Safety of outpatient management of cancer-associated pulmonary embolism: a retrospective study.

Not available.

Management strategies in persons with inherited haemophilia requiring antithrombotic therapy: A scoping review.

BACKGROUND: Thromboembolic events are increasingly reported in the aging haemophilia population. The purpose of this study was to understand current practices and identify knowledge and research gaps in the management of persons with haemophilia requiring antithrombotic therapy for cardiovascular disorders (CVD) or venous thromboembolism (VTE). METHODS: We searched MEDLINE, EMBASE and Scopus for studies reporting on more than two patients with inherited haemophilia A or B, without inhibitors, requiring antithrombotic therapy for CVD or VTE. Data were extracted by two independent reviewers and analysed using descriptive statistics and narrative synthesis. RESULTS: We included 32 studies reporting on 432 persons with haemophilia. Three themes described the observed practice variation: (1) Difficulty weighing competing bleeding and thrombotic risks; (2) Tensions in providing standards of care and minimizing bleeding risk; (3) Advocacy for individualized strategies and multidisciplinary care. Different management strategies were used to treat persons with haemophilia in the setting of thromboembolic events, such as avoiding or choosing lower intensity antithrombotic therapy, or procedural alternatives to antithrombotic therapy. Initiation or alteration in haemostatic therapies along with antithrombotic therapy were common strategies and reported in 30 studies. However, data on target factor levels and bleeding and thrombotic events were largely missing. DISCUSSION: Our scoping review highlights unmet needs in the management of an aging population of persons with haemophilia with increasing prevalence of CVD and VTE. Management is inconsistent and divergent from those of non-haemophilic patients. Prospective data are needed to inform optimal and evidence-based management strategies of CVD and VTE in persons with haemophilia.

Inherited thrombophilia gene mutations and risk of venous thromboembolism in patients with cancer: A systematic review and meta-analysis.

In the general population, individuals with an inherited thrombophilia have a higher risk of thrombosis, but the effect of inherited thrombophilia on the risk of cancer-associated venous thromboembolism (VTE) remains controversial. Our objective was to determine the risk of VTE in cancer patients with inherited thrombophilia. We conducted a systematic review and meta-analysis of studies reporting on VTE after a cancer diagnosis in adult patients who were tested for inherited thrombophilia. In September 2022, we searched Medline, EMBASE, and Cochrane Central. Two reviewers screened the abstracts/full texts and assessed study quality using the Quality in Prognostic Studies tool. We used Mantel-Haenszel random-effects models to estimate pooled odds ratios (OR) of VTE and 95% confidence intervals (95%CI). We included 37 and 28 studies in the systematic review and meta-analysis, respectively. Most studies focused on specific cancer types and hematologic malignancies were rare. The risk of VTE was significantly higher in cancer patients with non-O (compared with O) blood types (OR: 1.56 [95% CI: 1.28-1.90]), Factor V Leiden, and Prothrombin Factor II G20210A mutations compared with wild types (OR: 2.28 [95% CI: 1.51-3.48] and 2.14 [95% CI: 1.14-4.03], respectively). Additionally, heterozygous and homozygous methylenetetrahydrofolate reductase C677T had ORs of 1.50 (95% CI: 1.00-2.24) and 1.38 (95% CI: 0.87-2.22), respectively. Among those with Plasminogen-Activator Inhibitor-1 4G/5G, Vascular Endothelial Growth Factor (VEGF) A C634G, and VEGF C2578A mutations, there was no significant association with VTE. In conclusion, this meta-analysis provided evidence that non-O blood types, Factor V Leiden, and Prothrombin Factor II G20210A mutations are important genetic risk factors for VTE in cancer patients.

Updates in the Incidence, Pathogenesis, and Management of Cancer and Venous Thromboembolism.

Patients with cancer are at higher risk of developing venous thromboembolism (VTE) compared with the general population. This elevated risk is due to several risk factors and multiple, overlapping thrombotic and hemostatic pathophysiological pathways that are specific to this patient population. Hence, the management of cancer-associated VTE can be challenging for clinicians. Patients with cancer-associated VTE are at higher risk of both recurrent events despite anticoagulation and bleeding complications due to the anticoagulant regimens. Direct oral anticoagulants have recently been shown to be effective, safe, and more convenient than parenteral low-molecular-weight heparin for the management of cancer-associated VTE. Despite these recent advances in anticoagulant therapy, many unmet needs remain in these patients (increased risk of bleeding with specific cancer types, drug-drug interactions, liver dysfunction). Factor XI inhibitors are currently being assessed for the management of cancer-associated VTE and may help clinicians address these important knowledge gaps.

Treatment of Cancer-Associated Thrombosis: Recent Advances, Unmet Needs, and Future Direction.

Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE.

Risk of venous thromboembolism or hemorrhage among individuals with chronic kidney disease on prophylactic anticoagulant after hip or knee arthroplasty.

