Cancer-associated Venous Thrombosis Research Articles

Blocking podoplanin inhibits platelet activation and decreases cancer-associated venous thrombosis

BackgroundPatients with cancer are at a high risk of venous thromboembolism (VTE), studies have shown that high expression of podoplanin (PDPN) in tumors is associated with increased risk of VTE. MethodsTwo human malignant cell lines (NCI-H226 and C8161) expressing high levels of PDPN were selected to explore the role of platelet in cancer-associated venous thrombosis in vitro and in vivo. Immunohistochemical staining using anti-PDPN antibody was performed in the pulmonary carcinoma patients. ResultsBoth NCI-H226 and C8161 cells expressing high PDPN triggered platelet activation via CLEC-2 in vitro, which was abrogated by an anti-PDPN antibody SZ-168. Furthermore, the in vivo study revealed that injection of CHO-PDPN or C8161 in two mouse model of venous thrombosis activated platelets, increased platelet counts and enhanced thrombosis. More importantly, PDPN-enhanced thrombosis was reduced in mice treated with SZ168. A total of 63.3% tumor specimens stained positive for PDPN. High PDPN expression was associated with an increased risk of VTE and poor prognosis. ConclusionsPDPN expression in tumors induced platelet activation and was related to a high risk of VTE via platelet activation. SZ168 inhibited PDPN-induced platelet activation in vitro and decreased the incidence of VTE in mice.

Single-Drug Approach with Edoxaban is Effective for Resolving Non-Acute Cancer-Associated Venous Thrombosis: A Single-Arm Retrospective Analysis.

Recently, cancer-related venous thromboembolism (VTE) has been termed “cancer-associated thrombosis (CAT)” and is the focus of current research. We retrospectively investigated the efficacy of a single-drug approach with edoxaban for the treatment of non-acute CAT. Thirty-two non-acute CAT patients who received edoxaban were analyzed. The primary endpoint of this analysis was the thrombus disappearance rate at the first evaluation. Secondary endpoints included progression/recurrence of VTE, major bleeding, and D-dimer levels. The thrombus disappearance rate was 62.5%. Therefore, the null hypothesis for the primary endpoint (thrombus disappearance rate of ≤32.0%) was rejected (p = 0.00038) based on the rate of the previous study as the historical control. Recurrent VTE and major bleeding occurred in two patients each. After the start of treatment with edoxaban, a significant difference in D-dimer levels was observed (p = 0.00655). We demonstrated that a single-drug approach with edoxaban is a potential treatment option for non-acute CAT.

MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma.

Cancer-associated venous thrombosis (VTE) increases mortality and morbidity. However, limited tools are available to identify high risk patients. Upon activation, neutrophils release their content through different mechanisms, thereby prompting thrombosis. We explored plasma microRNAs (miRNAs) and neutrophil activation markers to predict VTE in pancreatic ductal adenocarcinoma (PDAC) and distal extrahepatic cholangiocarcinoma (DECC). Twenty-six PDAC and 6 DECC patients recruited at cancer diagnosis, were examined for deep vein thrombosis and pulmonary embolisms, and were then followed-up with clinical examinations, blood collections, and biCUS. Ten patients developed VTE and were compared with 22 age- and sex-matched controls. miRNA expression levels were measured at diagnosis and right before VTE, and neutrophil activation markers (cell-free DNA, nucleosomes, calprotectin, and myeloperoxidase) were measured in every sample obtained during follow-up. We obtained a profile of 7 miRNAs able to estimate the risk of future VTE at diagnosis (AUC = 0.95; 95% Confidence Interval (CI) (0.987, 1)) with targets involved in the pancreatic cancer and complement and coagulation cascades pathways. Seven miRNAs were up- or down-regulated before VTE compared with diagnosis. We obtained a predictive model of VTE with calprotectin as predictor (AUC = 0.77; 95% CI (0.57, 0.95)). This is the first study that addresses the ability of plasma miRNAs and neutrophil activation markers to predict VTE in PDAC and DECC.

