Cumulative Incidence Of Venous Thromboembolism Research Articles

Edoxaban, Rivaroxaban, or Apixaban for Cancer-Associated Venous Thromboembolism in the Real World: Insights from the COMMAND VTE Registry-2.

Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups. The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group. The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.

Statins use and recurrent venous thromboembolism in the direct oral anticoagulant era: insight from the COMMAND VTE Registry-2.

Statins were reported to have a potential effect of primary prevention of venous thromboembolism (VTE), although that of secondary prevention remains uncertain. To investigate the association between statins use and recurrent VTE in the current era. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive VTE patients among 31 centers in Japan between January 2015 and August 2020. We divided the entire cohort into 2 groups according to statins use at the time of discharge; the statins (N = 865) and no statins groups (N = 4332). The statins group was older (72.9 vs. 66.7 years, P < 0.001), and less often had active cancer (22.0% vs. 30.4%, P < 0.001). The cumulative incidence of discontinuation of anticoagulation was significantly lower in the statins group (60.3% vs. 52.6%, Log-rank P < 0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in the statins group (6.8% vs. 10.1%, Log-rank P = 0.01). Even after adjusting for the confounders, the lower risk of the statins group relative to the no statins group remained significant for recurrent VTE (HR 0.65, 95% CI 0.45-0.91, P = 0.01). The cumulative 5-year incidence of major bleeding was significantly lower in the statins group (12.2% vs. 14.1%, Log-rank P = 0.04), although, after adjusting for the confounders, the risk of the statins group relative to the no statins group turned to be insignificant (HR 0.77, 95% CI 0.59-1.00, P = 0.054). In this large real-world VTE registry, statins use was significantly associated with a lower risk for the recurrent VTE in the current era.

Clinical Characteristics and Outcomes of Patients With Venous Thromboembolism Receiving Edoxaban in the Real World.

The effectiveness and safety of edoxaban for venous thromboembolism (VTE) in unselected real-world patients have not been fully evaluated.Methods and Results: In the Japanese nationwide administrative database, we identified 6,262 VTE patients in whom edoxaban was initiated; these patients were divided into 3 groups based on their index doses: 15 mg/day (n=235), 30 mg/day (n=4,532), and 60 mg/day (n=1,495). We evaluated patient characteristics, recurrent VTEs, and a composite endpoint of intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding. Patient characteristics among the 15-, 30-, and 60-mg edoxaban groups varied widely regarding several aspects, including age (mean 81.0, 76.2, and 65.0 years, respectively) and body weight (mean 49.5, 51.8, and 70.3 kg, respectively). At 180 days, the cumulative incidence of recurrent VTEs in the 15-, 30-, and 60-mg edoxaban groups was 4.4%, 2.6%, and 1.8%, respectively, whereas that of ICH or GI bleeding was 7.3%, 5.4%, and 3.3%, respectively. Subgroup analyses showed that the cumulative incidence of ICH or GI bleeding in patients in the 15-mg edoxaban group was 3.6% for patients aged ≥80 years, 8.4% for those with a body weight <60 kg, and 31.3% for those with renal dysfunction. Only a minority of patients with VTEs received a super low dose (15 mg) of edoxaban, and these patients may be at higher risk of bleeding as well as VTE recurrence.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6–7.6), 8.6 % (95 % CI: 5.3–21.9) and 40.5 % (95 % CI: 24.9–55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65–0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

P1137 Long-term trend of cumulative incidence of venous thromboembolism in Korean patients with inflammatory bowel disease: A nationwide population-based cohort study

Abstract Background Venous thromboembolism (VTE) is a serious extraintestinal manifestation of inflammatory bowel disease (IBD). However, limited research has been conducted on the cumulative incidence of VTE in patients with IBD. Therefore, this study aimed to observe the trend of cumulative incidence of VTE after IBD diagnosis. Methods From 2005 to 2016, a population-based cohort study was conducted using health administration claims data from South Korea. IBD and VTE were defined by ICD-10 codes. Incidence density and cumulative incidence rate were analysed. The risk of variables including age, sex, and IBD subtype was comparatively analysed. Results A total of 35,508 newly diagnosed patients with IBD between 2005 and 2015 were followed up until 2016. Among them, 634 (1.8%) experienced VTE (619 adults and 15 children). The incidence densities of VTE per 10,000 person-year were 28.90 (range, 27.75–32.54) for overall IBD, 30.07 (range, 27.75–32.54) for adult IBD, and 11.08 (range, 6.20–18.27) for PIBD, respectively. The cumulative incidences of VTE at 0, 1-, 3-, 5-, and 10 years post-diagnosis were 0.01%, 0.30%, 0.80%, 1.30%, and 3.0%, respectively (Figure 1-A). Adulthood, female sex, and ulcerative colitis were associated with an increased risk of VTE (Figure 1-B, C, D). Conclusion The study showed a steady and gradual increase in the cumulative incidence of VTE in patients with IBD over a follow-up period of up to 11 years, with a slightly more rapid increase after 8 or 9 years. This trend was even more pronounced in children. This suggests that vigilant monitoring of VTE is necessary in the management of patients with IBD.

Incidence and Time Course of Symptomatic Thromboembolic Outcomes After Lower Extremity Arthroscopic Surgery, Ankle Fracture Surgery, and Achilles Tendon Repair.

