnosed with incident cancer from 2011-2020, we derived a parsimonious risk assessment model (RAM) using least absolute shrinkage and selection operator regression from the Harris Health System (HHS, n = 9,769) and externally validated it using the Veterans Affairs (VA) health care system (n = 79,517). Bootstrapped c statistics and calibration curves were used to assess external model discrimination and fit. Dichotomized risk strata using integer scores were created and compared against the Khorana score (KS)., Results: Incident VTE and PE/LE-DVT at 6 months occurred in 590 (6.2%) and 437 (4.6%) patients in HHS and 4,027 (5.1%) and 3,331 (4.2%) patients in the VA health care system. Assessed at the time of systemic therapy initiation, the new RAM included components of the KS with the modified cancer subtype, cancer staging, systemic therapy class, history of VTE, history of paralysis/immobility, recent hospitalization, and Asian/Pacific Islander race. The c statistic was 0.71 in HHS and 0.68 in the VA health care system (compared with 0.65 and 0.60, respectively, for KS). Furthermore, the new RAM appropriately reclassified 28% of patients and increased the proportion of VTEs in the high-risk group from 37% to 68% in the validation data set., Conclusion: The novel RAM stratified patients with cancer into a high-risk group with 8%-10% cumulative incidence of VTE and 7% PE/LE-DVT at 6 months ( v 3% and 2%, respectively, in the low-risk group). The model had improved performance over the original KS and doubled the number of VTE events in the high-risk stratum. We encourage additional external validation from prospective studies.[Media: see text].

Source Citation: CRISTAL Study Group; Sidhu VS, Kelly TL, Pratt N, et al. Effect of aspirin vs enoxaparin on symptomatic venous thromboembolism in patients undergoing hip or knee arthroplasty: the CRISTAL randomized trial. JAMA. 2022;328:719-27. 35997730.

Thromboembolism is a common and deadly consequence of COVID-19 infection for hospitalized patients. Based on clinical evidence pre-dating the COVID-19 pandemic and early observational reports, expert consensus and guidance documents have strongly encouraged the use of prophylactic anticoagulation for patients hospitalized for COVID-19 infection. More recently, multiple clinical trials and larger observational studies have provided evidence for tailoring the approach to thromboprophylaxis for patients with COVID-19. This document provides updated guidance for the use of anticoagulant therapies in patients with COVID-19 from the Anticoagulation Forum, the leading North American organization of anticoagulation providers. We discuss ambulatory, in-hospital, and post-hospital thromboprophylaxis strategies as well as provide guidance for patients with thrombotic conditions who are considering COVID-19 vaccination., (© 2022. The Author(s).)

The epidemiology of cancer-associated thrombosis (CAT) among uninsured and vulnerable populations in the US is not well-characterized. We performed a retrospective cohort study for patients with newly diagnosed cancer from 2011 to 2020 at Harris Health System, which cares for uninsured residents in the Houston metropolitan area. Patient demographics, NCI comorbidity index, area of deprivation index (ADI), cancer histology, staging, and systemic therapy data were extracted. CAT included overall venous thromboembolism (VTE) or pulmonary embolism +/- lower extremity deep vein thrombosis (PE/LE-DVT) within 1 year of diagnosis. We used multivariable Fine-Gray models to assess the associations with CAT accounting for death as a competing risk. Among 15 342 patients, 74% were uninsured and 84% lived in socioeconomically disadvantaged neighborhoods. There were 16% Non-Hispanic White (NHW), 28% Non-Hispanic Black (NHB), 50% Hispanic (27% Mexican), and 6% Asian/Pacific Islanders (API). The 1-year CAT incidence rate was 14.6%. Overall VTE was lower for Hispanics versus NHW (SHR 0.87 [0.76-0.99]) and API versus NHW (SHR 0.58 [0.44-0.77]). PE/LE-DVT was higher for NHB versus NHW (SHR 1.18 [1.01-1.39]). CAT was also associated with chemotherapy-based regimens (+/- immunotherapy), age, obesity, cancer type/staging, VTE history, and recent hospitalization. NCI comorbidity and ADI scores were associated with mortality but not CAT. In a large cohort of underserved patients with cancer, we identified an elevated incidence of CAT with known and novel risk predictors. Hispanics had lower adjusted rates of CAT and mortality. Our findings highlight the need to investigate and incorporate vulnerable populations in clinical trials., (© 2022 Wiley Periodicals LLC.)

