Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis (ONCO DVT Study): An Open-Label, Multicenter, Randomized Clinical Trial.

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.

Impact of Anemia on Clinical Outcomes of Patients With Cancer-Associated Isolated Distal Deep Vein Thrombosis Receiving Edoxaban　- Insights From the ONCO DVT Study.

BACKGROUND: The ONCO DVT study demonstrated potential benefits of extended edoxaban treatment in patients with isolated distal deep vein thrombosis in terms of thrombotic risk. However, the risk-benefit balance in patients with anemia remains unclear. METHODS AND RESULTS: This prespecified subgroup analysis included 601 patients, divided into anemia (n=402) and no-anemia (n=199) groups. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) or VTE-related death. Anemia was defined as hemoglobin <12 g/dL for women and <13 g/dL for men. In the anemia subgroup, the primary endpoint occurred in 3 (1.5%) and 17 (8.4%) patients in the 12- and 3-month edoxaban treatment groups, respectively (odds ratio [OR] 0.17; 95% confidence interval [CI] 0.05-0.58), compared with 0 and 5 (4.9%) patients, respectively, in the no-anemia subgroup (P interaction=0.997). Major bleeding occurred in 26 (13.1%) and 17 (8.4%) patients with anemia in the 12- and 3-month edoxaban treatment groups, respectively (OR 1.64; 95% CI 0.86-3.14), compared with 2 (2.1%) and 5 (4.9%) patients without anemia (OR 0.67; 95% CI 0.26-1.73; P interaction=0.13). CONCLUSIONS: Regardless of the presence of anemia, edoxaban treatment for 12 months was superior to treatment for 3 months in reducing thrombotic events, whereas the risk of major bleeding did not differ significantly between the 2 treatment groups.

Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

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.

Association Between the Development of Thrombosis and Worsening of Disease Severity in Patients With Moderate COVID-19 on Admission　- From the CLOT-COVID Study.

BACKGROUND: The worsening of coronavirus disease 2019 (COVID-19) severity is a critical issue in current clinical settings and may be associated with the development of thrombosis.Methods and Results: This study used patient data obtained in the CLOT-COVID study, a retrospective multicenter cohort study. The demographics of patients with moderate COVID-19 on admission with and without worsened severity during hospitalization were compared and predictors were identified. Of 927 patients with moderate COVID-19 on admission, 182 (19.6%) had worsened severity during hospitalization. Patients with worsening of severity were older, more likely to have hypertension, diabetes, heart disease, and active cancer, and more likely to use pharmacological thromboprophylaxis. Patients with worsening of severity had higher D-dimer levels on admission and were more likely to develop thrombosis and major bleeding during hospitalization than those without worsening. Increased age (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.03, P=0.005), diabetes (OR: 1.63, 95% CI: 1.11-2.33, P=0.012), D-dimer levels >1.0 µg/mL on admission (OR: 2.10, 95% CI: 1.45-3.03, P<0.001), and thrombosis (OR: 6.28, 95% CI: 2.72-14.53, P<0.001) were independently associated with worsening of COVID-19 severity. CONCLUSIONS: Approximately 20% of patients with moderate COVID-19 had worsened severity during hospitalization. Increased age, diabetes, D-dimer levels >1.0 µg/mL on admission, and the development of thrombosis during hospitalization were significantly associated with worsened COVID-19 severity.

Mortality-associated Risk Factors in Hospitalized COVID-19 Patients in Japan: Findings of the CLOT-COVID Study.