Chronic kidney disease (CKD) confers a high risk of thrombosis and bleeding. However, little evidence exists regarding the optimal choice of postoperative thromboprophylaxis in these patients. We conducted a population-based, retrospective cohort study among adults ≥66 years old with CKD undergoing hip or knee arthroplasty who had filled an outpatient prophylactic anticoagulant prescription between 2010 and 2020 in Ontario, Canada. The primary outcomes of venous thrombosis (VTE) and hemorrhage were identified by validated algorithms using relevant diagnoses and billing codes. Overlap-weighted cause-specific Cox proportional hazard models were used to examine the association of direct oral anticoagulants (DOAC) on the 90-day risk of VTE and hemorrhage compared with low-molecular-weight heparin (LMWH). A total of 27 645 patients were prescribed DOAC (N = 22 943) or LMWH (N = 4702) after arthroplasty. Rivaroxaban was the predominant DOAC (94.5%), while LMWH mainly included enoxaparin (67%) and dalteparin (31.5%). DOAC users had higher eGFRs, fewer co-morbidities, and surgery in more recent years compared to LMWH users. After weighing, DOAC (compared with LMWH) was associated with a lower risk of VTE (DOAC: 1.5% vs. LMWH: 2.1%, weighted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.94) and a higher risk of hemorrhage (DOAC: 1.3% vs. LMWH: 1.0%, weighted HR 1.44, 95% CI 1.04-1.99). Additional analyses including a more stringent VTE defining algorithm, different eGFR cut-offs, and limiting to rivaroxaban and enoxaparin showed consistent findings. Among elderly adults with CKD, DOAC was associated with a lower VTE risk and a higher hemorrhage risk compared to LMWH following hip or knee arthroplasty.

Direct oral anticoagulants and cancer-associated VTE: good for all, or just some?

Venous thromboembolism (VTE) is associated with significant mortality and morbidity in patients with cancer. Therefore, tailoring anticoagulation is of utmost importance to decrease the risk of recurrent VTE while minimizing the risk of bleeding. Direct oral anticoagulants have been recently compared with low-molecular-weight heparin for the management of acute cancer-associated thrombosis. Although direct oral anticoagulants are a welcome addition, clinicians need to incorporate clinical characteristics, drug-drug interactions, and patient preference in decision making.

How I treat obese patients with oral anticoagulants.

Obesity has become a major threat to health worldwide. The prevalence of obesity is rapidly increasing, so much so that the World Health Organization has declared obesity as a global epidemic. Obesity is associated with multiple health problems, including venous thromboembolism and atrial fibrillation, both of which are treated with anticoagulation. However, obesity and treatments for obesity such as bariatric surgery can influence absorption, excretion, pharmacokinetics, and pharmacodynamics of various anticoagulants. This results in uncertainty regarding the best antithrombotic strategies in this population, particularly in the morbidly obese. In the recent years, several studies have attempted to investigate anticoagulation use in this population and provided more insight. Herein, we present 4 cases of anticoagulant use in the obese to illustrate the common challenges faced by clinicians and discuss our approach. Whenever possible, we provide a review of the literature and base our recommendations on the best available evidence.

Increased bleeding risk associated with concurrent vascular endothelial growth factor receptor tyrosine kinase inhibitors and low-molecular-weight heparin.

BACKGROUND: Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low-molecular-weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized. METHODS: Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups. RESULTS: Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow-up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28-4.69 [P = .007]) and first-onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13-4.42 [P = .02]). Analysis of 6-month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone. CONCLUSIONS: Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.

Approach to Cancer-Associated Thrombosis: Challenging Situations and Knowledge Gaps.

Malignancy is a significant risk factor for venous thromboembolism (VTE). It is estimated that up to 20% of patients with cancer may develop VTE at some time in their cancer journey. Cancer-associated VTE can lead to hospitalizations, morbidity, delayed cancer treatment, and mortality. The optimal prevention and management of cancer-associated thrombosis (CAT) is of utmost importance. Direct oral anticoagulants have been recommended as first-line therapy for VTE treatment in the general population and their efficacy has recently been demonstrated in the cancer population, leading to increased use. However, patients with cancer have unique challenges and comorbidities that can lead to increased risks and concerns with anticoagulation. Herein we will discuss commonly encountered challenges in patients with CAT, review available literature, and provide practice suggestions. IMPLICATIONS FOR PRACTICE: This article aims to specifically address cancer-associated thrombosis issues for which there is limited or absent evidence to guide best practice, for circumstances that pose unique challenges for clinicians, and for directions when the literature is conflicting. It reviews pertinent data for each selected topic and provides guidance for patient management based on the best available evidence and experiences from the panel.

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism.

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 .).

Clinical implications of incidental venous thromboembolism in cancer patients.