In patients undergoing hematopoietic cell transplantation (HCT), venous thromboembolism (VTE) remains a serious complication that lacks validated risk assessment models (RAMs) to guide thromboprophylaxis. To address this dilemma, we performed a temporal and external validation study of the recently derived HIGH-2-LOW RAM. We selected adult patients undergoing allogeneic HCT from Fred Hutchinson Cancer Research Center (FHCRC) and MD Anderson Cancer Center (MDACC). Patients who died, received anticoagulation, or did not engraft platelets by day 30 were excluded. Primary outcomes were defined as overall VTE and pulmonary embolism ± lower-extremity deep venous thromboembolism (PE/LE-DVT) by day 180. Covariates were weighted according to the original model, except that grade 2-4 GVHD was substituted for grade 3-4. Discrimination and calibration were assessed. A total of 765 patients from FHCRC and 954 patients from MDACC were included. Incident VTE by day 180 was 5.1% at FHCRC and 6.8% at MDACC. The HIGH-2-LOW score had a c-statistic of 0.67 (0.59-0.75) for VTE and 0.75 (0.64-0.81) for PE/LE-DVT at FHCRC and 0.62 (0.55-0.70) for VTE and 0.70 (0.56-0.83) for PE/LE-DVT at MDACC. Twenty-five percent and 23% of patients were classified as high risk (2+ points) in the two cohorts, respectively. High versus low-risk was associated with odds ratio (OR) of 2.80 (1.46-5.38) for VTE and 4.21 (1.82-9.77) for PE/LE-DVT at FHCRC and OR of 3.54 (2.12-5.91) for VTE and 6.82 (2.30-20.16) for PE-LE-DVT at MDACC. The HIGH-2-LOW RAM identified allogeneic HCT recipients at high risk for VTE in both validation cohorts. It can improve evidence-based decision-making for thromboprophylaxis post-transplant., (© 2022 Wiley Periodicals LLC.)

Source Citation: Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181:1612-20. 34617959.

Background: In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients., Objectives: To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban., Patients/methods: In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type., Results: Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5)., Conclusion: Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: The International Society on Thrombosis and Haemostasis (ISTH)'s Scientific and Standardization Committee (SSC) recently proposed a definition of pulmonary embolism (PE)-related death., Objectives: To evaluate the accuracy and interrater reliability of the ISTH definition of PE-related death in an autopsy cohort., Methods: We reviewed reports of 1064 consecutive adult autopsies that were performed at the NewYork-Presbyterian Hospital from January 2010 until July 2019. We included all patients with autopsy-confirmed PE-related death (cases) during that time frame, combined with patients who died in 2018 from a cause other than PE (controls). Based on clinical summaries, two adjudicators independently adjudicated the cause of death in each patient using the ISTH classification for the cause of death, blinded to the case/control status and ratio. The primary outcome was autopsy-confirmed PE-related death. We determined the sensitivity and specificity of the ISTH definition to identify autopsy-confirmed PE-related death, and its interrater reliability using the percentage agreement and Cohen's kappa., Results: A total of 126 patients who underwent autopsy were included in the analysis (median age, 68 years [range, 21-94], 60 [48%] women), of which 29 (23%) had died from PE as confirmed by autopsy. The ISTH definition's sensitivity and specificity for autopsy-confirmed PE-related death were 45% (95% CI, 26-64) and 99% (95% CI, 94-100), respectively. Interrater reliability for PE-related death was substantial (percentage agreement, 94% [95% CI, 89-97]; kappa, 0.73 [95% CI, 0.55-0.97])., Conclusion: Adjudication of the cause of death using the ISTH definition resulted in very high specificity, moderate sensitivity, and good interrater reliability for PE-related death., (© 2021 International Society on Thrombosis and Haemostasis.)

History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30 days. Patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset and underwent inverse probability weighting to assess primary outcomes of VTE recurrence and bleeding within 30 days post-HCT. Subsequently, multivariable logistic regression model was used to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued it. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30 days (3% vs 4%, p = 0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs discontinued anticoagulation (41% vs 31%, p = 0.08). In a subgroup of 250 allogeneic HCT patients, every one-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100 days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery., (© 2021 Wiley Periodicals LLC.)

Venous thromboembolism (VTE) after allogeneic hematopoietic cell transplantation (HCT) is a significant treatment-associated complication, although optimal timing of thromboprophylaxis remains uncertain when weighing concurrent risks of bleeding. We aimed to derive and internally validate a risk assessment model (RAM) using patients who underwent first allogeneic HCT from 2006 through 2015 (n = 1703). Index date was defined as the 30th day after transplant, at which point we estimated >75% of patients would have achieved platelet engraftment >50 × 109/L. Stepwise logistic regression modeling was used for model development, and internal validation was achieved by fitting a logistic regression model with 1000 bootstrapped resamples to estimate the optimism-corrected c-statistic. The final RAM, "HIGH-2-LOW," included 7 predictors obtained at 30 days after transplant: History of catheter-related deep venous thrombosis (DVT), Inpatient at day 30, Graft-versus-host disease grade 3 to 4, History of pulmonary embolism or lower-extremity DVT, Lymphoma diagnosis, Obesity with body mass index ≥35 kg/m2, and White blood cell count ≥11 × 109/L. Approximately 16% of patients were stratified as high risk, with incident VTE rate of 10.3% at 100 days compared with 1.5% for those at low risk. VTE odds ratios at 100 days were 5.87 (95% confidence interval [CI], 2.98-11.57) and 2.71 (95% CI, 1.38-5.35) in the high- and intermediate-risk vs low-risk groups, respectively. HIGH-2-LOW model serves as a novel and potentially clinically meaningful tool to identify high-risk allogeneic HCT patients who may benefit from early thromboprophylaxis after platelet engraftment., (© 2021 by The American Society of Hematology.)