Prevention of venous thromboembolism in patients with cancer with direct oral anticoagulants: A systematic review and meta-analysis.

Background:Patients with cancer are of a high level risk of venous thromboembolism (VTE). Low molecular weight heparin (LMWH) is recommended as the normal treatment for cancer-associated venous thrombosis. Recently, some studies suggest that patients with cancer-associated venous thrombosis can get a good efficacy and safety profile from treating with direct oral anticoagulants (DOACs) compared with other anticoagulants. However, when it comes to the efficacy of DAOCs in preventing VTE in patient with cancer, the data are limited. Thus, we performed such a meta-analysis to determine the efficacy and safety of DOACs in preventing VTE in patient with cancer compared with LMWHs.Methods:Medline/PubMed and CENTRAL (The Cochrane Central Register of Controlled Trials) were systematically searched for relevant studies. For each trial, data on VTE, major bleeding, or bleeding were extracted by 2 reviewers independently. Pooled risk ratios (RRs) were calculated by using Review Manager 5.3 software and the significance was determined by the Z test.Results:A total of 6 studies with 7185 patients were included in our meta-analysis. DOACs (RR = 0.55, 95% confidence interval [95%CI]: 0.34–0.90, I2 = 31%) had a similar prevention effect of VTE to LMWH (RR = 0.59, 95% CI: 0.37–0.95, I2 = 59%). DOACs (RR = 1.52, 95% CI: 0.99–2.33, I2 = 0%) yielded a similar bleeding occurrence rate compared with LMWH (RR = 1.35, 95% CI: 1.07–1.70, I2 = 35%). DOACs (RR = 1.95, 95% CI: 0.88–4.30, I2 = 0%) showed a sight higher major bleeding occurrence rate than LMWH (RR = 1.38, 95% CI: 0.88–2.14, I2 = 0%).Conclusion:DOACs show comparable efficacy to LMWH in cancer patients without VTE with a slightly higher major bleeding occurrence rate. DOACs are inclined to be an alternative thromboprophylaxis strategy in cancer patients as they have superiorities compared to traditional anticoagulation agents. Further studies are still demanded as exiting relevant researches are limited.

Direct oral anticoagulants in cancer-associated venous thromboembolism

This is a narrative review of the relevant literature on the epidemiology, pathogenesis, and treatment of venous thromboembolism (VTE) in cancer patients. In accordance with actual guidelines, the duration of anticoagulant therapy for cancer-associated venous thrombosis should be at least 6 months. The use of Vitamin K antagonists (VKA) is associated with an increased risk of VTE recurrence and bleeding, so low-molecular-weight heparin (LMWH), in particular dalteparin, has been the “gold standard” until recently. Compared to VKA, prolonged use of LMWH can reduce the incidence of VTE recurrence without affecting the risk of bleeding or death. The main disadvantage of LMWH is low compliance, leading to premature discontinuation of treatment or switching to alternative anticoagulants. Direct oral anticoagulants (DOACs) have changed the situation. Compared to VKA, they demonstrated increased efficacy with similar or improved safety in patients with cancer-related VTE. Recently, the results of specialized studies comparing the use of DOACs to the use of dalteparin in cancer patients have been published: SELECT-D (rivaroxaban), HOKUSAI-VTE Cancer (edoxaban), ADAM VTE (apixaban), and CARAVAGGIO (apixaban). Rivaroxaban showed higher efficacy than dalteparin with a similar risk of major bleeding, but with an increased risk of clinically relevant nonmajor (CRNM) bleeding. Edoxaban had the same efficacy as dalteparin, though it showed an increased risk of major but not CRNM bleeding. Apixaban showed similar efficacy and safety as dalteparin in the CARAVAGGIO study, but did not provide higher safety in the ADAM VTE study. It was noted that gastrointestinal and urogenital bleeding dominated the structure of hemorrhagic complications of DOACs. The results of published trials are reflected in the current guidelines of the specialized societies. DOACs are recommended for VTE treatment in cancer patients.

Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models.

Cancer patients have an increased risk of venous thromboembolism (VTE). The rate of VTE varies with cancer type, with pancreatic cancer having one of the highest rates, suggesting that there are cancer type-specific mechanisms of VTE. Risk assessment scores, such as the Khorana score, have been developed to identify ambulatory cancer patients at high risk of VTE. However, the Khorana score performed poorly in discriminating pancreatic cancer patients at risk of VTE. Currently, thromboprophylaxis is not recommended for cancer outpatients. Recent clinical trials showed that factor Xa (FXa) inhibitors reduced VTE in high-risk cancer patients but also increased major bleeding. Understanding the mechanisms of cancer-associated thrombosis should lead to the development of safer antithrombotic drugs. Mouse models can be used to study the role of different prothrombotic pathways in cancer-associated thrombosis. Human and mouse studies support the notion that 2 prothrombotic pathways contribute to VTE in pancreatic cancer patients: tumor-derived, tissue factor-positive (TF+) extracellular vesicles (EVs), and neutrophils and neutrophil extracellular traps (NETs). In pancreatic cancer patients, elevated levels of plasma EVTF activity and citrullinated histone H3 (H3Cit), a NET biomarker, are independently associated with VTE. We observed increased levels of circulating tumor-derived TF+ EVs, neutrophils, cell-free DNA, and H3Cit in nude mice bearing human pancreatic tumors. Importantly, inhibition of tumor-derived human TF, depletion of neutrophils, or administration of DNAse I to degrade cell-free DNA (including NETs) reduced venous thrombosis in tumor-bearing mice. These studies demonstrate that tumor-derived TF+ EVs, neutrophils, and cell-free DNA contribute to venous thrombosis in a mouse model of pancreatic cancer.

Safety and Effectiveness of Rivaroxaban Versus Low Molecular Weight Heparin for Treatment of Cancer-Associated Venous Thrombosis: A SEER-Medicare-Linked Data Analysis

