Cancer-associated Venous Thromboembolism Research Articles

Comparison of Clinical Outcomes in Patients with Active Cancer Receiving Rivaroxaban or Low-Molecular-Weight Heparin: The OSCAR-UK Study.

In most patients with cancer-associated venous thromboembolism (CT), essentially those not at high risk of bleeding, guidelines recommend treatment with direct oral anticoagulants as an alternative to low-molecular-weight heparins (LMWHs). Population-based studies comparing these therapies are scarce. To compare the risk of venous thromboembolism (VTE) recurrences, significant bleeding, and all-cause mortality in patients with CT receiving rivaroxaban or LMWHs. Using UK Clinical Practice Research Datalink data from 2013 to 2020, we generated a cohort of patients with first CT treated initially with either rivaroxaban or LMWH. Patients were observed 12 months for VTE recurrences, significant bleeds (major bleeds or clinically relevant nonmajor bleeding requiring hospitalization), and all-cause mortality. Overlap weighted sub-distribution hazard ratios (SHRs) compared rivaroxaban with LMWH in an intention-to-treat analysis. The cohort consisted of 2,259 patients with first CT, 314 receiving rivaroxaban, and 1,945 LMWH, mean age 72.4 and 66.9 years, respectively. In the 12-month observational period, 184 person-years following rivaroxaban and 1,057 following LMWH, 10 and 66 incident recurrent VTE events, 20 and 102 significant bleeds, and 10 and 133 deaths were observed in rivaroxaban and LMWH users, respectively. The weighted SHR at 12 months for VTE recurrences in rivaroxaban compared with LMWH were 0.80 (0.37-1.73); for significant bleeds 1.01 (0.57-1.81); and for all-cause mortality 0.49 (0.23-1.06). Patients with CT, not at high risk of bleeding, treated with either rivaroxaban or LMWH have comparable effectiveness and safety outcomes. This supports the recommendation that rivaroxaban is a reasonable alternative to LMWH for the treatment of CT.

Extending venous thromboembolism secondary prevention with apixaban in cancer patients. The EVE trial

BackgroundCancer-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. ObjectivesThe study’s purpose was to determine whether this dose reduction is advisable for cancer-associated VTE. MethodsA 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. ResultsOf 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). ConclusionFor 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).

[Venous thromboembolism - was is new in the revised AWMF guideline?]

For the diagnosis of a lower-extremity deep vein thrombosis (LEDVT), venous duplex ultrasound is the method of first choice. If a qualified ultrasonography is not timely available, D-dimer testing, and limited ultrasound protocols (point-of-care ultrasound, POCUS) can contribute to therapeutic decision-making when clinical probability is low. A DOAC-based treatment regimen is preferable to a vitamin K antagonist for both acute therapy and secondary prophylaxis of venous thromboembolism (VTE). Treatment with DOACs is unproblematic up to a body weight (BW) of 120 kg or a body mass index (BMI) of 40 kg/m². Weight restrictions are no longer recommended for apixaban and rivaroxaban, but determination of DOAC trough and peak levels is recommended in the extremely obese and patients after bariatric surgery. In cancer-associated VTE, the direct factor Xa inhibitors are a good and safe alternative to low-molecular weight heparins (LMWH) for many patients; the adherence to oral therapy is also higher. Meaningful initial documentation and structured follow-up after LEDVT and pulmonary embolism (PE) are important in order to make an individualized risk-benefit assessment at the end of the therapy phase with regard to continued pharmacological secondary prophylaxis and to reassess patients' symptoms indicating post-thrombotic syndrome (PTS) or chronic thromboembolic pulmonary hypertension (CTEPH).

Interaction between NSCLC Cells, CD8+ T-Cells and Immune Checkpoint Inhibitors Potentiates Coagulation and Promotes Metabolic Remodeling-New Cues on CAT-VTE.