Venous thromboembolism (VTE; deep vein thrombosis and/or pulmonary embolism) is a well-established cause of morbidity and mortality in the medical and surgical patient populations. Clinical research in the prevention and treatment of VTE has been a dynamic field of study, with investigations into various treatment modalities ranging from mechanical prophylaxis to the direct oral anticoagulants. Aspirin has long been an inexpensive cornerstone of arterial vascular disease therapy, but its role in the primary or secondary prophylaxis of VTE has been debated. Risk-benefit tradeoffs between aspirin and anticoagulants have changed, in part due to advances in surgical technique and postoperative care, and in part due to the development of safe, easy-to-use oral anticoagulants. We review the proposed mechanisms in which aspirin may act on venous thrombosis, the evidence for aspirin use in the primary and secondary prophylaxis of VTE, and the risk of bleeding with aspirin as compared with anticoagulation., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests., (© 2020 by The American Society of Hematology.)

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appear to be at increased risk for venous thromboembolism (VTE), especially if they become critically ill with COVID-19. Some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis. The electronic health record (EHR) of a New Orleans-based health system was searched for all patients with polymerase chain reaction-confirmed SARS-CoV-2 infection who were either admitted to hospital or treated and discharged from an emergency department between 1 March 2020 and 1 May 2020. From this cohort, patients with confirmed VTE (either during or after their hospital encounter) were identified by administrative query of the EHR.: Between 1 March 2020 and 1 May 2020, 6153 patients with COVID-19 were identified; 2748 of these patients were admitted, while 3405 received care exclusively through the emergency department. In total, 637 patients required mechanical ventilation and 206 required renal replacement therapy. Within the hospitalized cohort, the overall mortality rate was 24.5% and VTE occurred in 86 patients (3.1%). In the 637 patients who required mechanical ventilation at some point during their hospital stay, 45 developed VTE (7.2%). After a median follow-up of 14.6 days, VTE had been diagnosed in 3 of the 2075 admitted who were discharged alive (0.14%). Among 6153 patients with COVID-19 who were hospitalized or treated in emergency departments, we did not find evidence of unusually high VTE risk. Pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary VTE prevention in patients with COVID-19., (© 2020 by The American Society of Hematology.)

Background: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type., Methods: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526., Findings: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93-1·06) and a hazard ratio of 1·01 (95% CI 0·96-1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47-0·71) for venous thromboembolism, 1·27 (0·92-1·74) for major bleeding, and 1·34 (1·19-1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42-0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high., Interpretation: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival., Funding: Canadian Institutes of Health Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Patients with antiphospholipid antibodies (aPL) and thromboembolism (TE) are at risk for recurrent TE. Few studies, however, distinguish patients based on the initial event., Objectives: We performed a systematic review and meta-analysis to investigate patients with aPL and venous TE (VTE), provoked or unprovoked, and patients with arterial TE (ATE)., Patients/methods: We conducted searches in PubMed, CINAHL, Cochrane, and EMBASE. Inclusion criteria were prospective trials or cohort studies investigating patients with aPL and ATE or VTE. Excluded studies did not provide estimated recurrence rates, did not specify whether the incident event was ATE or VTE, included patients with multiple events, or included <10 patients. Two-year summary proportions were estimated using a random effects model., Results: Ten studies described patients with VTE, 2 with ATE, and 5 with VTE or ATE. The 2-year proportion for recurrent TE in patients with VTE who were taking anticoagulant therapy was 0.054 (95% confidence interval [CI], 0.037-0.079); the 2-year proportion for patients not taking anticoagulant therapy was 0.178 (95% CI, 0.150-0.209). Most studies did not distinguish whether VTE were provoked or unprovoked. The 2-year proportion for recurrent TE in patients with ATE who were taking anticoagulant therapy was 0.220 (95% CI, 0.149-0.311); the 2-year proportion for patients taking antiplatelet therapy was 0.216 (95% CI, 0.177-0.261)., Conclusions: Patients with aPL and ATE may benefit from a different antithrombotic approach than patients with aPL and VTE. Prospective studies with well-defined cohorts with aPL and TE are necessary to determine optimal antithrombotic strategies., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Oncology guidelines suggest using the Khorana score to select ambulatory cancer patients receiving chemotherapy for primary venous thromboembolism (VTE) prevention, but its performance in different cancers remains uncertain., Objective: To examine the performance of the Khorana score in assessing 6-month VTE risk, and the efficacy and safety of low-molecular-weight heparin (LMWH) among high-risk Khorana score patients., Methods: This individual patient data meta-analysis evaluated (ultra)-LMWH in patients with solid cancer using data from seven randomized controlled trials., Results: A total of 3293 patients from the control groups with an available Khorana score had lung (n = 1913; 58%), colorectal (n = 452; 14%), pancreatic (n = 264; 8%), gastric (n = 201; 6%), ovarian (n = 184; 56%), breast (n = 164; 5%), brain (n = 84; 3%), or bladder cancer (n = 31; 1%). The 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate-risk patients (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95% CI, 0.72-1.7) than in the group with other cancer types (OR 3.2; 95% CI, 1.8-5.6; P interaction  = .002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared with controls (OR 0.36; 95% CI, 0.22-0.58), without increasing the risk of major bleeding (OR 1.1; 95% CI, 0.59-2.1)., Conclusion: The Khorana score was unable to stratify patients with lung cancer based on their VTE risk. Among those with other cancer types, a high-risk score was associated with a three-fold increased risk of VTE compared with a low-to-intermediate risk score. Thromboprophylaxis was effective and safe in patients with a high-risk Khorana score., (© 2020 International Society on Thrombosis and Haemostasis.)