The incidence and time course of acute venous thromboembolism (VTE) after ambulatory surgery for lower extremity orthopaedic conditions is not well-defined. The purpose of this study was to analyze the incidence, the time course, and risk factors associated with clinically diagnosed acute deep vein thrombosis or pulmonary embolism within 3 months of surgery in patients undergoing specific operations for lower extremity injuries. Patients undergoing arthroscopic procedures of the knee, ankle fracture surgery, Achilles tendon repair, and ankle arthroscopy from January 1, 2005, to December 31, 2010, were identified in the California Ambulatory Surgery database with linkage to hospital discharge data, emergency department data, and a death registry. Outcomes were acute VTE and death within 90 days. Time courses were compared using Kaplan-Meier analysis, and risk factors were analyzed using proportional hazard modeling. Analysis of data from 468,699 surgeries showed that the cumulative incidence of acute VTE was significantly higher after Achilles tendon repair (0.72%, P < 0.001) than ankle fracture surgery (0.33%), knee arthroscopy procedures (range, 0.29% to 0.41%), or ankle arthroscopy (0.24%). The time course of diagnosis of VTE was similar for all arthroscopic procedures (median postoperative day for diagnosis = 9 to 10; 80% by 22 to 36 days), whereas for Achilles tendon surgery, the time course was protracted (median postoperative day for diagnosis = 29 days; 80% by 51 days). Ninety-day mortality was low (<0.06%) after all procedures except ankle fracture (0.12%). Predictors of pulmonary embolism included age older than 60 years (HR, 3.1; 95% CI; 2.0 to 4.8, versus younger than 30 years), Achilles tendon repair (HR, 3.8; 95% CI; 2.8 to 5.3), and ankle fracture surgery (Hazard Ratio [HR], 2.1; 95% Confidence Interval [CI]; 1.5 to 2.8); Asian/Pacific Islander (HR, 0.3; 95% CI; 0.1 to 0.6) and Hispanic patients (HR, 0.5; 95% CI; 0.4 to 0.7) had significantly lower risk. The incidence and time course of onset of acute VTE after lower extremity orthopaedic surgeries varies significantly depending on the surgical procedure. These findings have implications regarding the use and duration of pharmacologic thromboprophylaxis.

Incidence of venous thromboembolism and association with PD-L1 expression in advanced non-small cell lung cancer patients treated with first-line chemo-immunotherapy.

Venous thromboembolism (VTE) is a serious complication in non-small cell lung cancer (NSCLC) patients. The use of thromboprophylactic therapy is subject to an accurate assessment of the VTE risk depending on patients, tumor characteristics and type of systemic antineoplastic treatments. However, little is known concerning the risk of VTE in patients suffering from an advanced NSCLC treated with first-line chemo-immunotherapy and the impact of tumor biomarkers such as PD-L1 expression. We performed a retrospective, observational, single-centre study in a cohort of advanced NSCLC patients treated with first-line chemo-immunotherapy. The primary endpoint was the incidence of VTE. Secondary endpoints were the cumulative incidence of VTE, the impact of PD-L1 on VTE occurrence, overall survival, the rate of VTE recurrence under anticoagulant treatment and the rate of bleeding complications. 109 patients were included, of whom 21 (19.3%) presented a VTE event during a median follow-up of 13 months. VTE incidence at 3, 6 and 12 months was 12.1%, 15.1% and 17.5% respectively. 61% were pulmonary embolisms, 9.5% were isolated deep vein thrombosis and 14.3% were central venous catheter-related thrombosis. Our study did not show a significant impact of PD-L1 on VTE occurrence. Overall survival at 6, 12 and 24 months was 81.9%, 74.4% and 70.3% respectively. Four patients developed a recurrent VTE under anticoagulation therapy 3 to 5 months after the first VTE event. One patient suffered from a major bleeding complication while under anticoagulation therapy, leading to death. VTE is a common complication in advanced NSCLC patients treated with concomitant chemo-immunotherapy. In our study, 19.3% of patients developed a VTE during a median follow-up of 13 months. PD-L1 did not appear to be associated with VTE occurrence. We recorded high VTE recurrence rates despite anticoagulant treatment. Further investigations are needed to determine if high PD-L1 expression is associated with 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.

Incidence of venous thromboembolism and predictive ability of age-adjusted international prognostic index for prediction of venous thromboembolism in Asian patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is one of the malignancies at high risk for the development of venous thromboembolism (VTE). We aimed to evaluate the incidence of VTE and the predictive ability of the age-adjusted international prognostic index (aaIPI) for the prediction of VTE among DLBCL patients.This was a retrospective cohort study including adult patients with newly diagnosed DLBCL. Differences in VTE occurrence within one year after diagnosis of DLBCL were estimated across aaIPI groups using the Kaplan-Meier model, Cox's model, and Gray's model with deaths regarded as competing events.Five hundred and ninety-one newly diagnosed DLBCL patients with a median age of 58 (range 16-93) years were included in this study. At a median follow-up time of 365 (range 2-365) days, VTE events were objectively diagnosed in 32 patients, giving a one-year cumulative incidence of VTE of 5.4% (95% confidence interval [CI], 3.7-7.6). Patients with aaIPI ≥ 2 had a significantly higher risk of VTE than patients with aaIPI < 2 (hazard ratio, 3.5; 95% CI, 1.6-7.8; p = 0.001 based on Cox's model and sub-distribution hazard ratio, 3.0; 95% CI, 1.3-6.7; p = 0.007 using Gray's model). The C-statistic of aaIPI was 0.65 (95% CI, 0.58-0.72).We demonstrated thatthe incidence of VTE in Asian DLBCL patients was not uncommon. The aaIPI was effective in determining the risk of VTE in DLBCL patients, even when including death as a competing event. aaIPI may be helpful in identifying patients at higher risk of VTE in DLBCL patients.