Cancer-associated thrombosis (CAT) and venous thromboembolism (VTE) are frequent cancer-related complications associated with high mortality; thus, this urges the identification of predictive markers. Immune checkpoint inhibitors (ICIs) used in cancer immunotherapy allow T-cell activation against cancer cells. Retrospective studies showed increased VTE following ICI administration in some patients. Non-small cell lung cancer (NSCLC) patients are at high risk of thrombosis and thus, the adoption of immunotherapy, as a first-line treatment, seems to be associated with coagulation-fibrinolysis derangement. We pharmacologically modulated NSCLC cell lines in co-culture with CD8+ T-cells (TCD8+) and myeloid-derived suppressor cells (MDSCs), isolated from healthy blood donors. The effects of ICIs Nivolumab and Ipilimumab on NSCLC cell death were assessed by annexin V and propidium iodide (PI) flow cytometry analysis. The potential procoagulant properties were analyzed by in vitro clotting assays and enzyme-linked immunosorbent assays (ELISAs). The metabolic remodeling induced by the ICIs was explored by 1H nuclear magnetic resonance (NMR) spectroscopy. Flow cytometry analysis showed that TCD8+ and ICIs increase cell death in H292 and PC-9 cells but not in A549 cells. Conditioned media from NSCLC cells exposed to TCD8+ and ICI induced in vitro platelet aggregation. In A549, Podoplanin (PDPN) levels increased with Nivolumab. In H292, ICIs increased PDPN levels in the absence of TCD8+. In PC-9, Ipilimumab decreased PDPN levels, this effect being rescued by TCD8+. MDSCs did not interfere with the effect of TCD8+ in the production of TF or PDPN in any NSCLC cell lines. The exometabolome showed a metabolic remodeling in NSCLC cells upon exposure to TCD8+ and ICIs. This study provides some insights into the interplay of immune cells, ICIs and cancer cells influencing the coagulation status. ICIs are important promoters of coagulation, benefiting from TCD8+ mediation. The exometabolome analysis highlighted the relevance of acetate, pyruvate, glycine, glutamine, valine, leucine and isoleucine as biomarkers. Further investigation is needed to validate this finding in a cohort of NSCLC patients.

Management of venous thromboembolism in patients with active cancer.

Venous thromboembolism (VTE) is a major health burden in patients with cancer, causing morbidity, emergency room visits, hospitalizations, and death. Treatment is challenging, as it is necessary to balance the risk of recurrent thrombosis and bleeding associated with anticoagulants. Treatment paradigms are shifting from low-molecular-weight heparin monotherapy. Multiple recent randomized controlled trials have demonstrated the safety and efficacy of direct oral anticoagulants in this setting. Current studies are evaluating factor XI inhibitors as potential treatments for cancer-associated VTE.

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.

Early Time Courses of Recurrent Venous Thromboembolism and Bleeding during Apixaban or Dalteparin Therapy for Patients with Cancer.

In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE. The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding. In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group. The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE.

Cancer-associated venous thromboembolism in the direct oral anticoagulants era: Insight from the COMMAND VTE Registry-2

BackgroundThere is a paucity of data on real-world management strategies and clinical outcomes of cancer-associated venous thromboembolism (VTE) in the direct oral anticoagulants (DOACs) era. ObjectivesTo investigate the status of cancer-associated VTE in the DOAC era. MethodsThis multicenter, retrospective cohort study among 31 centers in Japan between 2015 and 2020 enrolled 5197 consecutive patients with acute symptomatic VTE, who were divided into 1507 patients (29 %) with active cancer and 3690 patients (71 %) without. ResultsThe cumulative 3-year rate of anticoagulation discontinuation was significantly higher in patients with active cancer than in those without (62.7 % vs. 59.1 %, P < 0.001). The cumulative 5-year incidence of recurrent VTE was higher in patients with active cancer than in those without (10.1 % vs. 9.1 %, P = 0.01), however, after adjusting for the confounders and competing risk of mortality, the excess risk of the active cancer group relative to the no active cancer group was no longer significant (HR: 0.95, 95 % CI: 0.73-1.24). The cumulative 5-year incidence of major bleeding was much higher in the active cancer group (20.4 % vs. 11.6 %, P < 0.001). Even after adjusting for the confounders and competing risk of mortality, the risk of the active cancer group relative to the no active cancer group remained significant (HR: 1.36, 95 % CI: 1.11–1.66). ConclusionsThe current large real-world registry revealed that the risk of major bleeding was still higher in patients with active cancer than in those without, leading to the frequent anticoagulation discontinuation, which has been still a huge challenge to overcome in the DOAC era.

Treatment Patterns of Cancer-associated Thrombosis in the Netherlands: The Four Cities Study.

Background  Current guidelines recommend either low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs) as first-line treatment in cancer-associated venous thromboembolism (VTE). Aim  This study aimed to investigate treatment regimens for cancer-associated VTE over the past 5 years, explore predictors for initial treatment (LMWH vs. DOAC), and to assess the risks of recurrent VTE and bleeding. Methods  This was a Dutch, multicenter, retrospective cohort study including consecutive patients with cancer-associated VTE between 2017 and 2021. Treatment predictors were assessed with multivariable logistic regression models. Six-month cumulative incidences for recurrent VTE and major bleeding (MB) were estimated with death as competing risk. Results  In total, 1,215 patients were included. The majority (1,134/1,192; 95%) started VTE treatment with anticoagulation: 561 LMWH (47%), 510 DOACs (43%), 27 vitamin K antagonist (2.3%), and 36 other/unknown type (3.0%). The proportion of patients primarily treated with DOACs increased from 18% (95% confidence interval [CI] 12-25) in 2017 to 70% (95% CI 62-78) in 2021. Poor performance status (adjusted odds ratio [aOR] 0.72, 95% CI 0.53-0.99) and distant metastases (aOR 0.61, 95% CI 0.45-0.82) were associated with primary treatment with LMWH. Total 6-month cumulative incidences were 6.0% (95% CI 4.8-7.5) for recurrent VTE and 7.0% (95% CI 5.7-8.6) for MB. During follow-up, 182 patients (15%) switched from LMWH to a DOAC, and 54 patients (4.4%) vice versa, for various reasons, including patient preference, recurrent thrombosis, and/or bleeding. Conclusion  DOAC use in cancer-associated VTE has increased rapidly over the past years. Changes in anticoagulation regimen were frequent over time, and were often related to recurrent thrombotic and bleeding complications, illustrating the complexity and challenges of managing cancer-associated VTE.