Coronavirus disease 2019 (COVID-19) is a viral infection that can, in severe cases, result in cytokine storm, systemic inflammatory response and coagulopathy that is prognostic of poor outcomes. While some, but not all, laboratory findings appear similar to sepsis-associated disseminated intravascular coagulopathy (DIC), COVID-19- induced coagulopathy (CIC) appears to be more prothrombotic than hemorrhagic. It has been postulated that CIC may be an uncontrolled immunothrombotic response to COVID-19, and there is growing evidence of venous and arterial thromboembolic events in these critically ill patients. Clinicians around the globe are challenged with rapidly identifying reasonable diagnostic, monitoring and anticoagulant strategies to safely and effectively manage these patients. Thoughtful use of proven, evidence-based approaches must be carefully balanced with integration of rapidly emerging evidence and growing experience. The goal of this document is to provide guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of anticoagulant therapies in patients with COVID-19. We discuss in-hospital and post-discharge venous thromboembolism (VTE) prevention, treatment of suspected but unconfirmed VTE, laboratory monitoring of COVID-19, associated anticoagulant therapies, and essential elements for optimized transitions of care specific to patients with COVID-19.

Oncology patients are at a high risk of experiencing venous thromboembolism. Historically, venous thromboembolisms in cancer patients have been managed with low-molecular-weight heparin on the basis of the CLOT trial published in 2003. However, recent prospective data provide evidence for safe and effective direct oral anticoagulant use in this population. The purpose of this review article is to evaluate the current body of literature surrounding direct oral anticoagulant use in the oncology population and to highlight key practical considerations when prescribing these agents for patients with cancer.

Background: Venous thromboembolism (VTE) is a common source of perioperative morbidity and mortality., Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about preventing VTE in patients undergoing surgery., Methods: ASH formed a multidisciplinary guideline panel balanced to minimize bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic reviews. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment., Results: The panel agreed on 30 recommendations, including for major surgery in general (n = 8), orthopedic surgery (n = 7), major general surgery (n = 3), major neurosurgical procedures (n = 2), urological surgery (n = 4), cardiac surgery and major vascular surgery (n = 2), major trauma (n = 2), and major gynecological surgery (n = 2)., Conclusions: For patients undergoing major surgery in general, the panel made conditional recommendations for mechanical prophylaxis over no prophylaxis, for pneumatic compression prophylaxis over graduated compression stockings, and against inferior vena cava filters. In patients undergoing total hip or total knee arthroplasty, conditional recommendations included using either aspirin or anticoagulants, as well as for a direct oral anticoagulant over low-molecular-weight heparin (LMWH). For major general surgery, the panel suggested pharmacological prophylaxis over no prophylaxis, using LMWH or unfractionated heparin. For major neurosurgery, transurethral resection of the prostate, or radical prostatectomy, the panel suggested against pharmacological prophylaxis. For major trauma surgery or major gynecological surgery, the panel suggested pharmacological prophylaxis over no prophylaxis.

Background: It is unclear if direct oral anticoagulant (DOAC) is efficacious and safe for prophylaxis of venous thromboembolism (VTE) in ambulatory patients with cancer., Methods: We performed a systematic review using EMBASE, MEDLINE, and CENTRAL. Inclusion criteria included adult ambulatory patients with cancer, prophylactic use of DOAC, and randomized controlled trials. Exclusion criteria included pediatric patients, inpatient or postoperative setting, therapeutic indication of DOAC, or non-phase III randomized controlled trial. Two authors screened/reviewed articles and abstracted the data. Meta-analysis was performed using random-effects model. Efficacy outcome included overall and symptomatic VTE incidence during the first 6 months. Safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB) incidence during the on-treatment period. Subgroup analysis was performed for intermediate- and high-risk Khorana score., Results: A total of 202 records were identified and 28 full-text articles were assessed. Two studies with 1415 participants were included for meta-analysis. For DOAC vs placebo, the relative risks for overall and symptomatic VTE incidence by 6 months were 0.56 (0.35-0.89) and 0.58 (0.29-1.13), respectively. The relative risks for major bleeding and CRNMB while on-treatment were 1.96 (0.80-4.82) and 1.28 (0.74-2.20), respectively. Patients with high-risk Khorana score (3+) derived the largest absolute risk reduction of VTE., Conclusions: Low-dose DOAC reduces the rate of overall VTE in higher risk cancer patients starting systemic chemotherapy. It may reduce the rate of symptomatic VTE but increase the likelihood of bleeding., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: Patients with active cancer and venous thromboembolism (VTE) are at high risk of recurrence. Therefore, continued anticoagulant therapy beyond the initial 6 months is suggested in this patient population, but evidence supporting this approach is limited., Methods: The Hokusai VTE Cancer trial compared edoxaban with dalteparin for VTE treatment in patients with active cancer. This post hoc analysis focused on the follow-up period from 6 to 12 months. The primary outcome was the composite of adjudicated first recurrent VTE or major bleeding. Secondary outcomes included recurrent VTE, major bleeding, and clinically relevant bleeding., Results: Of the 522 and 524 patients randomized to edoxaban or dalteparin, 294 (56%) received edoxaban and 273 (52%) received dalteparin for more than 6 months (median duration of 318 and 211 days, respectively). Between 6 and 12 months, the primary outcome during study treatment occurred in seven patients (2.4%) in the edoxaban group and six patients (2.2%) in the dalteparin group (unadjusted hazard ratio 1.05; 95% confidence interval, 0.36-3.05). Recurrent VTE occurred in two patients (0.7%) in the edoxaban group and in three patients (1.1%) in the dalteparin group, whereas major bleeding occurred in 5 (1.7%) and three patients (1.1%), respectively., Conclusions: The rates of recurrent VTE or major bleeding are relatively low among patients with active cancer receiving extended anticoagulant therapy beyond 6 months. Extended treatment with oral edoxaban appears as effective and safe as subcutaneous dalteparin., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: Although venous thromboembolism (VTE) is a significant complication for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), no validated clinical model predicts VTE in this population. This study aimed to derive and validate a new risk assessment model (RAM) for IMiD-associated VTE., Methods: Patients with newly diagnosed MM receiving IMiDs were selected from the SEER-Medicare database (n=2,397) to derive a RAM and then data from the Veterans Health Administration database (n=1,251) were used to externally validate the model. A multivariable cause-specific Cox regression model was used for model development., Results: The final RAM, named the "SAVED" score, included 5 clinical variables: prior surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The model stratified approximately 30% of patients in both the derivation and the validation cohorts as high-risk. Hazard ratios (HRs) were 1.85 (P<.01) and 1.98 (P<.01) for high- versus low-risk groups in the derivation and validation cohorts, respectively. In contrast, the method of stratification recommended in the current NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease had HRs of 1.21 (P=.17) and 1.41 (P=.07) for the corresponding risk groups in the 2 datasets., Conclusions: The SAVED score outperformed the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy. This clinical model can help inform providers and patients of VTE risk before IMiD initiation and provides a simplified clinical backbone for further prognostic biomarker development in this population.