Venous Thromboembolism in Total Hip and Total Knee Arthroplasty

The optimal pharmacologic thromboprophylaxis agent after total hip and total knee arthroplasty is uncertain and consensus is lacking. Quantifying the risk of postoperative venous thromboembolism (VTE) and bleeding and evaluating comparative effectiveness and safety of the thromboprophylaxis strategies can inform care. To quantify risk factors for postoperative VTE and bleeding and compare patient outcomes among pharmacological thromboprophylaxis agents used after total hip and knee arthroplasty. This retrospective cohort study used data from a large health care claims database. Participants included patients in the United States with hip or knee arthroplasty and continuous insurance enrollment 3 months prior to and following their surgical procedure. Patients were excluded if they received anticoagulation before surgery, received no postsurgical pharmacological thromboprophylaxis, or had multiple postsurgery thromboprophylactic agents. In a propensity-matched analysis, patients receiving a direct oral anticoagulant (DOAC) were matched with those receiving aspirin. Aspirin, apixaban, rivaroxaban, enoxaparin, or warfarin. The primary outcome was 30-day cumulative incidence of postdischarge VTE. Other outcomes included postdischarge bleeding. Among 29 264 patients included in the final cohort, 17 040 (58.2%) were female, 27 897 (95.2%) had inpatient admissions with median (IQR) length of stay of 2 (1-2) days, 10 948 (37.4%) underwent total hip arthroplasty, 18 316 (62.6%) underwent total knee arthroplasty; and median (IQR) age was 59 (55-63) years. At 30 days, cumulative incidence of VTE was 1.19% (95% CI, 1.06%-1.32%) and cumulative incidence of bleeding was 3.43% (95% CI, 3.22%-3.64%). In the multivariate analysis, leading risk factors associated with increased VTE risk included prior VTE history (odds ratio [OR], 5.94 [95% CI, 4.29-8.24]), a hereditary hypercoagulable state (OR, 2.64 [95% CI, 1.32-5.28]), knee arthroplasty (OR, 1.65 [95% CI, 1.29-2.10]), and male sex (OR, 1.34 [95% CI, 1.08-1.67]). In a propensity-matched cohort of 7844 DOAC-aspirin pairs, there was no significant difference in the risk of VTE in the first 30 days after the surgical procedure (OR, 1.14 [95% CI, 0.82-1.59]), but postoperative bleeding was more frequent in patients receiving DOACs (OR, 1.36 [95% CI, 1.13-1.62]). In this cohort study of patients who underwent total hip or total knee arthroplasty, underlying patient risk factors, but not choice of aspirin or DOAC, were associated with postsurgical VTE. Postoperative bleeding rates were lower in patients prescribed aspirin. These results suggest that thromboprophylaxis strategies should be patient-centric and tailored to individual risk of thrombosis and bleeding.

Development of a Combined Risk Assessment Model for Venous Thromboembolism and Bleeding in Hematopoietic Stem Cell Transplantation Patients

Background: Venous thromboembolism (VTE) and bleeding are common complications amongst allogeneic and autologous hematopoietic stem cell transplant (HSCT) patients. Balancing risk of bleeding and thrombosis in this population is particularly challenging as HSCT patients are concurrently pancytopenic and coagulopathic. However, risk factors for bleeding and thrombosis in HSCT patients are understudied. We aimed to derive a combined bleeding and VTE risk assessment tool to be used in the immediate post-transplant period (90 days). Methods: We conducted a retrospective cohort study of adult patients who underwent allogeneic or autologous HSCT between January 1, 2011 and December 31, 2021 at a tertiary care centre in Canada. The risk models patients were followed from transplant until occurrence of the event of interest with last follow up at Day 90 post-transplant, or death. Primary outcome for VTE was the occurrence of a confirmed thrombosis including proximal upper and lower extremity deep vein thrombosis, pulmonary embolism, or thrombosis of unusual sites, including cerebral and splanchnic. Primary outcome for bleeding was the occurrence of a major or clinically significant non-major bleeding event, not related to anticoagulation, as per the definition of the International Society of Thrombosis and Hemostasis. Group characteristics were compared using chi-square, Fisher's exact, or Student's T-tests as appropriate. Potential predictors for VTE and bleed amongst our patients were evaluated using single variable logistic regression and confirmed with multiple variable logistic regression with forward selection. For continuous variables, optimal cut-off points were estimated using ROC curves. Final VTE and bleed risk scores were derived based on weighted variables and compared using Cox regression with non-parametric bootstrapping used for internal validation. Results: A total of 476 patients (317 autologous, 159 allogeneic) were included. 47 patients (9.8%) suffered from VTE, and 32 patients (6.7%) suffered from bleed unrelated to anticoagulation within 90 days post-HSCT. A VTE risk assessment tool was derived, and internally validated, and it included: second central venous catheter insertion (due to complications from first central line) (2 points), and previous cancer treatment with steroids (1 point). The overall cumulative incidence of VTE was 31.8% in the high-risk group (&amp;gt;2 points) versus 7.6% in the low-risk group (0-1 points). The high-risk group was associated with higher mortality at 90 days (15.9% versus 3.2%, p &amp;lt;0.001; Figure 1). A bleeding risk assessment tool was also derived, and internally validated, and it included: baseline (day 0 of transplant) platelet count of &amp;lt;90 (1 point), and baseline hemoglobin of &amp;lt;96 (1 point). The overall cumulative incidence of bleed was 17.2% in the high-risk group (2 points), versus 4.3% in the low-risk group (0-1 points). The high-risk group was associated with higher mortality at 90 days (12.6% versus 2.6%, p&amp;lt;0.001). Amongst the low-risk bleed group, overall cumulative incidence of VTE was 10.03%, with 31.03% in the high-risk VTE group versus 8.33% in the low-risk VTE group (p&amp;lt;0.001). The positive VTE group was associated with higher mortality at 90 days (10.26% versus 1.72%, p=0.001; Figure 2). Amongst the high-risk bleed group, overall cumulative incidence of VTE was 9.19%, with 33.33% in the high-risk VTE group, versus 4.17% in the low-risk VTE group (p&amp;lt;0.001). The positive VTE group was associated with higher mortality at 90 days (37.5% versus 10.13%, p=0.026). Conclusion: We derived a predictive score, VTE and Bleeding in Marrow Transplant (VBMT) - risk score, for both VTE and bleeding in the immediate post-transplant period (90 days), to be used in conjunction with other criteria for bleeding and thrombosis. Amongst the low-risk bleed patients, we recommend strong consideration of chemical VTE prophylaxis, especially amongst the high-risk VTE group. These risk assessment models will help stratify patients based on bleed and thrombosis risk, and ultimately help guide VTE prophylaxis and surveillance strategies amongst HSCT patients.