BACKGROUND: Reports of mortality-associated risk factors in patients with the novel coronavirus disease 2019 (COVID-19) are limited. METHODS: We evaluated the clinical features that were associated with mortality among patients who died during hospitalization (n = 158) and those who were alive at discharge (n = 2,736) from the large-scale, multicenter, retrospective, observational cohort CLOT-COVID study, which enrolled consecutively hospitalized COVID-19 patients from 16 centers in Japan from April to September 2021. Data from 2,894 hospitalized COVID-19 participants of the CLOT-COVID study were analyzed in this study. RESULTS: Patients who died were older (71.1 years vs 51.6 years, P < 0.001), had higher median D-dimer values on admission (1.7 µg/mL vs 0.8 µg/mL, P < 0.001), and had more comorbidities. On admission, the patients who died had more severe COVID-19 than did those who survived (mild: 16% vs 63%, moderate: 47% vs 31%, and severe: 37% vs 6.2%, P < 0.001). In patients who died, the incidence of thrombosis and major bleeding during hospitalization was significantly higher than that in those who survived (thrombosis: 8.2% vs 1.5%, P < 0.001; major bleeding: 12.7% vs 1.4%, P < 0.001). Multivariable logistic regression analysis revealed that age >70 years, high D-dimer values on admission, heart disease, active cancer, higher COVID-19 severity on admission, and development of major bleeding during hospitalization were independently associated with a higher mortality risk. CONCLUSION: This large-scale observational study in Japan identified several independent risk factors for mortality in hospitalized patients with COVID-19 that could facilitate appropriate risk stratification of patients with COVID-19.

Prevalence and Clinical Characteristics of Proximal Deep Venous Thrombosis After a High-Density Coronavirus Disease 2019 Cluster in a Japanese Psychiatric Hospital.

BACKGROUND: The prevalence of deep venous thrombosis (DVT) among hospitalized psychiatric patients after coronavirus disease 2019 (COVID-19) infection remains unclear.Methods and Results:We retrospectively investigated the prevalence of proximal DVT after COVID-19 infection among 50 hospitalized patients in a Japanese psychiatric hospital that in which a COVID-19 cluster developed between August and September 2020. The prevalence of proximal DVT was 10.0%. Patients with proximal DVT had a lower body weight and higher maximum D-dimer levels and International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE scores. CONCLUSIONS: After COVID-19 infection, hospitalized psychiatric patients are at high risk of DVT and should be carefully followed up.

Therapeutic-Dose vs. Prophylactic-Dose Anticoagulation Therapy for Critically Ill Patients With COVID-19 in a Practice-Based Observational Study.

BACKGROUND: The potential benefit of therapeutic-dose anticoagulation for critically ill patients with coronavirus disease 2019 (COVID-19) is still controversial.Methods and Results: In the CLOT-COVID study, 225 patients with severe COVID-19 on admission requiring mechanical ventilation or extracorporeal membrane oxygenation were divided into patients with therapeutic-dose anticoagulation (N=110) and those with prophylactic-dose anticoagulation (N=115). There was no significant difference in the incidence of thrombosis between the groups (9.1% vs. 7.8%, P=0.73). CONCLUSIONS: Among a cohort of critically ill patients with COVID-19, approximately half received therapeutic-dose anticoagulation, although it did not show a potential benefit compared with prophylactic-dose anticoagulation.

Prognostic Impact of Peak Aortic Jet Velocity on Patients With Acute Myocardial Infarction.

BACKGROUND: Aortic valve stenosis (AS) leads to increased cardiovascular mortality and morbidity, and recent studies reported that even mild-to-moderate AS was associated with poor prognosis in the general population. This study investigated the prognostic impact of mild or moderate AS, defined as 2.0 m/s ≤ peak aortic jet velocity (Vmax) ≤3.9 m/s using echocardiography in acute myocardial infarction (AMI) patients.Methods and Results: This study enrolled 3,049 AMI patients using data from the Mie ACS registry. Patients were divided into 2 groups according to Vmax: Group 1: Vmax <2.0 m/s and/or visually intact aortic valve in which all 3 leaflets are fully and evenly open; Group 2: 2.0 m/s ≤ Vmax ≤ 3.9 m/s. There were 2,976 patients in Group 1and 73 patients in Group 2. The Group 2 patients were older, had a higher percentage of males and had lower body mass index and Killip ≥2 than the Group 1 patients. Angiographic data, door-to-balloon time, and mechanical support were not different between the 2 groups. The Group 2 patients demonstrated a significantly higher all-cause mortality rate (P<0.01) and composite of cardiovascular death and heart failure hospitalization (P<0.01), and Kaplan-Meier analysis showed the same tendency in propensity score-matched patients. CONCLUSIONS: The present study revealed that mild or moderate AS based on Vmax is associated with poor prognosis following AMI.