Introduction: Venous thromboembolism (VTE) affects ~20% of patients with cancer prior to death and may be present in up to half of cancer patients upon autopsy. International Society of Thrombosis and Haemostasis (ISTH) guidelines recommend oral factor Xa inhibitors for the acute treatment and secondary prevention of cancer-associated thrombosis (CAT) in patients considered low risk of bleeding and without a potential for drug-drug interactions with current systemic therapy. We sought to evaluate the effectiveness and safety of rivaroxaban versus a low molecular weight heparin (LMWH) for the treatment of CAT in routine practice. Methods: Using United States Surveillance, Epidemiology and End Results (SEER)-Medicare-linked data from 2013 to 2015, we identified adults diagnosed with lung, breast, pancreatic, prostate or ovarian cancer, having at ≥1 hospitalization or emergency department admission (index event) with a primary discharge diagnosis code for VTE (indicating VTE was the foremost reason for admission) , ≥12-months of continuous medical and prescription benefits prior to the index CAT and who received rivaroxaban or a LMWH as their first outpatient anticoagulant. Patients with primary or metastatic gastrointestinal cancers, stage 4 or worse chronic kidney disease or liver failure were excluded. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the composite outcome of recurrent VTE or major bleeding, each of these outcomes alone as well as all-cause mortality in the subsequent 12-months were calculated using a multivariable Fine-Gray (competing risk) Cox regression model adjusted for baseline covariates and propensity score decile (c-index=0.76) estimated using generalized boosted models on the basis of 10,000 regression trees. Results: We included 259 rivaroxaban- and 559 LMWH-managed patients with CAT. The median age (25%, 75% range) of patients was 73 (68, 79) years, 62.5% were men and 43.6% had pulmonary embolism. The incident cancer diagnosis was made between 2010 and 2013 in 87.8% of patients. Primary cancer locations included lung (41.8%), breast (21.8%), pancreatic (12.1%), prostate (11.9%), ovarian (5.3%) and other (7.1%). Nearly all patients (96.5%) were diagnosed with stage 2 or 3 disease. During the 12-month follow-up period, the incidence of the composite of recurrent VTE or major bleeding was 13.8%, recurrent VTE alone occurred in 11.4% and major bleeding alone in 2.9% of patients and all-cause mortality occurred in 48.4%. No significant difference in patients' relative hazard of the experiencing the composite outcome (HR=0.86, 95%CI=0.52-1.41), recurrent VTE (HR=0.91, 95%CI=0.51-1.62), major bleeding (HR=0.90, 95%CI=0.29-2.83) or all-cause mortality (HR=0.86, 95%CI=0.62-1.21) were observed between the rivaroxaban and LMWH-managed cohorts. Conclusions: In this real-world study of rivaroxaban- and LMWH-managed CAT patients, no significant difference in patients' relative hazard of experiencing the composite outcome, recurrent thrombosis, major bleeding or all-cause mortality were observed between the two cohorts. These data are consistent with recommendation that the oral factor Xa inhibitor, rivaroxaban, is a reasonable alternative to LMWH for the treatment of CAT and prevention of recurrent thrombosis. Disclosures Lyman: Amgen Inc.: Other: Research support, Research Funding; Janssen Scientific Affairs, LLC: Research Funding; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics, Halozyme Therapeutics, Partners Healthcare, Hexal, Bristol-Myers Squibb, Helsinn Therapeutics, Amgen Inc., Pfizer, Agendia, Genomic Health, Inc.: Consultancy. Kuderer:Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Celldex: Consultancy; Myriad Genetics: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Halozyme: Consultancy; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses. Coleman:Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs LLC: Consultancy, Honoraria, Research Funding.

Impact of anticoagulant choice on hospitalized bleeding risk when treating cancer‐associated venous thromboembolism

Essentials Bleeding risk by anticoagulant choice for cancer-associated venous thrombosis (CA-VTE) is unknown. 26894 people with CA-VTE were followed for bleeding in a claims database in the United States. Hospitalized bleeding risk was similar with direct acting oral anticoagulants vs. warfarin. Relative hospitalized bleeding risk varied by cancer type and anticoagulant choice. SUMMARY: Background Direct acting oral anticoagulants (DOACs) are associated with less bleeding than traditional venous thromboembolism (VTE) treatments in the general population but are little studied in cancer-associated VTE (CA-VTE). Objective To determine whether different anticoagulation strategies for CA-VTE have different hospitalized bleeding rates. Patients/Methods We conducted a retrospective study of patients with CA-VTE, diagnosed between 2011 and 2015, in a large administrative database. Using validated algorithms, we identified 26894 CA-VTE patients treated with anticoagulants and followed them for hospitalized severe bleeding. Cox models were used to assess bleeding risk, adjusted for age, sex, high dimensional propensity score and frailty. Results Over 27281 person-years of follow-up (median 0.6years), 1204 bleeding events occurred, for a bleeding rate of 4.4% per patient-year. Bleeding rates varied by cancer type, with the highest rate for upper gastrointestinal cancers (8.6%) and the lowest for breast cancer (2.9%). In Cox models (hazard ratio [HR]; 95% confidence interval [CI]), compared with warfarin, DOACS and low-molecular-weight heparin (LMWH) had similar hazards of bleeding (HR, 0.88; 95% CI, 0.69-1.11 and 0.98; 0.85-1.13). Compared with LMWH, there was no difference in hazard of bleeding with DOACs (0.86; 0.66-1.12). There was heterogeneity in bleeding risk with DOACs by cancer type, with a higher risk of bleeding in upper gastrointestinal cancers and lower risk of bleeding in prostate cancer and hematologic cancers. Conclusions In this practice-based sample of CA-VTE patients, DOACs were associated with similar bleeding risks to warfarin and LMWH. These findings suggest a complex association of bleeding risk with anticoagulant choice in cancer patients.