The Need for Next-generation Anticoagulation Therapies for Cancer-associated Venous Thromboembolism.

The Need for Next-generation Anticoagulation Therapies for Cancer-associated Venous Thromboembolism.

Treatment Complications of Venous Thromboembolism in Patients with Central Nervous System Tumors

Introduction: In the last decade, landmark studies have been conducted in patients with cancer-associated venous thromboembolism (CA-VTE), helping to guide treatment decisions of anticoagulant therapy. Although these trials outlined new treatment opportunities, they either completely excluded or included only a small number of patients with primary brain tumors or central nervous system (CNS) metastasis. Additionally, there are very limited data on complication rates of anticoagulants in patients with spinal metastasis. Consequently, there is an ongoing knowledge gap for safe and effective anticoagulation options for patients with acute VTE in this high-risk patient population. Methods: We conducted a single institution IRB-approved retrospective study evaluating the rates of hemorrhage and recurrent thromboses in patients with CA-VTE and a diagnosis of a primary brain tumor or brain and/or spinal metastases. Our investigation was conducted at The Preston Robert Tisch Brain Tumor Center and the Center for Brain and Spine Metastasis at Duke between 2017 and 2021. The cohort was built through identifying patients by ICD-10 codes searched within the electronic medical records. Inclusion criteria consisted of patients ≥ 18 years of age, a history of confirmed primary brain tumor or brain and/or spinal metastases prior to VTE, treatment with anticoagulation or an inferior vena cava (IVC) filter, and followed up at least once since starting treatment beyond 1 month of VTE diagnosis . We compared complication event rates and the anticoagulant selected for treatment. Data obtained included patient demographic information, medical and social histories, cancer-related history, VTE history and treatment, recurrent thrombotic and hemorrhagic events, and patient mortality. Results: We identified 3584 total patients during the study timeframe. Eight hundred and twenty-five patients were included and 2759 were excluded for not meeting our inclusion criteria. Of the 825 included patients, 766 were treated with either apixaban (348/766; 45%), rivaroxaban (178/766; 23%), or enoxaparin (240/766; 31%) for their initial CA-VTE (Table 1). The other 59 patients were treated with another anticoagulant or received an IVC filter without anticoagulation. The median age for our cohort of 766 patients was 61.0 (20.0 - 87.0). There was no significant statistical association between relevant past medical histories of obesity or hypertension among the 3 anticoagulant groups. There was no significant statistical association between the 3 anticoagulant cohorts and primary brain tumors, or brain and/or spinal metastases ( p= 0.06). Although it trended towards significance, there was no statistically significant difference in the proportion of patients receiving anti-VEGF inhibitors at time of initial VTE among the 3 anticoagulant cohorts ( p = 0.052). When looking at our primary outcomes of recurrent thrombosis, major hemorrhage, or clinically relevant non-major bleeding, 171 individual patients experienced a total of 188 unique events that occurred during treatment with apixaban, rivaroxaban, or enoxaparin (Table 2). Of the 171 unique patients, enoxaparin use was the most common (80/171; 47%), followed by apixaban (61/171; 36%), rivaroxaban (28/171; 16%), and a small percentage (2/171; 1%) were treated with a combination of apixaban, rivaroxaban, or enoxaparin during their unique event. When excluding the 2 patients with multiple anticoagulant treatments, there was no statistical difference among anticoagulant rates and any event of recurrent thrombosis, major hemorrhage, clinically relevant non-major bleeding, or any multiple events ( p = 0.07). Conclusions: We present the largest unique data set comparing anticoagulant use in a known high-risk patient population of primary brain tumors, brain and/or spinal metastases. Our data demonstrate up to 22% of patients with CA-VTE and primary brain tumors, brain and/or spinal metastases have a subsequent hemorrhagic or recurrent thrombotic complication during treatment with apixaban, rivaroxaban, or enoxaparin for their initial event. However, our data did not demonstrate a statistically significant difference in complication rates between these 3 anticoagulants. These findings indicate a need for future large-scale prospective investigations to determine optimal treatment in this high-risk patient population.