External Validation of PRISM Score in Multiple Myeloma Patients in a Community Setting: A Retrospective Cohort Study

Background: Newly diagnosed Multiple Myeloma (MM) patients have a 10 to 20 times higher risk of developing venous thromboembolism (VTE) than the general population. The pathogenesis may involve several factors such as activation of procoagulant factors, acquired activated protein C resistance, and inflammation. In addition to the general risk factors for venous thromboembolism such as older age, immobility, and surgery, some MM treatment-related factors such as the use of immunomodulatory drug therapy and abnormal cytogenetics contribute to the increased risk. The PRISM score (Prior VTE, Race, IMiD, Surgery, Metaphase Cytogenetics) is a risk prediction tool for VTE in MM and was published in 2022. The score ranges from 0 to 18 and patients were stratified into three groups: low (0), intermediate (1-6), and high risk (≥ 7). Our primary objective was to assess the external validity of the PRISM score in our community hospital setting. Methods: All consecutive newly diagnosed MM treated at Saint Vincent Hospital from 1/1/2008 to 12/22/2022 were included in our analysis. Patients receiving therapeutic anticoagulation for other indications or a diagnosis of VTE within 6 months preceding the MM diagnosis were excluded. Variables were collected through a retrospective chart review during MM treatment initiation. Model discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Logistic regression was used to calculate the odds ratio (OR) of VTE occurrence in the risk prediction model. Results: A total of 214 patients with newly diagnosed MM and available data on VTE occurrence were included. The median age of our cohort at treatment initiation was 74 years (range 31- 96). The median BMI was 27.8. 56% were male, and 44% were female. The mean PRISM score was 2.9, and 73% of MM were IgG/IgA subtype. IMiD-based induction regimen was used in 63 % of patients. A total of 24 patients (11.2%) were diagnosed with VTE after treatment initiation, of which 8 (3.7%) patients had a previous history of VTE. Prophylactic aspirin was used in 53.8% and abnormal metaphase cytogenetics was identified in 13% of MM cases. The median time to VTE from induction therapy was 4.8 months. The PRISM score was low in 116 patients, intermediate in 89, and high in 9 patients. The AUROC of the model was 0.759 (95% CI, 0.644-0.874) (1). The cumulative incidence of VTE at 6 months, 12 months, and more than 1 year was 6%, 7%, and 11.2% of the patients respectively. Each 1-point increase in the score was associated with a significantly higher chance of VTE occurrence in the model [ HR= 1.53, 95% CI (1.27-1.85), P&amp;lt;0.001]. Among the parameters, patients with a history of VTE [ HR= 1.55, 95% CI (1.26-1.91), P&amp;lt;0.001] and with abnormal metaphase cytogenetics [HR= 2.35, 95% CI (1.37-4.05), P&amp;lt;0.001] had a higher strength of association with the development of VTE after induction (2). Furthermore, among 9 patients with a high-risk PRISM score (≥ 7), 7 (77%) developed VTE within the first 6 months after treatment initiation. Conclusions: Our findings suggest that PRISM [AUROC=0.75, 95% CI (0.644-0.874), P&amp;lt;0.001] score could statistically predict VTE outcomes in our patient population. Abnormal metaphase cytogenetics was a significant predictor of VTE in the validation cohort. Abnormal cytogenetics has been well established to be an indicator of aggressive tumor biology and proliferation in stroma-independent MM. It has been established to be a predictor of VTE in acute myeloid leukemia as well. Also, high-risk scores were predictive of earlier development of VTE after treatment induction. Our study strengthens the evidence of using PRISM as a predictive tool. Further studies are needed to enhance the sensitivity of our existing tool.

Incidence and risk factors of venous thromboembolism in kidney transplantation patients: a prospective cohort study.

To investigate the incidence and explore the risk factors of venous thromboembolism (VTE) within 6months after kidney transplantation. Total of 331 kidney transplant recipients were assessed by venous ultrasonography for VTE at 14days, 1month, 3months, and 6months post-transplantation. Cox forward regression were used to identify the independent risk factors of VTE. This study registration number is ChiCTR1900020567 and the date of registration was 2019/01/08. The cumulative incidence of VTE was 2.72% (9/331) within 6months after transplant. 77.8% (7/9) of VTEs occurred in the first 3months post-transplantation. 88.9% (1/9) of VTEs were asymptomatic, 66.7% (6/9) of VTEs were mural thromboses and in the right lower extremity. Central vena catheterization (HR = 6.94) and severe pulmonary disease (including pneumonia) (HR = 57.35) were the risk factors for VTE in kidney transplantation recipients. KT patients are the high risk population of VTE. Future interventions should be strengthen for KT patients to receive a minimum of 3-month of precautionary measures for VTE, including infection prevention, and strengthening thromboprophylaxis on the CVC or transplanted side of lower extremity.