Platelet (hem)ITAM Signaling Mediated Cancer-Associated Venous Thrombosis

Background-Patients with cancer are at a high risk of venous thromboembolism (VTE) and underlying mechanisms are unclear. Recent studies have shown that podoplanin (PDPN) expressing highly in primary brain tumors is associated with increasingly risk of VTE by activate platelets. The C-type lectin-like receptor 2(CLEC-2) is a type II transmembrane protein expressed on the surface of platelets and PDPN is the only known endogenous ligand for it. CLEC-2 mediates platelet activation through a hem-immunoreceptor tyrosine-based activation motif ((hem)ITAM).Objective: We tested the hypothesis that the platelet (hem)ITAM signaling is involved in the development of VTE in patients with malignant tumors, and targeted inhibitors may reduce thrombosis and improve prognosis in patients with cancer.Materials and Methods-We selected two human malignant cell lines (NCI-H226 and C8161) expressing high levels of PDPN as models to study the role of the platelet (hem)ITAM signaling in cancer-associated venous thrombosis in vitro and in vivo.Results and Conclusions-Our results showed that both types of cell lines expressing PDPN triggered platelet activation via CLEC-2 in vitro, which could be abrogated by an anti-PDPN antibody SZ-168 or syk inhibitor R406. Further, in vivo study showed that injection of NCI-H226 or C8161 in two mouse models of venous thrombosis activated platelets, increased platelet counts and enhanced thrombosis. These results suggested that platelet activation induced by PDPN was correlated with hypercoagulability, contributed to thrombosis in cancer patients. Importantly, PDPN enhanced thrombosis was reduced in mice treated with SZ168 or R406. Immunohistochemical staining using anti-PDPN antibody was also performed in pulmonary squamous cell carcinoma specimens of 166 patients. During up to 4-year-follow-up, 20 (12.05%) patients developed VTE. 105 tumor specimens stained positive for PDPN (27 high expression, 43 medium expression, 35 low expression). High PDPN expression was associated with an increased risk of VTE and poor prognosis, independently of age, sex and tumor type. In this study, we found that PDPN expression in tumors induced platelet aggregation and was associated with a high risk of VTE via platelet (hem)ITAM signaling. Our data also suggested that SZ168 inhibited PDPN-induced platelet aggregation in vitro and decreased the incidence of VTE in mice. In conclusion, our research demonstrated novel insights into the pathogenesis of cancer-associated venous thrombosis. DisclosuresNo relevant conflicts of interest to declare.

The Role of Neutrophil Extracellular Traps in Cancer-Associated Arterial Thrombosis