INTRODUCTION: In cancer patients, current guidance suggests similar treatment for incidental and symptomatic venous thromboembolism (VTE), mainly based on retrospective data. We aimed to evaluate anticoagulant therapy in cancer patients with incidental and symptomatic VTE. METHODS: The Hokusai VTE Cancer Study was a randomised controlled trial comparing edoxaban with dalteparin for cancer-associated VTE. The primary outcome was the composite of first recurrent VTE or major bleeding. Secondary outcomes included major bleeding, recurrent VTE and mortality. Outcomes in patients with incidental and symptomatic VTE were evaluated during the 12-month study period. RESULTS: 331 patients with incidental VTE and 679 patients with symptomatic VTE were enrolled, of whom the index event was confirmed by an independent radiologist. Median durations of anticoagulant treatment were 195 and 189 days, respectively. In patients with incidental VTE, the primary outcome occurred in 12.7% of patients, major bleeding in 6.6% of patients and recurrent VTE in 7.9% of patients. Out of the 26 VTE recurrences in patients with incidental VTE, five (31%) were incidental, seven (44%) were symptomatic and four (25%) were deaths for which pulmonary embolism could not be ruled out. In patients with symptomatic VTE, the primary outcome occurred in 13.8% of patients, major bleeding in 4.9% of patients and recurrent VTE in 10.9% of patients. All-cause mortality was similar in both groups. CONCLUSION: Clinical adverse outcomes are substantial in both cancer patients with incidental and symptomatic VTE, supporting current guideline recommendations that suggest treating incidental VTE in the same manner as symptomatic VTE.

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). The International Myeloma Working Group (IMWG) developed guidelines recommending primary thromboprophylaxis, in those identified at high-risk of VTE by the presence of risk factors. The National Comprehensive Cancer Network (NCCN) has adopted these guidelines; however, they lack validation. We sought to develop and validate a risk prediction score for VTE in MM and to evaluate the performance of the current IMWG/NCCN guidelines. Using 4446 patients within the Veterans Administration Central Cancer Registry, we used time-to-event analyses to develop a risk score for VTE in patients with newly diagnosed MM starting chemotherapy. We externally validated the score using the Surveillance, Epidemiology, End Results (SEER)-Medicare database (N = 4256). After identifying independent predictors of VTE, we combined the variables to develop the IMPEDE VTE score (Immunomodulatory agent; Body Mass Index ≥25 kg/m2 ; Pelvic, hip or femur fracture; Erythropoietin stimulating agent; Dexamethasone/Doxorubicin; Asian Ethnicity/Race; VTE history; Tunneled line/central venous catheter; Existing thromboprophylaxis). The score showed satisfactory discrimination in the derivation cohort, c-statistic = 0.66. Risk of VTE significantly increased as score increased (hazard ratio 1.20, P = <.0001). Within the external validation cohort, IMPEDE VTE had a c-statistic of 0.64. For comparison, when evaluating the performance of the IMWG/NCCN guidelines, the c-statistic was 0.55. In summary, the IMPEDE VTE score outperformed the current IMWG/NCCN guidelines and could be considered as the new standard risk stratification for VTE in MM.

A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer - A real world experience.

INTRODUCTION: Low-molecular-weight heparins are the standard treatment for cancer-associated thrombosis. Recently, direct oral anticoagulants are a new option for thrombosis treatment; however, data supporting the use of direct oral anticoagulants for cancer-associated thrombosis are limited. OBJECTIVES: The primary objective of this study was to determine the rate of recurrent cancer-associated thrombosis and major bleeding within 6 months of starting either low-molecular-weight heparin or direct oral anticoagulant for treatment of cancer-associated thrombosis. Secondary objectives were to determine the rates of clinically relevant-non-major bleeding and all-cause mortality. PATIENTS/METHODS: This is a retrospective cohort study including adults with cancer-associated thrombosis treated with low-molecular-weight heparin or direct oral anticoagulant between 2010 and 2016 at the Ohio State University. Medical records were reviewed for 6 months after initiation of anticoagulation or until the occurrence of recurrent cancer-associated thrombosis, major bleeding, cessation of anticoagulation of interest, or death, whichever occurred first. RESULTS: Four hundred and eighty patients were included (290 low-molecular-weight heparin and 190 direct oral anticoagulant). Patients treated with direct oral anticoagulant were found to carry "lower risk" features including cancer with lower VTE risk and lower rate of metastatic disease. After adjustment for baseline differences, there was no significant difference in the rate of recurrent cancer-associated thrombosis (7.2% low-molecular-weight heparin vs 6.3% direct oral anticoagulant, p = 0.71) or major bleeding (7.6% low-molecular-weight heparin vs 2.6% direct oral anticoagulant, p = 0.08). CONCLUSIONS: Our study demonstrates that in a select population of cancer patients with VTE, direct oral anticoagulant use can be as effective and safe compared to the standard therapy with low-molecular-weight heparin.

NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.

Cancer-Associated Venous Thromboembolic Disease, Version 1.2015.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.