Risks for Venous Thromboembolism with Immune Checkpoint Inhibitor Therapy

Background: Immune checkpoint inhibitor therapy (ICI) has been variably associated with increased risk of VTE, with some reports suggesting increased risk and others suggesting risk is not different from the baseline venous thromboembolism (VTE) risk in unselected ambulatory patients with cancer. Methods: Patients treated with ICI at our institution between 2009 and 2022 were retrospectively identified. Standard baseline characteristics (age, sex, race/ethnicity, BMI), cancer type and stage, type of ICI, KS risk score variables not already captured including white cell count, hemoglobin, and platelet count at time of initiating ICI therapy, as well as other patient and treatment characteristics were collected. Those with history of VTE prior to start of ICI were removed from the analysis population; anticoagulation after starting ICI was a time dependent factor. Cumulative incidence of VTE with death as a competing risk was determined using Fine and Gray technique. Univariate analysis for baseline characteristics was completed. Characteristics that were statistically significant at the 0.1-level or less were carried forward as candidate predictors in multivariable, competing risks models of VTE. Results are presented as hazard ratios with 95% confidence intervals adjusted for multiple comparisons against a reference group. Results: Of 12,007 patients starting ICI therapy, 10,638 were analyzed with median follow-up of 25.1 months. The majority of tumor types included lung (30.3%), skin (15.8%; melanoma, squamous cell), gastrointestinal (11.7%), and genitourinary (11.6%). The most frequently used ICI agents were the anti-PD-1 monoclonal antibodies pembrolizumab (49.7%) and nivolumab (31.8%). The overall cumulative incidence estimates of VTE are summarized in Figure 1. The estimate at six months was 7.6% (95% CI: 7.1 to 8.1%); at one year: 11.1% (95% CI: 10.5 to 11.8%); and at two years 13.8% (95% CI: 13.0 to 14.5%). Among the 1,328 patients who developed VTE, the median time after starting ICI therapy was 5.4 months [IQR: 1.8 to 12.0 months]. Univariate comparison findings carried forward as candidate predictors in the multivariable analyses included sex, age, BMI, race, history of prior anticoagulant therapy (before ICI start), cancer type, disease stage, ICI therapy (by drug), KS, and platelets. The first multivariable model using all predictors identified gender, Khorana risk score, and race as no longer significant. The second model examined the inter-relationships between remaining predictors and the incidence of VTE; as the KS is partially comprised of cancer type, BMI, and platelets, having these as separate predictors removed the influence of the Khorana score since they would provide similar information. Predictors of VTE identified in this model included type of ICI with the use of ipilumumab associated with the highest risk with HR of 1.90 (95% CI: 1.33-2.71) and durvalumab the lowest HR 0.59 (95% CI:0.36-0.96), when compared with pembrolizumab. Type of cancer, stage of cancer, BMI, and high platelet count were also predictive. Starting anticoagulation at the time of or after beginning ICI but not for treatment of VTE was associated with approximately a 40% reduced hazard of VTE compared to patients who had not yet or never started anticoagulation. (HR: 0.59, 95% adj. CI: 0.48 to 0.73). (Table 1) Conclusion In this large sample of patients, the use of ICI in VTE naïve patients was associated with an increased risk of VTE, with a cumulative incidence of 7.6% at 6 months compared with a baseline 3-4% risk in general ambulatory patients with cancer. Type of ICI treatment was associated with VTE risk, as was stage of cancer. The individual KS risk predictors of cancer type and BMI were predictive but only elevated platelet count was associated with increased VTE risk-hemoglobin and white cell count were not. Importantly, those that started anticoagulation for reasons other than development of VTE had a significant reduction in VTE risk, suggesting that anticoagulant prophylaxis may be indicated in those patients with multiple risk factors in the setting of ICI treatment. Further analysis of these data will help identify at risk patients starting treatment with ICI who will benefit from VTE prophylaxis.