Introduction: Prior studies have indicated that Neutrophil extracellular traps (NETs) trigger arterial thromboembolism (ATE) and play a role in the pathogenesis of cancer-associated venous thrombosis. We investigated the association between NET biomarkers (citrullinated histone H3 [H3Cit], cell-free DNA [cfDNA], and nucleosomes) and the risk of ATE in patients with cancer.Methods: In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for objectively confirmed, symptomatic ATE and death. Fine&Gray competing-risk regression was used to model risk of ATE. Overall survival (OS) was analyzed with Kaplan-Meier estimators.Results: Nine-hundred and fifty-eight patients with cancer (median age: 61 years; 46.8% female; Table 1) were recruited. ATE occurred in 22 patients; the cumulative 6-, 12-, and 24-month risks of ATE were 1.1%, 1.8%, and 2.3%, respectively. The subdistribution hazard ratios (SHR) for ATE of H3Cit, cfDNA, and nucleosomes per unit increase were 1.0 (95% confidence interval [CI]: 1.0-1.0, p=.882), 1.0 (1.0-1.0, p=.639), and 1.1 (1.0-1.2, p=.246) respectively. The 6-, 12-, and 24-month ATE probability was 1.3%, 1.7%, and 2.6% in patients with a H3Cit level ≤ 75thpercentile, and 0.8%, 1.3%, and 1.7% in patients above this cut-off (SHR=0.7, 0.2-2.0, p=.460).The 6-, 12-, 24-month overall survival of the study cohort was 87.0% (95%CI: 84.6-89.0), 73.6% (70.6-76.3), and 57.6% (54.3-60.8), respectively. The hazard ratio (HR) for mortality of H3Cit, cfDNA, and nucleosomes per unit increase were 1.0 (1.0-1.0, p<.001), 1.0 (1.0-1.0, p<.001), and 1.0 (1.0-1.1, p=.181) respectively. For better illustration we defined two groups of patients with elevated or non-elevated NET biomarkers. Therefore, we set an empiric cut-off at the 75thpercentile of the study cohort. Elevated H3Cit (HR=1.7, 1.3-2.1, p<.001), and cfDNA levels (HR=1.4, 1.1-1.7, p=.008) were associated with an increased risk of mortality after adjusting for age, and sex (Figure 1A&B). No association was found between higher nucleosome levels and the risk of all-cause mortality in patients with cancer (HR=1.2, 1.0-1.5, p=.088, Figure 1C).Conclusion: There was no significant association between H3Cit, cfDNA, and nucleosomes and ATE occurrence in patients with cancer. However, elevated levels of H3Cit, and cfDNA, were independently associated with an increased risk of mortality in patients with cancer.Table 1.Baseline characteristics of the total study population. Continuous data is reported as medians with first and third quartiles. Categorical variables are given as absolute frequencies and percentages. Data on body mass index, and cancer stage are missing in 2, and 76 patients, respectively. aPatients with brain and hematologic cancerFigure 1.Kaplan-Meier estimated for overall survival probability of patients with cancer according to baseline H3Cit, cfDNA, and nucleosome levels. MoM = Multiple-of-the-mean (i.e. Nucleosome results were compared to pooled plasma from 5 young male healthy controls to obtain a multiple-of-the-median) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and safety of anticoagulant agents in patients with venous thromboembolism and cancer: A network meta-analysis

BackgroundLow-molecular-weight heparins (LMWHs) are the recommended treatment for cancer-associated venous thrombosis (CAT). Recent evidences suggest a role for direct-acting oral anticoagulants (DOACs) in this clinical setting. MethodsTo evaluate the efficacy and safety of different anticoagulants we performed a network meta-analysis of RCTs including patients with CAT treated with LMWHs, vitamin K antagonists (VKAs) or DOACs. MEDLINE and EMBASE were searched up to February 2018. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. ResultsOverall, 4720 CAT patients from 12 studies were included: 1430 from 2 studies comparing DOACs with LMWHs, 1212 from 4 studies comparing DOACs with VKAs and 2078 from 6 studies comparing VKAs to LMWHs.Recurrent VTE occurred in 4.9% of patients receiving DOACs, 9.6% receiving VKAs and 8.4% receiving LMWHs. The network meta-analysis showed a not significant increase of recurrent VTE in patients receiving LMWHs compared to those receiving DOACs (RR 1.3, 95% CI 0.9 to 2.0). The risk of recurrent VTE was higher in patients receiving VKAs compared to LMWHs (RR 1.5, 95% CI 1.0 to 2.0) or DOACs (RR 2.0, 95% CI 1.3 to 3.0) with no heterogeneity.Major bleeding occurred in 4.9, 4.1 and 4.3% of patients with CAT treated with DOAC, VKA or LMWH, respectively. No significant differences were observed from the direct, indirect and network meta-analyses. ConclusionIn patients with CAT, DOACs showed a good efficacy and safety profile compared to other anticoagulants and is candidates to be an alternative to LMWHs.