Background: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain., Methods: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding., Results: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49)., Conclusions: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.)., (Copyright © 2019 Massachusetts Medical Society.)

Introduction: It is unclear if direct oral anticoagulants (DOACs) are effective and safe alternatives to low-molecular-weight heparin (LMWHs) for the treatment of cancer-associated venous thromboembolism (VTE). We aim to synthesize existing literature that compared DOACs versus LMWHs in this high-risk population., Materials and Methods: We conducted a systematic review using EMBASE, MEDLINE and CENTRAL for all observational studies and randomized controlled trials (RCTs) (PROSPERO: CRD42017080898). Two authors independently reviewed study eligibility, extracted data, and assessed bias. Primary outcomes included 6-month recurrent VTE and major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and mortality., Results: We screened 426 articles, reviewed 25 in full-text, and selected 13 and 2 for qualitative and quantitative synthesis, respectively. Based on a meta-analysis of the 2 RCTs, DOACs had lower 6-month recurrent VTE (42/725) when compared to LMWH (64/727) (RR: 0.65 (0.42-1.01)). However, DOACs had higher major bleeding (40/725) when compared to LMWH (23/727) (RR 1.74 (1.05-2.88)). Similarly, CRNMB was higher (RR 2.31 (0.85-6.28)) for patients receiving DOACs. There was no difference in mortality (RR 1.03 (0.85-1.26)). Observational studies were heterogeneous with high risks of bias but showed recurrent VTE rates consistent with the meta-analysis., Conclusions: DOACs were more effective than LMWHs to prevent recurrent VTE but were associated with a significantly increased risk of major bleeding as well as a trend toward more CRNMB. The absolute risk differences were small (2-3%) for both primary outcomes and may reflect better compliance with DOACs than LMWHs., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting., Competing Interests: N. Kraaijpoel has nothing to disclose. M. Di Nisio reports personal fees from Daiichi Sankyo. F.I. Mulder has nothing to disclose. N. van Es reports personal fees from Daiichi Sankyo and Pfizer. J. Beyer-Westendorf reports grants and personal fees from Bayer AG, Boehringer-Ingelheim, Daiichi Sankyo, Pfizer and Portola. M. Carrier reports grants from BMS and Leo Pharma, and personal fees from Pfizer, Bayer, Sanofi and Leo Pharma. D. Garcia reports grants and personal fees from Daiichi Sankyo, Janssen and Incyte, and personal fees from BMS and Boehringer-Ingelheim. M. Grosso, M.F. Mercuri, G. Zhang and L. Schwocho are employees of Daiichi Sankyo Inc. A.K. Kakkar reports grants and personal fees from Bayer AG, and personal fees from Boehringer-Ingelheim, Janssen Pharma, Sanofi SA and Verseon. S. Middeldorp reports grants and personal fees from GSK, BMS/Pfizer, Aspen and Daiichi Sankyo, and personal fees from Bayer, Boehringer-Ingelheim, and grants from Sanquin. C. Rojas Hernandez reports personal fees from Daiichi Sankyo. A. Santamaria reports personal fees from Bayer AG, Boehringer-Ingelheim, Pfizer, Bristol-Myers Squibb, Daiichi Sankyo, LeoPharma, Sanofi-Aventis, Rovia and SOBI. A. Segers reports grants from Daiichi Sankyo, IONIS Pharmaceuticals and Janssen Pharmaceuticals. P. Verhamme reports grants and personal fees from Bayer Healthcare, LeoPharma, Daiichi Sankyo and Boehringer-Ingelheim, and personal fees from BMS, Portola, Medscape, Medtronic and Pfizer. T.F. Wang has nothing to disclose. J.I. Weitz reports personal fees from Daiichi-Sankyo, Bayer Healthcare, BMS, Boehringer-Ingelheim, Ionis Pharmaceuticals, Janssen, Johnson and Johnson, Pfizer, Portola, Medscape and Novartis. J.I. Zwicker reports grants from Quercegen and Incyte, and personal fees from Daichii Sankyo and Parexel. H.R. Büller reports personal fees from Daiichi Sankyo, Bayer Healthcare, BMS/Pfizer, Boehringer-Ingelheim, Portola, Medscape, Eli Lilly, Sanofi Aventis and Ionis. G.E. Raskob reports personal fees from Daiichi Sankyo, Itreas, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Isis Pharmaceuticals, Janssen, Pfizer and Portola., (Georg Thieme Verlag KG Stuttgart · New York.)