Incidence, risk factors, and clinical impact of major bleeding in hospitalized patients with COVID-19: a sub-analysis of the CLOT-COVID Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) causes extensive coagulopathy and a potential benefit of anticoagulation therapy has been documented for prevention of thromboembolic events. Bleeding events has also been reported as a notable complication; whereas, the incidence, risks, and clinical impact of bleeding remain unclear. METHOD: The CLOT-COVID Study was a nationwide, retrospective, multicenter cohort study on consecutive hospitalized patients with COVID-19 in Japan between April 2021 and September 2021. In this sub-analysis, we compared the characteristics of patients with and without major bleeding; moreover, we examined the risk factors for and clinical impact of bleeding events. RESULTS: Among 2882 patients with COVID-19, 57 (2.0%) had major bleeding. The incidence of major bleeding increased with COVID-19 severity as follows: 0.5%, 2.3%, and 12.3% in patients with mild, moderate, and severe COVID-19, respectively. COVID-19 severity, history of major bleeding, and anticoagulant type/dose were independently and additively associated with the bleeding incidence. Compared with patients without major bleeding, those with major bleeding exhibited a longer duration of hospitalization (9 [6-14] vs 28 [19-43] days, P < 0.001) and higher mortality during hospitalization (4.9% vs. 35.1%, P < 0.001). CONCLUSIONS: In the real-world clinical practice, the incidence of major bleeding was not uncommon, especially in patients with severe COVID-19. Independent risk factors for major bleeding included history of major bleeding, COVID-19 severity, and anticoagulant use, which could be associated with poor clinical outcomes including higher mortality. Precise recognition of the risks for bleeding may be helpful for an optimal use of anticoagulants and for better outcomes in patients with COVID-19.

Incidence and Clinical Features of Venous Thromboembolism in Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) reportedly causes venous thromboembolism (VTE), but the status of this complication in Japan was unclear.Methods and Results:The VTE and COVID-19 in Japan Study is a retrospective, multicenter cohort study enrolling hospitalized patients with COVID-19 who were evaluated with contrast-enhanced computed tomography (CT) examination at 22 centers in Japan between March 2020 and October 2020. Among 1,236 patients with COVID-19, 45 (3.6%) were evaluated with contrast-enhanced CT examination. VTE events occurred in 10 patients (22.2%), and the incidence of VTE in mild, moderate, and severe COVID-19 was 0%, 11.8%, and 40.0%, respectively. COVID-19 patients with VTE showed a higher body weight (81.6 vs. 64.0 kg, P=0.005) and body mass index (26.9 vs. 23.2 kg/m2, P=0.04), and a higher proportion had a severe status for COVID-19 compared with those without. There was no significant difference in the proportion of patients alive at discharge between patients with and without VTE (80.0% vs. 88.6%, P=0.48). Among 8 pulmonary embolism (PE) patients, all were low-risk PE. CONCLUSIONS: Among a relatively small number of patients undergoing contrast-enhanced CT examination in Japanese real-world clinical practice, there were no VTE patients among those with mild COVID-19, but the incidence of VTE seemed to be relatively high among severe COVID-19 patients, although all PE events were low-risk without significant effect on mortality risk.

Acute Pulmonary Thromboembolism in a Patient with Nutcracker Syndrome and Antiphospholipid Syndrome.

Nutcracker syndrome (NCS), which is defined as compression of the left renal vein between the aorta and the superior mesenteric artery, is usually benign and self-limiting. Long-term renal venous retention increases the risk of renal vein thrombosis. However, NCS rarely develops into isolated thrombosis of the left renal vein; the reason for this process remains unknown. We describe a young man with antiphospholipid syndrome, who developed overt pulmonary thromboembolism due to an isolated thrombus in the left renal vein. Complicating antiphospholipid syndrome might trigger acute pulmonary thromboembolism (APTE) in patients with NCS. To the best of our knowledge, this is the first report of APTE arising due to isolated left renal vein thrombosis in patients with NCS.

Incidence, Characteristics and Management of Venous Thromboembolism in Japan During 2011.