Systematic Review and Meta-Analysis of Real-World Studies Evaluating Rivaroxaban for Cancer-Associated Venous Thrombosis.

While not designated as guideline-recommended first-line anticoagulation therapy, about one in five patients in the United States receive rivaroxaban for the treatment of cancer-associated venous thrombosis (CAT). A systematic review and meta-analysis were performed to evaluate the incidences of recurrent venous thromboembolism (VTE), major bleeding, and all-cause mortality in rivaroxaban patients treated for CAT in routine practice. Literature searches of MEDLINE and SCOPUS were performed through September 2017 to identify real-world studies of ≥ 20 patients evaluating the incidence of recurrent VTE, major bleeding, or all-cause mortality in CAT patients anticoagulated with rivaroxaban. Using a Hartung-Knapp random-effects model, the pooled incidence estimates and 95% confidence intervals (CIs) were calculated for each end point. Six studies evaluating rivaroxaban for CAT were identified. Of these, three were prospective and three were retrospective. Study sample sizes ranged from 41 to 949 patients, and duration of follow-up ranged from 164 to 496 days. The most frequent active cancer sites reported in studies were gastrointestinal (range: 12.0-56.0%), genitourinary (range: 8.6-26.0%), and breast (range: 9.3-25.5%). The weighted average incidences of recurrent VTE, major bleeding, and all-cause mortality were 4.2% (95% CI = 2.6-6.6%; I2 = 31%), 2.9% (95% CI = 1.6-5.0%; I2 = 59%), and 16.1% (95% CI = 6.0-36.6%; I2 = 96%). This meta-analysis suggests that incidences of recurrent VTE and major bleeding among rivaroxaban-managed patients are not dissimilar to those seen in recent randomized trials of anticoagulation in CAT. The pooled incidence for mortality was lower than reported in many anticoagulation CAT trials. This may suggest that rivaroxaban is being used in CAT patients who have less severe cancer.

Effectiveness and Safety of Rivaroxaban in Patients With Cancer-Associated Venous Thrombosis.

Background: Although not designated as guideline-recommended first-line anticoagulation therapy, patients are receiving rivaroxaban for the treatment and secondary prevention of cancer-associated venous thrombosis (CAT). We sought to estimate the cumulative incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality/hospice care in patients with CAT treated with outpatient rivaroxaban in routine practice. Methods: Using US MarketScan claims data from January 2012 through June 2015, we identified adults with active cancer (using SEER program coding) who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received rivaroxaban as their first outpatient anticoagulant within 30 days of the index VTE. Patients were required to have ≥180 days of continuous medical/prescription benefits prior to the index VTE. Patients with a previous claim for VTE, atrial fibrillation, or valvular disease or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% CIs of recurrent VTE, major bleeding, and mortality or need for hospice care at 180 days, assuming competing risks. Results: A total of 949 patients with active cancer were initiated on rivaroxaban following their index VTE. Time from active cancer diagnosis to index CAT was ≤90 days for 27% of patients, 91 to 180 days for 19%, and >180 days for 54%. The mean [SD] age of patients was 62.5 [12.8] years, 43.6% had pulmonary embolism, and metastatic disease was present in 42.6%. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding (17 gastrointestinal, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims. The cumulative incidence estimate was 4.0% (95% CI, 2.8%-5.4%) for recurrent VTE, 2.7% (95% CI, 1.7%-4.0%) for major bleeding, and 11.3% (95% CI, 9.2%-13.6%) for mortality/hospice care. Conclusions: Event rates observed in this rivaroxaban-treated cohort were overall consistent with previous studies of patients with rivaroxaban- and warfarin-managed CAT.