Venous thromboembolism (VTE) represents a major global burden of disease and requires collaborative efforts to conduct large, high-quality investigator-initiated and academically sponsored studies addressing the most relevant clinical questions. Owing to increasing regulatory requirements, the highly competitive nature of peer-reviewed funding and costs associated with conducting large, multinational clinical trials, completing practice-changing research constitutes a growing challenge for clinical investigators. As clinical trialists interested in VTE, we founded INVENT (International Network of Venous Thromboembolism Clinical Research Networks) in an effort to promote and accelerate patient-oriented, investigator-initiated, international collaborative research, to identify, prioritize and answer key clinical research questions for patients with VTE. We report on our activities to formalize the INVENT network and our accomplishments in our first year., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear., Methods: In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration., Results: Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6)., Conclusions: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).

Background: Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban., Methods: PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results., Results: We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation (r 2  = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation (r 2  = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban., Conclusions: An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Direct oral anticoagulants (DOACs) have been approved for the treatment of venous thromboembolism and atrial fibrillation based on randomized controlled trials (RCTs) of direct comparisons with vitamin K antagonists. Despite having more than 100,000 patients enrolled, safety and efficacy are debated in selected populations. Although DOACs are reviewed as a class of anticoagulant, pharmacokinetic differences exist such that different medications may be beneficial in distinct clinical settings. Synthesizing available evidence based on phase III RCTs, post hoc subgroup analyses, and pooled metaanalyses, this review provides an overview of DOACs and scrutinizes individual differences in their applications for the special populations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Vitamin K antagonists (VKA) are highly effective for the primary and secondary prevention of arterial and venous thromboembolic events. However, patients treated with VKA have on average only 60% of their international normalized ratio (INR) values within the therapeutic range and INR instability is associated with an increased risk of thrombosis and bleeding events. Recent evidence suggests that poor dietary vitamin K intake may affect anticoagulation control, but the role of vitamin K in INR stability remains to be established. We performed a systematic review of the literature to assess the role of vitamin K dietary intake on the stability of VKA and the potential effect of daily vitamin K supplementation on VKA therapy. After a search in Medline and EMBASE databases, 15 studies for a total of 1,838 patients were included in our systematic review. Observational studies suggest an increased risk of unstable anticoagulation control in patients with lower daily vitamin K intake. On the other hand, the role of daily vitamin K supplementation or a diet with controlled vitamin K content in patients on VKA treatment remains to be established. Use of daily vitamin K supplementation may be associated with a clinically relevant increase in the time in therapeutic range in patients with unstable anticoagulation control. Conversely, this effect appears small and not clinically relevant when vitamin K was administered to an unselected population receiving VKA. Other large prospective studies are necessary to confirm our preliminary findings., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: Parenteral anticoagulants may improve outcomes in patients with cancer by reducing risk of venous thromboembolic disease and through a direct antitumour effect. Study-level systematic reviews indicate a reduction in venous thromboembolism and provide moderate confidence that a small survival benefit exists. It remains unclear if any patient subgroups experience potential benefits., Methods and Analysis: First, we will perform a comprehensive systematic search of MEDLINE, EMBASE and The Cochrane Library, hand search scientific conference abstracts and check clinical trials registries for randomised control trials of participants with solid cancers who are administered parenteral anticoagulants. We anticipate identifying at least 15 trials, exceeding 9000 participants. Second, we will perform an individual participant data meta-analysis to explore the magnitude of survival benefit and address whether subgroups of patients are more likely to benefit from parenteral anticoagulants. All analyses will follow the intention-to-treat principle. For our primary outcome, mortality, we will use multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We will adjust analysis for important prognostic characteristics. To investigate whether intervention effects vary by predefined subgroups of patients, we will test interaction terms in the statistical model. Furthermore, we will develop a risk-prediction model for venous thromboembolism, with a focus on control patients of randomised trials., Ethics and Dissemination: Aside from maintaining participant anonymity, there are no major ethical concerns. This will be the first individual participant data meta-analysis addressing heparin use among patients with cancer and will directly influence recommendations in clinical practice guidelines. Major cancer guideline development organisations will use eventual results to inform their guideline recommendations. Several knowledge users will disseminate results through presentations at clinical rounds as well as national and international conferences. We will prepare an evidence brief and facilitate dialogue to engage policymakers and stakeholders in acting on findings., Trial Registration Number: PROSPERO CRD42013003526., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Venous thromboembolism (VTE) is a highly prevalent complication of malignancy with emerging changes in incidence, diagnosis and treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. We address a) the appropriate workup to search for occult malignancy in patients with idiopathic VTE, b) identification of high-risk cancer patients for primary thromboprophylaxis, c) the appropriate immediate and long-term treatment for people with cancer diagnosed with acute thromboembolism, d) the appropriate duration of anticoagulation and e) the appropriate treatment strategy in patients with recurrent VTE on anticoagulation. Areas of controversy and future directions in this field are highlighted.