Dynamic Modelling for Cancer-Associated Venous Thromboembolism

Background: Cancer-associated venous thromboembolism (VTE) is an important source of morbidity and mortality. Current risk prediction models for thrombosis are handicapped by static applicability (i.e. one-time evaluation prior to the first cycle of chemotherapy). We hypothesized that event forecasting using time series modelling could account for important changes in clinical state, variations in treatment and aspects of cancer progression over time. Methods: The cohort consisted of adult patients with a solid tumor enrolled in the MSK-IMPACT study between 2014 and 2019. VTE was defined as any symptomatic or asymptomatic pulmonary embolus or lower extremity deep vein thrombosis. We derived time series mixed-effects logistic regression models in order to predict cancer-associated VTE events using baseline patient characteristics (cancer type, time from diagnosis and age) along with time-dependent covariates including total white blood cell count, hemoglobin, platelet count, albumin, creatinine and parenteral chemotherapy type. Time-periods of one month were used and models were fitted to predict the presence or absence of a VTE episode in the following period (time = t+1) based on predictor values in the current period (time = t). The laboratory test result ascribed to a given period could be either the last value in the interval or the mean of all interval-specific values (both approaches tested). Missing laboratory results were imputed using the previously known value when available. Differences in laboratory values between periods t-1 and t were included as predictors in the initial model along with indicators of missingness (see Figure for flow of information between time-period cells). We hypothesized that absence of laboratory testing for a time-period would be a marker of stable medical state and hence associated with a lower risk of VTE. A previously defined training set comprising 80% of the cohort was used and different modelling approaches were evaluated using 5-fold cross-validation. The final selected model was evaluated in a separate dedicated validation set including the remaining 20% of the cohort. Results: The original cohort included 35,391 patients, from which 26,075 individuals with no cancer-associated VTE episode before observation start and sufficient laboratory test information could be included in the analysis, comprising 276,579 months of observation and 1,463 VTE events. The initial logistic regression model including all available predictors was fitted on the training set, revealing associations between predictors and VTE risk largely consistent with data reported by other groups (see Table). After adjusting for multiple comparisons, significant predictors of cancer-associated VTE identified included albumin, cell count result missingness (decreased risk for missing value), treatment with a platinum analogue (increased risk), hemoglobin, white blood cell count, breast cancer (decreased risk) and high-grade glioma (increased risk). Based on model metrics and prior knowledge from published literature, the set of covariates selected for inclusion in the final model consisted of cell counts along with the corresponding missingness indicator, platelet count change over time, albumin and chemotherapy types. The c-index for the final model using 5-fold cross-validation in the training set was 0.77 (95% CI = 0.75-0.80), compared to 0.77 (95% CI = 0.74-0.79) in the validation set. The latter corresponded to a specificity of 0.83 (95% CI = 0.79-0.86) when fixing sensitivity at 50%. Conclusions: A simple mixed-effects logistic regression time series model demonstrated promising potential to estimate the risk of cancer-associated VTE on a dynamic basis using routine laboratory test results and chemotherapy prescription data widely available in most electronic health record systems. Validation of this dynamic VTE risk model has the potential to optimize outpatient thromboprophylaxis during periods of high thrombotic risk.

Overall Survival of Warfarin Compared to LMWH/Doacs in Cancer-Associated Venous Thromboembolism: VA Cohort Study