Systematic review and meta-analysis of real-world studies evaluating rivaroxaban for cancer-associated venous thrombosis

Introduction: Current cancer-associated venous thrombosis (CAT) guidelines are unanimous in their recommendation of low molecular-weight heparins (LMWHs) as first-line treatment; with oral anticoagulants reserved for patients unable or unwilling to use long-term parenteral therapy. Despite guideline recommendations, up to 1 in 5 patients in routine practice are prescribed rivaroxaban for CAT treatment.

Clinical dilemmas with cancer-associated splanchnic venous thrombosis in current oncological practice: a case study

Clinical dilemmas with cancer-associated splanchnic venous thrombosis in current oncological practice: a case study

Cancer-associated splanchnic venous thrombosis: clinical findings at presentation

Cancer-associated splanchnic venous thrombosis: clinical findings at presentation

Treatment Outcomes of Cancer Associated Venous Thrombosis; The Cleveland Clinic Experience

Introduction: Despite guideline recommendations to use low molecular weight heparin (LMWH) for the treatment of cancer associated thrombosis (CAT), the use of direct oral anticoagulatns (DOACs) is gaining more popularity given the ease of administration, lower cost, and emerging data. Here we report patient outcomes from our experience in treating CAT.

Effectiveness and safety of rivaroxaban versus warfarin for treatment of cancer-associated venous thrombosis

Effectiveness and safety of rivaroxaban versus warfarin for treatment of cancer-associated venous thrombosis

The Efficacy and Safety of Rivaroxaban and Dalteparin in the Treatment of Cancer Associated Venous Thrombosis.

Venous thromboembolism (VTE) is a complication of malignancy that is associated with significant mortality. The CLOT trial showed superiority of dalteparin in comparison to warfarin in preventing VTE recurrence. Rivaroxaban has been approved for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). In the absence of large randomized trials in the oncology population, the efficacy and safety of rivaroxaban for the treatment of VTE in cancer patients needs to be assessed. A single-center retrospective chart review was conducted to assess the efficacy and safety of rivaroxaban compared with dalteparin in cancer-associated thrombosis. Out of 671 patients identified, 286 patients (107 in the rivaroxaban group and 179 in the dalteparin group) were eligible for analysis. The rivaroxaban group had a rate of VTE recurrence at 6months of 4.9 versus 11.1% with dalteparin (p=0.252). The incidence of recurrent DVT at 6months was lower in patients treated with rivaroxaban (0%) compared with dalteparin (8.2%) at 6months (p=0.025). Incidence of recurrent PE in the rivaroxaban group (5%) versus dalteparin group (3.1%) at 6months was not statistically significant (p=0.675). No significant difference was identified between the rivaroxaban group and dalteparin group in the rate of major bleeding (2.8 vs. 1.1%, respectively). Rivaroxaban was comparable to dalteparin in prevention of VTE recurrence while having no significant differences with major or minor bleeding.

Heparins in cancer-associated venous thrombosis.

A close causal relationship between cancer and venous thrombosis gives rise to questions about the effect of treatment modalities, in particular of the administered drugs, in patients with cancer-related venous thrombosis. An increased risk of chemotherapy-associated venous thromboembolism (VTE) has been well documented, while the effect of heparins used in VTE treatment on the disease course and prognosis in cancer patients has not been fully elucidated. This paper discusses the outcomes of the studies conducted so far investigating the role of heparins, in particular, low-molecular-weight heparins (LMWHs), in the prevention of thrombosis in cancer patients. It also focuses on such aspects of the treatment for cancer-associated VTE as treatment duration and drugs used. The paper summarizes the often discrepant results of long-term therapies with various LMWH products, emphasising that in this specific case the class effect is rather unlikely. It also presents the possible effects of heparins administered as part of cancer treatment, and points to the effects of LMWHs on cancer that are not related to an antithrombotic effect. On the 100th anniversary of heparin discovery, it can be said that heparin is irreversibly connected with thrombosis in the course of cancer.