Natural History of Isolated Splanchnic Vein Thrombosis in Cancer Patients

Introduction : Venous thromboembolism (VTE), especially pulmonary embolism (PE) and deep vein thrombosis (DVT), is associated with increased morbidity in cancer patients. However, the clinical course and optimal management of unusual and isolated splanchnic vein thrombosis (iSpVT) remain unclear. Past studies often excluded cancer patients or combined them in heterogeneous cohorts. We aimed to describe the natural history of cancer associated iSpVT. Methods : We queried a cancer registry linked database from a large safety-net hospital system from 2011-2020. Patients with incident cancer diagnosis and intra-abdominal venous thrombosis were identified by a combination of International Classification of Diseases (ICD) code and natural language processing (NLP) algorithm (Figure 1). iSpVT was defined as symptomatic or incidental portal, hepatic, splenic, mesenteric vein thrombosis without concurrent PE/DVT. Patients were excluded for remote SpVT &amp;gt;6 months (mo) before or &amp;gt;36 mo after cancer diagnosis, concurrent PE/DVT, existing anticoagulation (AC), or inadequate follow-up &amp;lt;3 mo (unless death). Thrombus type was classified as bland vs. tumor/mixed based on radiology impression. AC was defined by intention for extended therapeutic AC. Venous recanalization was defined as resolution or reduction in thrombus size in a subset of patients with repeat contrast radiology scans in 3-12 mo. VTE was defined as PE or DVT. Bleeding was defined as ISTH major (MB) or clinically relevant non-major (CRNMB). Cumulative incidence of VTE at 180 days (d) was estimated using competing risk method and overall mortality was assessed by Kaplan Meier estimator. Results : Figure 1 highlights the cohort selection where 298 of 15,342 patients (1.9%) met inclusion criteria for iSpVT. Median time from cancer diagnosis to iSpVT was 19d (IQR 0-138). Most occurred in upper gastrointestinal cancers; 54% were bland and 46% were tumor/mixed. Tumor (n=99) and bland (n-44) thrombi in hepatocellular carcinoma (HCC), along with bland thrombi in pancreatic ductal adenocarcinoma (PDCA) (n=24) comprised over half of iSpVT. AC rate differed by cancer and thrombus type. Most tumor thrombi regardless of cancer type did not receive AC (97%). Most HCC and PDCA regardless of thrombus type did not receive AC (96%). Among those with bland thrombi in other cancers, 39% received AC. Due to strong selection bias for AC, we analyzed future VTE, bleeding, recanalization, and mortality in different subgroups: 1) untreated iSpVT in HCC/PDCA (compare to similar patients without SpVT); 2) all other cancers with bland iSpVT (compare AC vs. no AC) (Table 2). Among 143 HCC patients with untreated iSpVT, 44 had bland thrombi. The 180d VTE incidence was 2.4% (95% CI 0.2-10.7), which was non-significantly lower than HCC patients without iSpVT at 4.7% (95% CI 3.2-6.7). In contrast, 99 HCC patients with tumor thrombi had twice the risk of VTE and mortality compared to bland thrombi. Among 32 PDCA patients with untreated iSpVT, 24 had bland splenic vein thrombi due to tumor encasement. The 180d VTE incidence was 13.5% (3.3-30.7), similar to PDCA patients without SpVT at 17.2% (13.2-21.7). Among 87 mixed cancer type patients with bland iSpVT, the overall 180d VTE incidence was 4.6% (1.5-10.6). Thirty-four received AC with a median duration of 81d (IQR 31-181). AC was associated with increased recanalization rate (46.7% vs. 21.7%); however, it was not associated with decreased VTE (12.1% vs. 0%) or mortality (42% vs. 42%) due to confounding by treatment indication. Notably, 3 of 4 VTE occurred &amp;lt; 2 weeks after stopping AC. Bleeding occurred in 26% (n=9) of patients on AC with 15% MB (n=5) and 12% CRNMB (n=4), at a median of 28d (IQR 7.5-115) after starting AC. Conclusion: iSpVT in cancer patients is not a singular entity but rather a heterogeneous disease based on cancer and thrombus type. Tumor thrombi are associated with higher risk of future VTE and mortality. Untreated iSpVT in HCC and PDCA appear to have similar risk of VTE as those without SpVT, which supports current practice of not anticoagulating these patients. Beyond these cancers, AC varies by perceived risk of thrombosis vs bleeding. Despite strong selection bias, AC is associated with higher recanalization rate but at a cost of high bleeding risk. Prospective studies in a cancer-specific context are needed to determine if iSpVT should be treated similarly as PE/DVT among cancer patients.

CDKN2C Deletion on 1p32 Locus As Part of Irwazh Score, a New Risk Assessment Model for Venous Thromboembolism Occurring within 6-12 Months of Treatment Initiation in Newly Diagnosed Multiple Myeloma