Background: Warfarin has been shown in pre-clinical models to have anti-neoplastic activity. In a population-based study using the SEER-Medicare Linked Database warfarin was associated with improved survival compared to low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs) in the treatment of cancer-associated thrombosis (CAT). To assess whether the observed survival advantage is consistent in other large cohorts, we performed a matched cohort study utilizing the Veterans Affairs (VA) database. The VA is a large, integrated health care system with comprehensive data for their patients at the individual level, which provides the optimal observational cohort to confirm the novel hypothesis warfarin confers a mortality benefit over LMWH. Method: Using the retrospective data from the VA health care system from 2000-2021, we identified patients with CAT who were &amp;gt; 18 years, had available prescription data for anticoagulation within 30 days of venous thromboembolism (VTE), and survived &amp;gt; 14 days after the index VTE event. Patients were excluded if they had prior diagnosis of VTE or had any anticoagulation prescription prior to the first coded VTE event. The primary outcome was overall survival (OS). Patients were matched 1:1 using nearest neighbor matching on the propensity score. The matching variables included cancer site, cancer stage, date of cancer diagnosis, date of VTE diagnosis, age at VTE diagnosis, gender, race, BMI, Elixhauser-based weighted comorbidity score, and rurality of residential status. Cox proportional-hazards regression was performed to estimate hazard ratios (HR) and 95% confidence intervals. Log-rank test was utilized to estimate the p-value. Subgroup analyses were performed in the largest groups of cancer available in the data set including prostate cancer, lung cancer, gastrointestinal cancer (excluding hepatobiliary cancer), and malignant hematologic neoplasms (including myeloid malignancy, lymphoid malignancy, and multiple myeloma). Finally subgroup analysis was also performed on localized cancer and metastatic disease based on AJCC stage grouping. Result: There were a total of 20,078 patients that met the inclusion and exclusion criteria without missing data. The warfarin cohort consistent of 8383 patients while non-warfarin cohort comprised 11696 patients. Among the non-warfarin cohort, 54% of the patients were prescribed LMWH exclusively and 38% of the patients were prescribed DOAC exclusively within 30days of the VTE diagnosis. The most common malignancies in the cohort included prostate (29.4%), lung (20.9%), gastrointestinal (15.7%) and hematologic malignancies (10.3%). Of patients with solid tumors, 22% had metastatic cancer. Among the VTE events, 33.3% were acute lower extremity deep vein thrombosis, 48.4% were acute pulmonary embolism, and 18.3% were acute upper extremity deep vein thrombosis. After propensity score matching, 8,383 patients were included in the warfarin arm and 8,383 patients in the non-warfarin arm. The median age at VTE diagnosis of the matched cohort was 69 [IQR 63 - 75] and the majority of the patients (96.7%) were male. Warfarin was associated with a significant improvement in OS compared to non-vitamin K antagonists (median OS, 1204 days [95% CI, 1137-1276 days] vs 703 days [95% CI, 665-747 days]; HR 0.79 [95% CI 0.76 - 0.82]; p-value &amp;lt;2x10 -16) (Figure1). The difference was also preserved in gastrointestinal malignancy (HR 0.8 v95% CI 0.73-0.87), lung cancer (HR 0.8, 95% CI 0.79-0.92) and prostate cancer (HR 0.71, 95% CI 0.65-0.77). The survival advantage was preserved in patients with metastatic (HR 0.86, 95% CI 0.78-0.83) and localized cancer (HR 0.80, 95% CI 0.76-0.84) (Figure 2). Conclusion and Relevance: In a population level propensity matched study, warfarin for the treatment of CAT was associated with significantly improved survival over non-vitamin K antagonist anticoagulation in CAT. These provocative finding confirm the previous observation in SEER-Medicare database and have important implications on patient care and health care costs. Further investigation into the biological basis of these findings could potentially lead to biomarker and drug discovery for cancer therapies and prognostication.

Blood Biomarkers and Risk of Venous Thromboembolism in Cancer Patients: A Systematic Review and Meta-Analysis

Patients with cancer have an increased risk of venous thromboembolism (VTE). Currently, several VTE risk prediction tools have been developed to identify candidates for primary VTE thromboprophylaxis. However, the availability of reliable and highly discriminatory prediction models for VTE risk assessment in cancer patients is limited, warranting further improvement of VTE risk stratification strategies. The implementation of biomarkers in risk assessment models might lead to refined VTE risk prediction, but it remains to be more comprehensively investigated. In this systematic review and meta-analysis, we aimed to evaluate and summarize all candidate biomarkers and their association with cancer-associated VTE. We conducted an electronic search in Medline, EMBASE and Cochrane central databases for studies that evaluated biomarkers in adult patients with cancer from inception to September 26 th 2022. We included observational and interventional studies reporting on subsequent VTE occurring after a cancer diagnosis. The baseline or index event of the biomarker measurements had to be definitively and uniformly applied to all enrolled patients. Two reviewers independently screened titles, abstracts and full-text articles for inclusion. Median differences (for continuous measures) and Odds Ratios (OR) (for dichotomous cut-off measures) with 95% confidence intervals (95% CI) were estimated and pooled using random-effects models. We assessed each studies risk of bias using the Quality in Prognostic Studies (QUIPS) risk of bias tool. Our search identified 4274 studies that were screened for inclusion (Figure 1). Following the screening, 109 studies (with 520 biomarker measurements) met the inclusion criteria and were included in the systematic review. Of these, 51 studies (with 174 biomarker measurements) were included in the meta-analysis. The majority of the studies were cohort studies (n=47; 32 prospective and 15 retrospective), while the other 4 studies were nested case-control studies. Eighteen studies had a study population of mixed cancer types and the remaining studies had a study population of specific cancer types, including: lung (n=6), gynecologic (n=5), breast (n=3), stomach (n=3), lymphoma (n=2), myeloma (n=2), ovarian (n=2), pancreas (n=2), brain (n=1), colorectal (n=1), gastrointestinal (n=1), genitourinary (n=1), gynecologic or breast (n=1), head and neck (n=1), liver (n=1), and prostate (n=1). We calculated the median difference and 95% CI for 23 different biomarkers. Cancer patients who experienced subsequent VTE events had significantly higher pre-treatment factor VIII activity, peak thrombin, platelet count and prothrombin fragment F1+2 levels compared to patients who did not experience VTE events (Table 1). Pre-treatment d-dimer levels were also higher in cancer patients who developed VTE, however, considerable heterogeneity was observed (Table 1). Contrastingly, pre-treatment hemoglobin, lag time - thrombin generation, prothrombin time and time to peak thrombin levels were significantly lower in those experiencing VTE events compared to patients who did not experience any events (Table 1). D-dimer levels on day-1 after cancer surgery were reported in two studies which, when pooled, revealed that cancer patients with subsequent VTE had higher d-dimer levels post-operatively compared to those with no events (Table 1). Moreover, pre-treatment hemoglobin levels 100 g/L was significantly associated with future VTE risk [OR: 1.42 (95%CI: 1.03-1.97), I 2=0%, n=11] while neutrophil lymphocyte ratio 3 was associated, yet insignificant [OR: 1.60 (95%CI: 0.99-2.60), I 2=43%, n=4]. Pre-treatment platelet count 350 x 10 9/L and white blood count levels 11 x 10 9/L were not significantly associated with future VTE risk [OR: 0.84 (95%CI: 0.66-1.06), I 2=0%, n=9 and 1.32 (0.86-2.03), I 2=56%, n=8, respectively]. From the 51 studies included in the meta-analyses, 27 studies had a low risk of bias, 19 studies had a moderate risk of bias and 5 studies had a high risk of bias. In conclusion, nine blood biomarkers were found to be significantly associated with VTE in cancer patients. Their utility as predictors of VTE in thrombotic risk assessment models may help in optimising VTE prediction and should be further explored in future studies.