BACKGROUND: This study aimed to determine the incidence, characteristics and management of venous thromboembolism (VTE) in Japan during 2011.Methods and Results:A retrospective study assessed responses to a questionnaire regarding treating newly diagnosed VTE at all admitting hospitals throughout Japan during 2011. More individuals were diagnosed with VTE than ever before, with 16,096 cases of diagnosed pulmonary embolism (PE) and 24,538 cases of diagnosed deep vein thrombosis (DVT). Almost half (47.2%) of the PE patients had a relatively mild condition with no right ventricular overload. Similarly, almost half (43.8%) of the DVT patients had a relatively mild condition with isolated calf thrombus. Most of PE patients were treated by anticoagulation, and fewer were treated using thrombolytic agent or inferior vena cava (IVC) filter. CONCLUSIONS: The present study showed a remarkable increase in the incidence of VTE in Japan during 2011. Relatively mild conditions such as non-massive PE and isolated calf DVT were frequently diagnosed. Among PE patients, thrombolytic therapy or IVC filter implantation decreased compared with previous surveys. The appropriate management of isolated calf DVT requires further investigation.

Detrimental Impact of Vasopressin V2 Receptor Antagonism in a SU5416/Hypoxia/Normoxia-Exposed Rat Model of Pulmonary Arterial Hypertension.

BACKGROUND: The expression of vasopressin type 2 receptor (V2R) in the lung, and the long-term effects of tolvaptan, a selective V2R antagonist, on pulmonary circulation and right ventricular (RV) remodeling in a pulmonary arterial hypertension (PAH) rat model were evaluated. METHODS AND RESULTS: Six-week-old male Sprague-Dawley rats were injected subcutaneously with 20 mg/kg of SU5416 and were exposed to hypoxia for 3 weeks followed by re-exposure to normoxia for 7 weeks. These rats showed signs of RV failure and upregulation of V2R and cAMP in the lung tissue at 10 weeks after SU5416 injection. They were then treated with either 0.05% tolvaptan in diet (SUHx+Tolv) or normal diet (SUHx) during 5-10 weeks of SU5416 injection. Normal control rats (Cont) were also used for comparison. SUHx+Tolv had significantly higher pulmonary arterial pressure, more progressive pulmonary arterial remodeling, and more severe myocyte hypertrophy and interstitial myocardial fibrosis in the right ventricle compared with SUHx despite achieving successful preload reduction. CONCLUSIONS: Chronic vasopressin V2R antagonism may contribute to the worsening of PAH and the development of RV remodeling.

Early and long-term outcomes of venous stent implantation for iliac venous stenosis after catheter-directed thrombolysis for acute deep vein thrombosis.

BACKGROUND: Although stent implantation is used worldwide for peripheral arterial disease, there is little data on the safety and long-term patency of stents implanted for venous disease. METHODS AND RESULTS: We studied 13 patients with 14 lesions (6 males, 7 females, mean age: 63.2±10.2 years) diagnosed with venous stenosis and who underwent venous stenting. We examined the location of the stenosis, safety of venous stenting, implantation success rate, and long-term stent patency rate. All patients were suffering from venous stenosis in the left common iliac vein because of iliac vein compression syndrome. No major complications occurred during stent implantation. Acute stent occlusion occurred in 1 patient, who was given additional thrombolytic therapy. Of the 13 patients, 10 underwent venography or contrast-enhanced computed tomography (CT) during mid-term follow-up (mean: 12.9±16.1 months), and only 1 stent was occluded, resulting in a patency rate of 90.0%. The latter patient decided to stop taking warfarin soon after stent implantation. Furthermore, 5 patients underwent contrast-enhanced CT to assess the long-term patency of their stents (mean: 79.6±31.2 months), and none was occluded. CONCLUSIONS: Venous stents display a high long-term patency rate, and hence are a useful tool for treating iliac venous stenosis.

Diagnostic performance of fluoroscopic video analysis for pulmonary embolism: a prospective observational study.