Venous thromboembolism (VTE) is a serious medical condition associated with significant morbidity and mortality, and an incidence that is expected to double in the next forty years. The advent of direct oral anticoagulants (DOACs) has catalyzed significant changes in the therapeutic landscape of VTE treatment. As such, it is imperative that clinicians become familiar with and appropriately implement new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for VTE treatment with the DOACs. When possible, guidance statements are supported by existing published evidence and guidelines. In instances where evidence or guidelines are lacking, guidance statements represent the consensus opinion of all authors of this manuscript and are endorsed by the Board of Directors of the Anticoagulation Forum.The authors of this manuscript first developed a list of pivotal practical questions related to real-world clinical scenarios involving the use of DOACs for VTE treatment. We then performed a PubMed search for topics and key words including, but not limited to, apixaban, antidote, bridging, cancer, care transitions, dabigatran, direct oral anticoagulant, deep vein thrombosis, edoxaban, interactions, measurement, perioperative, pregnancy, pulmonary embolism, reversal, rivaroxaban, switching, \thrombophilia, venous thromboembolism, and warfarin to answer these questions. Non- English publications and publications > 10 years old were excluded. In an effort to provide practical information about the use of DOACs for VTE treatment, answers to each question are provided in the form of guidance statements, with the intent of high utility and applicability for frontline clinicians across a multitude of care settings.

Venous thromboembolism (VTE) is a serious and often fatal medical condition with an increasing incidence. The treatment of VTE is undergoing tremendous changes with the introduction of the new direct oral anticoagulants and clinicians need to understand new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. In this chapter, we address the management of patients presenting with venous thrombosis in unusual sites, such as cerebral vein thrombosis, splanchnic vein thrombosis, and retinal vein occlusion. These events are less common than venous thrombosis of the lower limbs or pulmonary embolism, but are often more challenging, both for the severity of clinical presentations and outcomes and for the substantial lack of adequate evidence from clinical trials. Based on the available data, we suggest anticoagulant treatment for all patients with cerebral vein thrombosis and splanchnic vein thrombosis. However, in both groups a non-negligible proportion of patients may present with concomitant bleeding at the time of diagnosis. This should not contraindicate immediate anticoagulation in patients with cerebral vein thrombosis, whereas for patients with splanchnic vein thrombosis anticoagulant treatment should be considered only after the bleeding source has been successfully treated and after a careful assessment of the risk of recurrence. Finally, there is no sufficient evidence to support the routine use of antithrombotic drugs in patients with retinal vein occlusion. Future studies need to assess the safety and efficacy of the direct oral anticoagulants in these settings.

Background: Whether and when to resume oral anticoagulant therapy for patients who survive warfarin-related intracranial hemorrhage (ICH) remains a dilemma lacking consensus recommendations and high-quality evidence to guide clinical decision making., Objective: To determine the incidences of recurrent ICH, thrombosis, and death in relation to resumption or non-resumption of warfarin therapy during the 365 days after incident ICH., Methods: We conducted a retrospective cohort study of adult patients in an integrated healthcare delivery system who were receiving warfarin therapy at the time of incident (index) ICH between 1/1/2000 and 12/31/2007 and survived to hospital discharge. The primary outcomes were recurrent ICH, thrombosis (stroke, systemic embolism, and venous thromboembolism), and all-cause mortality during the 365 days following index ICH. Patients were assigned to one of two groups defined by warfarin therapy resumption after the index ICH., Results: There were 160 patients discharged from the hospital following warfarin-related index ICH; of these 54 (33.8%) resumed warfarin therapy and 106 (66.2%) did not. Recurrent ICH occurred in a numerically greater, but statistically non-significant, proportion of patients who did not resume warfarin therapy (7.6% vs. 3.7%, p=0.497). Similarly, patients who did not resume warfarin had a three-fold higher (12.3% vs. 3.7%, p=0.092) and approximately two-fold higher (31.1% vs. 18.5%, p=0.089) rates of thrombosis and all-cause mortality, respectively, during follow up., Conclusion: Resumption of warfarin therapy following warfarin-associated ICH appeared not to be associated with increased risk of recurrent ICH but trended toward reduced thrombosis and all-cause mortality., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Patients with cancer have long been an important and enigmatic part of basic science and clinical research in thromboembolic disease. The reciprocal deleterious effects on outcomes of a cancer diagnosis on patients with thrombosis and a thrombotic event on patients with cancer have been observed and documented for more than a century. Patients with cancer continue to be one of the more difficult populations to manage using the available unfractionated and low-molecular-weight heparins and the oral vitamin K antagonists. High rates of failure and bleeding complications have made researchers and practitioners alike seek newer more effective anticoagulation agents. The novel oral direct thrombin and activated factor Xa inhibitors have been shown in large clinical trials to be safe and efficacious in many prophylaxis and treatment settings. However, practitioners who treat patients with cancer should be cautious using these agents until more studies are specifically performed in this thrombophilic patient population.