DNA Liquid Biopsies for Cancer-Associated Venous Thromboembolism Prediction

Introduction Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying an optimal population for prophylactic anticoagulation is challenging and adds to clinician overhead. Circulating tumor (ct)DNA sequencing assays (“liquid biopsies”) are increasingly deployed in clinic, with multiple US FDA approvals for matching to molecularly targeted therapy. Preliminary data suggest that cell-free (cf)DNA, which is also measured as part of liquid biopsies and may consist of tumor or wild-type DNA, is thrombogenic due to its association with neutrophil extracellular traps. However, clinical validation of cfDNA for VTE prediction is lacking. ctDNA detection is associated with aggressive tumor biology and worse survival; however, whether it is associated with VTE is unknown. To address these gaps, we studied the clinical utility of ctDNA and cfDNA from liquid biopsies for predicting VTE. Methods We conducted an observational study in two cohorts: 1) Patients with any cancer type at Memorial Sloan Kettering Cancer Center (MSK, New York USA), an academic medical center, with plasma ctDNA sequencing using MSK-ACCESS, a NY State-approved, 129-gene assay (N=4,141). 2) A nonoverlapping cohort of patients at MSK or GenesisCare (Sydney, Australia), a community oncology setting, with stage IV or recurrent non-small cell lung cancer and ctDNA sequencing using a separate commercial assay (Agilent ctDx Lung, N=463). We studied the independent contribution of ctDNA, cfDNA and related variables for predicting VTE using Cox proportional hazards. We studied the potential utility of DNA liquid biopsies for predicting VTE within six months using machine learning models, comparing their dynamic area under the receiver operating curve, precision, and recall to those of the Khorana score, the most widely implemented risk metric. We tested the impact of ongoing anticoagulation for non-VTE indications on future VTE in patients with and without detectable ctDNA using nonrandomized, real-world evidence. Results ctDNA detection was associated with an increased risk of VTE in a dose-dependent manner (Figure 1). This association was observed across assays and treatment sites and regardless of genomic subtype. ctDNA was associated with VTE risk in non-small cell lung, breast, pancreatic, prostate, and less represented cancers as well as melanoma but not in bladder, hepatobiliary, or colorectal cancer. By contrast, cfDNA concentration was associated with VTE risk in all cancer types. In multivariate analysis, ctDNA detection, cfDNA concentration, Khorana score, chemotherapy treatment within 30 days, and number of organ sites of metastasis were all independently associated with VTE. In a cohort of patients with treatment naive lung adenocarcinoma with segmented positron emission tomography scans, ctDNA was an independent predictor of VTE after controlling for metabolic tumor volume. A random survival forest machine learning model to predict VTE within six months of plasma draw using liquid biopsy data (i.e. cfDNA and ctDNA levels as well as genomic content), cancer type, and chemotherapy receipt (“LB+”) outperformed the Khorana score in 5-fold cross-validation and was similarly superior in the external lung cohort (Table 1). The superiority of the model was observed in patients treated or not treated with chemotherapy. Additional clinical and radiologic data, including demographics, metastatic sites of disease, and Khorana score components (“All”), did not improve the ctDNA assay-based LB+ model. Patients with anticoagulation had lower VTE rates if ctDNA was detectable (adjusted HR 0.54, 95%CI 0.33-0.87) but not if ctDNA was undetectable. Conclusion In patients with cancer, ctDNA and cfDNA are independent biomarkers for VTE. Risk models incorporating liquid biopsy data are feasible in academic or community settings and, if prospectively validated, would provide a means of VTE risk stratification at scale.