Background Adequate risk-stratification of venous thromboembolism (VTE) in multiple myeloma (MM) is an unmet need. Methods This is a retrospective study of 320 newly diagnosed MM (NDMM) patients treated from 2011 to 2023. All gave their informed consent. Required minimal follow-up (FU) length was 12 months or lower if VTE or death occurred. We aimed to evaluate VTE incidence at 6 and 12 months of first line treatment (L1) initiation, identify risk predictors and assess VTE impact on overall survival (OS). Comorbidities, baseline demographic (excluding race), clinical, biological (including FISH) and imaging data, treatment exposures, response profile and OS were all analyzed. Total scores for 4 existing risk assessment models (RAM) (IMPEDE-VTE, SAVED, PRISM, IFM/DFCI-related) were also calculated from L1 start. VTE events (VTEe) were adjudicated to exclude superficial ones and restrict analysis to documented deep vein thrombosis (DVT) and pulmonary embolism (PE). Predictors validated by Cox model were weighted based on their hazard ratios (HR). Results The cohort comprised 147 (45.9%) women and 111 (34.7%) transplant-eligible patients. Overall median age was 70.1 (36.6-98.4) years and 205 (64.1%) subjects were &amp;gt;65. Two hundred and twenty-five (70.3%) received standard-of-care regimens containing immunomodulatory drugs (IMID) (Thalidomide in 98: 30.6%; Revlimid in 127: 39.7%), while 130 (40.6%) received high-dose (≥160 mg) Dexamethasone (HDD) per L1 cycle. VTE prophylaxis was omitted in 32 (10%) or consisted of NSAID in 97 (30.3%), prophylactic low molecular weight heparin (LMWHp) in 115 (36%) and direct oral anticoagulant (DOA) in 55 (17.2%), while 10 (3.1%), 9 (2.8%) and 2 (0.6%) were previously receiving curative LMWH (LMWHc), vitamin K antagonist (VKA) or a mixed regimen, respectively, for prior VTE or other indications. In 33 (10.3%) patients, 34 VTEe occurred (31 [91.2%] within the first 6 months): 4 (11.8%) as both PE and DVT; 3 (8.8%) as PE; 27 (79.4%) as isolated proximal (12 [35.3%]) or distal (15 [44.1%]) DVT of the upper (2 [5.9%]) or lower (25 [73.5%]) limbs, including 3 (8.8%) with both proximal and distal and 3 (8.8%) close to central venous catheter. Based on Cox univariate analysis, VTEe were not related to usual parameters such as past VTE history, IMID, HDD or EPO exposure, prophylaxis omission or modality or recent surgery. A 6-parameter RAM, named Irwazh score, was built from multivariate Cox model, including: age &amp;lt;55 years (HR 0.34; 95% confidence interval [CI]: 0.0-0.8; p=0.014), prior diabetes (HR 3.41; 95% CI: 1.48-7.85; p=0.004), creatinine clearance (Cr-Cl) using MDRD &amp;lt;40 ml/mn (HR 2.64; 95% CI: 1.26-5.51; p=0.009), CRP ≥10 mg/dl (HR 2.65; 95% CI: 1.27-5.48; p=0.009), ≥50% 1p32 deletion (HR 3.44; 95% CI: 1.17-10.09; p=0.024) and minimal response (MR) to L1 (HR 4.67; 95% CI: 1.71-12.73; p=0.003). Area under the curve (AUC) was 0.718 (95% CI: 0.624-0.811; p&amp;lt;0.0001) at 12 months and 0.731 (95% CI: 0.636-0.825; p&amp;lt;0.0001) at 6. In comparison, AUC was 0.649 (95% CI: 0.546-0.751; p=0.004) for IMPEDE-VTE, 0.597 (95% CI: 0.505-0.689; p=0.039) for PRISM, 0.584 (95% CI: 0.486-0.682: p=0.091) for IFM/DFCI-related and 0.580 (95% CI: 0.473-0.687; p=0.141) for SAVED (Figure 1). Based on points attributed to each parameter (age &amp;lt;55 years: 1; prior diabetes: 9; Cr-Cl&amp;lt;40 ml/mn: 6; CRP≥10 mg/dl: 6; ≥50% 1p32 deletion: 9; MR: 11), patients were stratified into low (&amp;lt;6 points), intermediate (6-15) and high risk (≥16), with 12-month cumulative VTE incidence of 4,51% (6/133), 10,45% (16/153) and 35,29% (12/34), respectively. Of low-risk patients, 2 were receiving NSAID and 4 LMWHp; of intermediate-risk ones, 2 had no prophylaxis, 9 were under NSAID and 5 LMWHp; of high-risk ones, 2 had no prophylaxis, 5 were receiving NSAID, 2 LMWHp, 1 VKA, 1 LMWHc and 1 DOA. Using Kaplan-Meier analysis for VTE-free survival, statistical difference was found significant between low- and intermediate-risk ( p=0.043), low- and high-risk ( p&amp;lt;0.0001) and intermediate- and high-risk groups ( p=0.000) (Figure 2). Median total FU was 33.2 (0.2-147) months; OS assessment using Cox model did not find a significant statistical impact of VTE neither at 6 ( p=0.491) and 12 ( p=0.199) months nor during the whole FU length ( p=0.438). Conclusion The Irwazh score, with an unprecedented FISH feature, a statistically significant risk-stratifying power and a better AUC than existing VTE RAMs is worth validating in a larger clinical study.

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

Safety and effectiveness of initial high-dose anticoagulation therapy for cancer-associated venous thromboembolism in the real world: insight from the COMMAND VTE Registry-2

Abstract Background/Introduction Initial high-dose anticoagulation therapy by rivaroxaban and apixaban has been a standard treatment for venous thromboembolism (VTE), although there could be concerns of bleeding especially among high bleeding-risk patients including those with active cancer. However, there is limited data on the issue comparing those with and without initial high-dose anticoagulation therapy. Purpose The present study aimed to examine the safety and effectiveness of initial high-dose anticoagulation therapy in patients with cancer-associated VTE. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. The present study population was consisted of 1507 patients with cancer-associated VTE. We compared the patient characteristics and clinical outcomes between patients with initial high-dose anticoagulation therapy and those without. Results Patients with initial high-dose anticoagulation therapy and those without accounted for 344 (23%) and 1163 (77%) patients, respectively. Of patients with initial high-dose anticoagulation therapy, rivaroxaban and apixaban were administered in 210 and 134 patients, respectively, whereas, of those without, direct oral anticoagulant (DOAC), warfarin and other therapies were administered in 855, 164 and 144 patients, respectively. Patients with initial high-dose anticoagulation therapy were younger (66±12 vs. 79±13 years, P=0.002), had a higher body weight (59±13 vs. 56±12 kg, P=0.001), more frequently had pulmonary embolism (61% vs. 48%, P&amp;lt;0.001), and less frequently had chronic kidney disease (11% vs. 21%, P&amp;lt;0.001), anemia (70% vs. 79%, P&amp;lt;0.001) and terminal cancer (7% vs. 17%, P&amp;lt;0.001). The mean of durations of initial high-dose anticoagulation therapy were 18±8 days for rivaroxaban and 7±1 days for apixaban. There was no significant difference in the distribution of gastrointestinal cancer such as esophageal, stomach and colorectal cancer between the 2 groups (1.2% vs. 1.8%, P=0.63, 4.9% vs. 5.7%, P=0.69, 8.1% vs. 10.7%, P=0.19). The cumulative 180-day incidence of all cause-death was significantly lower in patients with initial high-dose anticoagulation therapy (23.6% vs. 34.7%, P&amp;lt;0.001), while there were no significant differences in the cumulative 180-day incidences of recurrent VTE (4.3% vs. 3.1%, P=0.30) nor major bleeding (8.3% vs. 10.1%, P=0.35) between the 2 groups. There were also no significant differences in the cumulative 180-day incidences of all bleeding (15.4% vs. 16.8%, P=0.43), gastrointestinal (GI) bleeding (9.1% vs. 8.2%, P=0.61), nor major GI bleeding (5.5% vs. 4.9%, P=0.70) (Figure). Conclusions In the real-world clinical practice, initial high-dose anticoagulation therapy for cancer-associated VTE seemed to be more frequently administered for low bleeding-risk patients and did not show a higher risk of bleeding including gastrointestinal bleeding.FigureFigure