Laboratory evidence of antiphospholipid antibodies (APLA) in patients with a first episode of venous thromboembolism (VTE) is often considered an indication for indefinite anticoagulant therapy, but it is uncertain if this practice is justified. We performed a systematic review to determine whether the presence of APLA in patients with a first VTE is associated with an increased risk of recurrence. We searched PubMed, CINAHL, Cochrane, EMBASE, and Web of Knowledge through February 2012 and included prospective studies that met prespecified design criteria. There were 109 recurrent VTE in 588 patients with APLA and 374 recurrent VTE in 1914 patients without APLA (relative risk 1.41; 95% confidence interval [CI], 0.99 to 2.36). The unadjusted risk ratio for recurrent VTE after stopping anticoagulant therapy in patients with an anticardiolipin antibody was 1.53 (95% CI, 0.76-3.11), and with a lupus anticoagulant was 2.83 (95% CI, 0.83-9.64). All studies had important methodologic limitations and we judged the overall quality of the evidence as very low. Although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality.

A 44-year-old otherwise healthy woman has completed 3 months of anticoagulation therapy for a first episode of unprovoked pulmonary embolism. At the time of diagnosis and before the initiation of anticoagulation, she was found to have an elevated IgG anticardiolipin antibody (ACLA), which was measured at 42 IgG phospholipid (GPL) units (reference range, <15 GPL units) with negative lupus anticoagulant (LAC) testing. Should this laboratory finding affect the recommended duration of anticoagulant therapy?

Background: VTE is a common cause of preventable death in surgical patients., Methods: We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement., Results: We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations., Conclusions: Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients.

The association between venous thromboembolism (VTE) and malignancy is well established. Recent interest has focused on standards of care for prophylaxis, diagnosis, and treatment of malignancy-associated thrombosis. Anticoagulant management in cancer patients has unique complexities such as prolonged hospitalization, extensive surgeries, extended periods of inactivity, indwelling central venous catheters (CVC), thrombocytopenia, and pro-thrombotic medications. Here we will explore current recommendations for various specific clinical scenarios for cancer-associated thromboses. We will make evidence-based recommendations wherever possible; however, several of the scenarios here were included because pertinent high-quality evidence does not exist., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Anti-factor Xa values in morbidly obese patients receiving standard doses of fondaparinux sodium for the prevention of venous thromboembolism (VTE) were analyzed in a retrospective chart evaluation., Summary: The administration of low-molecular-weight heparins to obese patients (body mass index [BMI] of ≥30 kg/m(2)) at the dose recommended for VTE prophylaxis has been reported to result in increased thromboembolic events and decreased anti-factor Xa levels, and some evidence indicates that weight-based dosing adjustments may be appropriate. To study this phenomenon among morbidly obese patients (BMI of ≥40 kg/m(2)), a review of the charts of 45 adult patients for whom steady-state anti-factor Xa laboratory values were obtained after at least four fondaparinux injections was conducted; in all instances, fondaparinux sodium was given at the standard dose (2.5 mg once daily). Of the total of 47 anti-factor Xa values analyzed, 22 (47%) were below the study institution's target peak range (0.3-0.5 mg/L), 20 values (43%) were within the range, and 5 (11%) were above the range. No documented thromboembolic events occurred during hospitalization in the cases evaluated. A stepwise linear regression analysis of selected demographic and clinical variables indicated that better renal function, male sex, increased BMI, and fewer fondaparinux doses were associated with a greater likelihood of diminished anti-factor Xa activity in the cases evaluated., Conclusion: Anti-factor Xa concentrations in morbidly obese patients receiving fondaparinux sodium 2.5 mg subcutaneously daily for VTE prophylaxis were within or above the target range in 53% of the instances evaluated.

Venous thromboembolism is a major cause of morbidity and mortality worldwide and most often affects hospitalized postoperative surgical and medical patients. Venous thromboembolism prophylaxis undoubtedly improves the care of these patients, as demonstrated by the current literature and guidelines. Failure to prescribe prophylaxis when indicated, however, remains a vital health care concern. The American College of Chest Physicians (ACCP) published their most recent guidelines regarding venous thromboembolism prophylaxis in 2008. In this review, we aim to summarize the most recent ACCP prophylaxis guidelines with practical application and interpretation for the practicing physician. Here we present the most practical information from these guidelines and summarize essential recommendations in key tables. We will briefly review the grading system used in the guidelines for the level of evidence and the strength of the recommendation. We will then discuss the recommendations for prophylaxis in the various patient populations described in these guidelines including general and orthopedic surgery, gynecologic surgery, urologic surgery, thoracic surgery, neurosurgery, trauma, medical conditions, cancer patients, and critical care. In addition, we will discuss recent clinical trials regarding novel anticoagulants for venous thromboembolism prophylaxis and share some conclusions.