Inherited Thrombophilia Gene Mutations and Risk of Venous Thromboembolism in Cancer: A Systematic Review and Meta-Analysis

Inherited thrombophilia and cancer are both recognized risk factors for venous thromboembolism (VTE). In the general population, the risk of thrombosis is increased in patients with inherited thrombophilia, but the role of inherited thrombophilia on the risk of cancer-associated VTE remains controversial. The objective of this study was to summarize and determine whether cancer patients with inherited thrombophilia gene mutations have an increased risk of developing VTE. We conducted a systematic literature search in Medline, EMBASE and Cochrane Central databases, as well as references of included studies from inception until September 26 th 2022. We included observational (cohort or case-control) and interventional studies comprising of human adult cancer patients who were tested for any inherited thrombophilia gene mutation. The outcome was objectively confirmed symptomatic or asymptomatic first VTE (upper or lower limbs deep vein thrombosis, pulmonary embolism, and/or splanchnic or cerebral vein thrombosis) occurring after a cancer diagnosis. Two reviewers independently screened the titles/abstracts and full texts of all potentially eligible articles. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using Mantel-Haenszel random-effects models. We used the Quality in Prognostic Studies (QUIPS) risk of bias tool to assess study risk of bias. A total of 4274 studies were screened for eligibility. Thirty-six studies involving different cancer types and treatments were included in the systematic review, of which 28 studies were included in the meta-analysis (Figure 1). Among studies included in the meta-analysis, 9 studies included various cancer types while the remaining 19 studies were in selected cancer types (3 lung, 3 myeloma, 2 brain, 2 bladder, 2 breast, 2 gynecologic, 1 testicular, 1 lung or gastrointestinal, 1 pancreas, 1 colorectal and 1 breast or gastrointestinal). There were 18 cohort (11 prospective and 7 retrospective) and 10 case-control studies. The following seven inherited thrombophilia gene mutations were meta-analyzed: ABO blood type, Factor V Leiden (FVL), Methylenetrahydrofolate Reductase (MTHFR) C677T, Plasminogen-Activator Inhibitor-1 (PAI-1) 4G/5G, Prothrombin Factor II G20210A, Vascular Endothelial Growth Factor (VEGF) C634G and VEGF C2578A. In cancer patients with non-O blood types, FVL and Prothrombin Factor II G20210A mutations, the risk of VTE was significantly increased with ORs of 1.56 (95% CI: 1.28-1.90), 2.28 (95% CI: 1.51-3.48) and 2.14 (95% CI: 1.14-4.03), respectively, compared to patients with O blood and wild types (Table 1). In addition, heterozygous and homozygous MTHFR C677T were associated with ORs of 1.50 (95% CI: 1.00-2.24) and 1.38 (95% CI: 0.87-2.22), respectively (Table 1). Among those with heterozygous and homozygous PAI-1 4G/5G, VEGF C634G and VEGF C2578A, no significant increase in the odds of VTE and moderate to considerable heterogeneity were observed (Table 1). Few studies had low risk of bias, except for studies of ABO blood group, which predominantly had low risk of bias. In conclusion, this meta-analysis provides evidence that non-O blood type, FVL, Prothrombin Factor II G20210A and heterozygous MTHFR C677T significantly increase the risk of VTE in cancer patients. However, there is moderate to high risk of bias in the currently available data, further well-designed studies are needed.

Prediction of Venous Thromboembolism in Patients with Cancer Using Neural Network