Clinical features and long-term outcomes of venous thromboembolism in the warfarin era versus in 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, which could 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 demographics, practice patterns and long-term clinical outcomes in patients with 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. Results Patients characteristics were comparable in most of aspects between the groups, whereas prevalence of active cancer was higher in the Registry-2 (Registry-1: 23% vs. Registry-2: 29%, P&amp;lt;0.001). As for oral anticoagulation therapy, 88% (2,676/3,027) of patients were treated with warfarin in the Registry-1 and 79% (4,128/5,197) of patients were treated with DOAC in the Registry-2. The proportion of patients admitted to the hospital was lower in the Registry-2 (80% vs. 69%, P&amp;lt;0.001). The discontinuation rate of anticoagulation therapy was significantly higher in the Registry-2 (42.8% vs. 52.5% at 3-year, Log rank P&amp;lt;0.001). The cumulative 5-year incidence of recurrent VTE was lower in the Registry-2 (10.5% vs. 9.5%, Log rank P=0.02), which remained significant even after adjusting the confounders (adjusted hazard ratio [HR]: 0.78 (0.65-0.93), P=0.006). There was no significant difference in the cumulative incidence of major bleeding between the groups (12.1% vs. 13.7%, Log-rank P=0.26), which remained insignificant even after adjusting the confounders (adjusted HR: 1.03 (0.89-1.20), P=0.67). After stratifying a total cohort into sub-groups according to the risk classification of recurrent VTE in the current guidelines (major transient risk factors, minor transient risk factors, unprovoked, non-malignant persistent risk factors, and active cancer), the risks of recurrent VTE and major bleeding were significantly lower in the Registry-2 among active cancer group (recurrent VTE: 17.7% vs 10.1% at 5-year, Log rank P&amp;lt;0.001, major bleeding: 26.6% vs 20.4% at 5-year, Log rank P=0.04), while those were not significantly different between the groups among other sub-groups. Conclusion In the current series of large real-world VTE registries, there seemed to be a significant risk reduction of recurrent VTE in the DOAC era compared with in the warfarin era, while there was no sign of increased risk of major bleeding in the DOAC era.

Clinical characteristics and outcomes of super-low-dose edoxaban of 15 mg in patients with acute venous thromboembolism: insight from the COMMAND VTE Registry-2

Abstract Background/Introduction The current guidelines recommend specific durations of anticoagulation therapy depending on the risks of recurrent venous thromboembolism (VTE), and prolonged anticoagulation therapy is recommended for patients at not-low risk of recurrence. However, clinicians are sometimes reluctant to continue anticoagulation therapy for patients with high-bleeding risk. A recent study reported that super-low-dose edoxaban of 15 mg was useful in preventing thromboembolic events for elderly patients with atrial fibrillation who were considered as high-bleeding risk patients. However, super-low-dose edoxaban of 15 mg is currently off-label for VTE all over the world, which could be a potential option for patient with VTE at high-bleeding risk. Purpose The current study aimed to investigate clinical characteristics and outcomes of VTE patients with super-low-dose edoxaban of 15 mg, using a large-scale multicenter observational database of patients with VTE. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. After excluding 3193 patients without edoxaban as oral anticoagulation therapy, the current study population was consisted of 2004 patients with edoxaban, who were divided into 3 groups according to initial dosage of edoxaban; 60 mg/day (N=664, 33%) 30 mg/day (N=1309, 65%) and 15 mg/day (N=31, 1.5%). Results Patients with edoxaban of 15 mg/day were oldest (60 mg/day: 62.3 years, 30 mg/day: 72.9 years and 15 mg/day: 79.2 years, P&amp;lt;0.001), were most often women (44%, 73% and 84%, P&amp;lt;0.001), showed a lowest mean body weight (68.4, 51.9 and 48.7 kg, P&amp;lt;0.001). Pulmonary embolism as initial presentation was least frequent in patients with edoxaban of 15 mg/day (58%, 44% and 13%, P&amp;lt;0.001). Patients with edoxaban of 15 mg/day most frequently had chronic kidney disease (10%, 22% and 26%, P&amp;lt;0.001) and anemia (45%, 66% and 74%, P&amp;lt;0.001). The discontinuation rates of anticoagulation therapy were not significantly different among the 3 groups (54.4%, 56.5% and 64.8% at 3-year, Log rank P=0.38). The cumulative incidences of recurrent VTE were not significantly different among the 3 groups (6.0%, 6.6% and 0.0% at 3-year, Log rank P=0.31). Similarly, the cumulative incidences of major bleeding were not significantly different among the 3 groups (9.2%, 11.6% and 15.3% at 3-year, Log rank P=0.11). Conclusions In the current real-world large VTE registry, a very minority of VTE patients received edoxaban of 15 mg/day, including patients at high-bleeding risk such as old age, low body weight and chronic kidney disease, who did not show significant worse outcomes in terms of recurrent VTE.