PURPOSE: Dynamic chest radiography using X-ray fluoroscopic video analysis has shown potential for the diagnosis of pulmonary embolism (PE), but its diagnostic performance remains uncertain. We aimed to evaluate the diagnostic performance of fluoroscopic video analysis for diagnosing PE. METHODS: A prospective single-center observational study was conducted between October 2020 and January 2022. Fifty consecutive adult patients, comprising definitive PE, pulmonary hypertension (PH), or suspected PH, were enrolled. The study population was classified into 23 PE and 27 non-PE cases by contrast-enhanced computed tomography, lung scintigraphy, right heart catheterization, and pulmonary angiography. Cineradiographic images of 10-second breath-holds were obtained and analyzed using a fluoroscopic video analysis workstation to generate pulmonary circulation images. Two blinded cardiologists qualitatively assessed the presence or absence of perfusion defects on the pulmonary circulation images. The diagnosis obtained from the fluoroscopic analysis was compared with the definitive diagnosis. The primary outcomes included sensitivity, specificity, positive and negative predictive values, and overall accuracy for diagnosing PE. RESULTS: Perfusion defects were observed in 21 of 23 PE patients and 13 of 27 non-PE patients. The diagnostic performance of fluoroscopic video analysis for diagnosing PE showed a sensitivity of 91%, specificity of 52%, positive predictive value of 62%, negative predictive value of 88%, and overall accuracy of 70%. CONCLUSIONS: The high sensitivity of the fluoroscopic video analysis suggests its potential usefulness in ruling out PE without the need for contrast media or radionuclide; however, its specificity and overall accuracy remain limited.

Management of pulmonary hemodynamics prior to delivery in a pregnant woman with development of decompensated pulmonary arterial hypertension.

Prompt termination of pregnancy in patients with decompensated pulmonary arterial hypertension (PAH) is imperative for improvement of maternal hemodynamics, but such termination may also result in maternal death due to further deterioration of PAH immediately after delivery. However, there have been limited reports on whether implementation of PAH therapy with continuation of pregnancy improves the maternal outcome, especially in treatment-naïve patients with PAH. A 24-year-old woman was admitted to our hospital with a chief complaint of dyspnea (WHO functional class IV) at 22 weeks and 3 days of gestation. She was diagnosed with PAH accompanied by right heart failure and low cardiac output. Intensive treatment was initiated with inotropic agents, oxygen therapy, and PAH therapy, resulting in improvement of her hemodynamics. A caesarean section was performed at 23 weeks and 3 days. Although her pulmonary arterial pressure transiently increased with oxygenation deteriorating immediately after delivery, worsening PAH improved without mechanical circulatory support. She continued receiving pulmonary vasodilators without relapse of pulmonary hypertension for three years. The improvement of pulmonary hemodynamics prior to delivery with PAH therapy led to a favorable outcome after delivery. Learning objective: Pulmonary hemodynamics in pregnant patients with pulmonary arterial hypertension (PAH) can deteriorate with the continuation of pregnancy, while termination can also cause PAH surge immediately after delivery. In treatment-naïve patients with PAH, who are most likely to benefit from PAH therapy, implementation of PAH therapy with continuation, even with a decompensated status, may improve the hemodynamics prior to delivery, resulting in a favorable outcome after delivery.

Exploratory rivaroxaban trial for isolated calf deep vein thrombosis with a risk factor of thrombosis extension: an open-label, multicenter, randomized controlled trial.

Background: Limited evidence exists regarding the incidence of recurrent venous thromboembolism (VTE) in patients diagnosed with isolated distal deep vein thrombosis (DVT) who are at risk of thrombosis extension whether they receive anticoagulation therapy or not. Objectives: The study aimed to investigate the incidence of recurrent VTE and the impact of rivaroxaban in this patient population. Methods: This open-label, exploratory, and randomized controlled trial was conducted at 7 centers in Japan between April 2019 and April 2022. Adult patients with isolated distal DVT at risk of thrombosis extension received either rivaroxaban combined with physical therapy or physical therapy alone for 90 days. Whole-leg ultrasound was performed at 14 and 90 days. We assessed a composite outcome of symptomatic or asymptomatic proximal DVT or symptomatic pulmonary embolism as the primary outcome until the end of the treatment period using an intention-to-treat analysis. Major bleeding was evaluated as a key secondary outcome. Results: Out of 90 enrolled patients, 3 were excluded due to withdrawal of consent; therefore, we analyzed 87 participants. The rivaroxaban group (n = 42) reported no primary outcomes (0%; 95% CI, 0.0%-8.4%), whereas the physical therapy group (n = 45) had 2 cases of symptomatic proximal DVT (4.4%; 95% CI, 0.5%-15.1%). Major bleeding events occurred in 4 patients in the rivaroxaban group (9.5%; 95% CI, 2.7%-22.6%), whereas no events occurred in the physical therapy group (0%; 95% CI, 0%-7.9%). Conclusion: Preliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events.