Background Venous thromboembolism (VTE) is a frequent complication in patients with cancer and can be provoked by the tumor or treatment.An imbalance between coagulation factors and anticoagulant proteinshas been associated with enhanced VTE risk in these patients. Particularly, elevated fibrinogen, FVIII and von Willebrand factor and decreased antithrombin, increase the risk of cancer-associated VTE. Aim To investigate whether artificial intelligence methodologies based on input of patient characteristics and coagulation parameters can predict VTE in patients with cancer. Methods In the ongoing study, all-type of cancer patients with or without previous VTE are enrolledand thrombotic events were followed up over a period of 2 years or until death. Demographics, cancer type and treatment, medications, and VTE events before and during the study were documented. Coagulation factors, antithrombin, fibrinogen, FVIII and Von Willebrand Factor were determined in all samples. The artificial intelligence method neural networks was used to develop a prediction model for VTE in patients with cancer. Final input parameters were age, sex, prior VTE, use of anticoagulants and statins, fibrinogen, antithrombin, FVIII and von Willebrand factor. Results To date, 118 patients were enrolled in the study, and 28 patients completed the follow-up (24%). A neural network was developed in the sub-cohort of patients that had completed the follow-up period (n=28), of which 7 patients had a VTE during the follow-up period. The top-performing neural network was selected. The developed neural network had an overall accuracy of 98%, a sensitivity of 100% and a specificity of 95%. Furthermore, the negative predictive value was 100% and the positive predictive value was 97% (Figure 1A). The most important variables in the neural network were Von Willebrand Factor, age, anticoagulant therapy and history of VTE, contributing 13% each. Sex, antithrombin and fibrinogen contributed 11%, 10% and 10%, respectively, whereas FVIII (6%) , statin use (5%) and antiplatelet therapy (5%) had a minor contribution (Figure 1B). We validated the neural network in the “on-study” sub-cohort, consisting of patients that did not yet complete the follow-up period. Until now, 2 VTE events were recorded in this group; other patients in the sub-cohort remain potentially at risk for VTE. The neural network was able to accurately discern the patients that experienced a VTE during follow-up, resulting in a sensitivity of 100%, and a negative predictive value of 100%. Moreover, the neural network indicated an increased risk of VTE in 37 subjects out of 88 “on-study” patients. The neural network scores the risk of VTE as a value ranging from 0 (no risk) to 1 (high risk). We stratified the neural network VTE risk estimate according to the Khorana and PROTECHT scores for each patient and found a positive association between both the Khorana and PROTECT scores and the neural network VTE estimate (p&amp;lt;0.05). Conclusions A neural network based on patient characteristics, coagulation parameters, and medication use predicts VTE in our cohort of cancer patients. Although the initial validation of the neural network is promising, further clinically validation is needed.

Cancer-Associated Venous Thromboembolism-Diagnostic and Therapeutic Considerations: An Update Based on the Revised AWMF S2k Guideline.

Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT.

Management of cancer-associated venous thromboembolism from diagnosis to treatment: State of the art and remaining unmet needs

Management of cancer-associated venous thromboembolism from diagnosis to treatment: State of the art and remaining unmet needs

Clinical features and long-term outcomes of cancer-associated venous thromboembolism: transition from the warfarin era to the direct oral anticoagulant era

Abstract Background/Introduction After the introduction of direct oral anticoagulant (DOAC) for venous thromboembolism (VTE), DOAC for VTE have prevailed all over the world. The usefulness of DOAC for cancer-associated VTE has also been recently reported and may change the daily clinical practice and clinical outcomes. However, there have been still limited data on the issue in the real world. Purpose We aimed to investigate the clinical characteristics, anticoagulation strategies, and long-term clinical outcomes of patients with cancer-associated VTE comparing a large observational study in the warfarin era and that in the DOAC era. Methods The COMMAND VTE Registry-1 (enrolled 3,027 VTE patients among 29 center between January 2010 and August 2014 in the warfarin era) and Registry-2 (enrolled 5,197 VTE patients among 31 centers between January 2015 and August 2020 in the DOAC era) are the series of a multicenter observational study in Japan enrolling consecutive patients with acute symptomatic VTE. In the present study, we evaluated patients with cancer-associated VTE of 695 cases from Registry-1 and 1507 cases from Registry-2. Results As for oral anticoagulation therapy, 83% (2,576/695) of patients were treated with warfarin in the Registry-1 and 80% (1,199/5,197) of patients were treated with DOAC in the Registry-2. Patients in the Registry-2 were slightly older (67±12 vs. 68±13 years, P=0.005), had a slightly higher body weight (55±12 vs. 57±13 kg, P=0.03), and more frequently had pulmonary embolism (44% vs. 49%, P=0.004). Patients in the Registry-2 were less frequently admitted to the hospital among those with out-of-hospital-onset VTE (83% vs. 66%, P&amp;lt;0.001), and median length of hospitalization was shorter in patients in the Registry-2 (16 [IQR: 11-26] vs. 14.5 [IQR: 9-24] days, P=0.01). AS for cancer types, lung cancer, colorectal cancer and stomach cancer were significantly higher in patients in the Registry-1 (18% vs. 15%, P=0.04; 14% vs. 10%, P=0.008; 9% vs. 6%, P=0.007). There was no significant difference in the discontinuation rate of anticoagulation therapy between the 2 groups (56.7% vs. 62.7% at 3-year, Log rank P=0.10). The cumulative 5-year incidence of recurrent VTE, major bleeding and all cause-death were significantly lower in patients in the Registry-2 (17.7% vs. 10.1%, P&amp;lt;0.001; 26.6% vs. 20.4%, P=0.045; 73.1% vs. 64.8%, P=0.003), while there were no significant differences in the cumulative 5-year incidences of intracranial bleeding (5.7% vs. 3.2%, P=0.056) nor major gastrointestinal bleeding between the 2 groups (13.9% vs. 10.1%, P=0.30) (Figure). Conclusion The introduction of DOAC for cancer-associated VTE could have a potential benefit of reducing the risk of recurrent VTE and major bleeding, although gastrointestinal bleeding might be still a major concerns even in the DOAC era.FigureFigure