BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03–0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75–2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03895502.

There has been limited data on anticoagulation strategies and long-term recurrence in patients with venous thromboembolism (VTE) in the era of direct oral anticoagulant (DOAC). The COMMAND VTE Registry-2 is a multicenter retrospective cohort study enrolling 5197 consecutive patients with acute symptomatic VTE between January 2015 and August 2020 among 31 centers in Japan. In this primary report, the entire cohort was divided into 5 groups; major transient risk factors (N = 475, 9.1%), minor transient risk factors (N = 788, 15%), unprovoked (N = 1913, 37%), non-malignant persistent risk factors (N = 514, 9.9%), and active cancer (N = 1507, 29%) groups. DOACs were administered in 79% of patients who received oral anticoagulants. Discontinuation of anticoagulant at 1 year was most frequent in the major transient risk factors group (57.2%, 46.3%, 29.1%, 32.0%, and 45.6%). The cumulative 5-year incidence of recurrent VTE was lowest in the major transient risk factors group (2.6%, 6.4%, 11.0%, 12.1%, and 10.1%, P < 0.001). The cumulative 5-year incidence of major bleeding was highest in the active cancer group (9.8%, 11.4%, 11.0%, 15.5%, and 20.4%, P < 0.001). After discontinuation of anticoagulation therapy, the cumulative 5-year incidence of recurrent VTE was highest in the unprovoked group (3.3%, 11.0%, 24.9%, 17.5%, and 11.8%, P < 0.001). In this large real-world VTE registry, anticoagulation strategies and long-term recurrence widely differed depending on the baseline characteristics. Detailed risk stratifications of recurrent VTE could be useful for decision-making of anticoagulation strategies, whereas the bleeding-risk assessment might be especially important in the era of DOAC. URL: http://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000044816.

BACKGROUND: The optimal duration of anticoagulation therapy for patients with cancer and acute low-risk pulmonary embolism (PE) is clinically relevant, but evidence is lacking. Prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 32 institutions in Japan, we randomly assigned patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, in a 1:1 ratio, to receive either an 18-month or a 6-month rivaroxaban treatment. The primary end point was recurrent venous thromboembolism (VTE) at 18 months. The major secondary end point was major bleeding at 18 months according to the criteria of the International Society on Thrombosis and Hemostasis. The primary hypothesis was that an 18-month treatment was superior to a 6-month treatment in terms of the primary end point. RESULTS: From February 2021 to March 2023, 179 patients were randomized, and after the exclusion of one patient who withdrew consent, 178 were included in the intention-to-treat population: 89 patients in the 18-month rivaroxaban group and 89 in the 6-month rivaroxaban group. The mean age was 65.7 years; 47% of the patients were men, and 12% had symptoms of PE at baseline. The primary end point of recurrent VTE occurred in 5 of the 89 patients (5.6%) in the 18-month rivaroxaban group and in 17 of the 89 (19.1%) in the 6-month rivaroxaban group (odds ratio, 0.25 [95% CI, 0.09–0.72]; P =0.01). Among 22 recurrent VTE, 5 patients presented with a symptomatic recurrent VTE; recurrent PE occurred in 11 patients, including 2 with main and 4 with lobar PEs; and recurrent deep vein thrombosis was seen in 11 patients, including 3 with proximal deep vein thromboses. The major secondary end point of major bleeding occurred in 7 of the 89 patients (7.8%) in the 18-month rivaroxaban group and in 5 of the 89 patients (5.6%) in the 6-month rivaroxaban group (odds ratio, 1.43 [95% CI, 0.44–4.70]; P =0.55). CONCLUSIONS: In patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, the 18-month rivaroxaban treatment was superior to the 6-month rivaroxaban treatment with respect to recurrent VTE events. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04724460.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life‐threatening complication post‐acute pulmonary embolism (PE). The assessment of CTEPH incidence and risk factors post‐acute PE in the era of direct oral anticoagulants remains insufficient. Methods and Results: The COMMAND VTE Registry‐2 (contemporary management and outcomes in patients with venous thromboembolism registry‐2) is a multicenter registry that recruited consecutive patients with acute symptomatic venous thromboembolism from 31 centers across Japan. The primary outcome was to demonstrate the detection rate of CTEPH after acute PE in routine clinical practice. Out of the 5197 patients with venous thromboembolism included in the COMMAND VTE Registry‐2, 2787 were diagnosed with acute PE. Following a median follow‐up duration of 747 days, 48 cases of CTEPH were detected, and the cumulative diagnosis of CTEPH in routine clinical practice was 2.3% at 3 years. Independent risk factors for the detection of CTEPH by multivariable Cox regression analysis included women (hazard ratio [HR] 2.09 [95% CI, 1.05–4.14]), longer interval from symptom onset to diagnosis of PE (each 1 day, HR 1.04 [95% CI, 1.01–1.07]), hypoxemia at diagnosis (HR 2.52 [95% CI, 1.26–5.04]), right heart load (HR 9.28 [95% CI, 3.19–27.00]), lower D‐dimer value (each 1 μg/mL, HR 0.96 [95% CI, 0.92–0.99]), and unprovoked PE (HR 2.77 [95% CI, 1.22–6.30]). Conclusions: In the direct oral anticoagulant era, the cumulative diagnosis of CTEPH after acute PE was 2.3% at 3 years, and several independent risk factors for CTEPH were identified, which could be useful for screening a high‐risk population after acute PE.

Background: The impact of peridevice leak (PDL) at device implantation on clinical outcomes after percutaneous left atrial appendage closure (LAAC) is unknown. This study aimed to investigate the association between PDL and clinical outcomes after LAAC. Methods: Using data from the OCEAN‐LAAC (Optimized Catheter Valvular Intervention‐Left Atrial Appendage Closure) Japanese multicenter registry, we examined 1397 patients who underwent LAAC between September 2019 and December 2022. The primary outcome was transient ischemic attack, ischemic stroke, or systemic embolism within 2 years of LAAC. Clinical outcomes were compared between patients with and without PDL at device implantation using Fine and Gray multivariable regression analyses and propensity score matching. Additional analyses were performed by categorizing PDL into 2 groups: ≤3 mm and >3 mm but ≤5 mm. Results: Of 1397 patients who underwent LAAC, 84 (6.0%) had PDL, of whom 73 (86.9%) had ≤3 mm PDL. Patients with PDL had a larger left atrium and higher CHADS2 scores than those without PDL. Multivariable analyses showed that PDL was significantly associated with a higher risk of transient ischemic attack, ischemic stroke, or systemic embolism (adjusted subdistribution hazard ratio [sHR], 4.25 [95% CI, 1.91–9.44]; P <0.001). Even PDL ≤3 mm was independently associated with an increased risk compared with no PDL (adjusted sHR, 3.53 [95% CI, 1.37–9.04]; P =0.016). Propensity score matching analyses revealed consistent findings. Conclusions: PDL was associated with a higher risk of transient ischemic attack, ischemic stroke, or systemic embolism, even PDL ≤3 mm. Therefore, it may be necessary to aim for no PDL as much as possible.