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Abstract Background Extracorporeal membrane oxygenation (ECMO) might be required as a treatment option in patients with critical pulmonary embolism (PE). However, the clinical features and outcomes of the use of ECMO for critical acute PE are still limited. The present study aimed to clarify the clinical characteristics, management strategies and outcomes of patients with acute PE requiring ECMO in the current era using data from a large-scale observational database. Methods We analyzed the data of the COMMAND VTE Registry-2: a physician-initiated, multicenter, retrospective cohort study enrolling consecutive patients with acute symptomatic venous thromboembolism (VTE). Among 2035 patients with acute symptomatic PE, there were 76 patients (3.7%) requiring ECMO. Results Overall, the mean age was 58.4 years, and 34 patients (44.7%) were men. Cardiac arrest or circulatory collapse at diagnosis was reported in 67 patients (88.2%). The 30-day incidence of all-cause death was 30.3%, which were all PE-related deaths. The 30-day incidence of major bleeding was 54.0%, and the vast majority of bleedings were procedure site-related bleeding events and surgery-related bleeding (22.4%). The 30-day incidence of all-cause death was 6.3% in 16 patients with surgical intervention, 43.8% in 16 patients with catheter intervention, 25.0% in 16 patients with thrombolytic therapy, and 39.3% in 28 patients with anticoagulation only. Conclusions The current large real-world VTE registry in Japan revealed clinical features and outcomes of critical acute PE requiring ECMO in the current era, which suggested several unmet needs for future clinical trials.

Background: Ischemic stroke is a serious complication in patients with cancer-associated venous thromboembolism (CAVTE), although data remain scarce in the direct oral anticoagulant era. Objectives: This study aimed to investigate the incidence and identify predictive risk factors of ischemic stroke in patients with CAVTE. Methods: From the Contemporary Management and Outcomes in Patients With Venous Thromboembolism Registry-2 enrolling 5197 venous thromboembolism (VTE) patients across 31 centers in Japan between January 2015 and August 2020, we selected 1507 patients with active cancer. We calculated the cumulative incidence function of ischemic stroke accounting for the competing risk of death and investigated risk factors for ischemic stroke in a subdistribution hazard model of multivariable analysis. Results: During a median follow-up period of 1020 days, 71 patients (4.7%) developed ischemic stroke, and the cumulative incidence of ischemic stroke was 4.0% at 1 year and 4.7% at 3 years. Independent risk factors of ischemic stroke included pancreatic cancer (hazard ratio [HR], 4.24; 95% CI, 2.13-8.43), ovarian cancer (HR, 2.82; 95% CI, 1.31-6.08), lung cancer (HR, 2.35; 95% CI, 1.20-4.57), dyslipidemia (HR, 1.76; 95% CI, 1.01-3.09), metastasis (HR, 1.70; 95% CI, 1.02-2.82), higher D-dimer at VTE diagnosis (HR, 1.09; 95% CI, 1.04-1.14), and younger age (HR, 0.84; 95% CI, 0.71-0.999). Conclusion: In this large VTE registry in the direct oral anticoagulant era, the cumulative incidence of ischemic stroke was 4.0% at 1 year and 4.7% at 3 years in patients with CAVTE, and several independent risk factors of ischemic stroke were identified, including pancreatic cancer, ovarian cancer, lung cancer, dyslipidemia, metastasis, higher D-dimer at VTE diagnosis, and younger age.

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 simplified Pulmonary Embolism Severity Index (sPESI) score could help identify low‐risk patients with pulmonary embolism for home treatment. However, the application of the sPESI score and selection for home treatment have not been fully evaluated in the direct oral anticoagulants era. Methods and Results The COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) Registry‐2 is a multicenter registry enrolling consecutive patients with acute symptomatic venous thromboembolism. The current study population consists of 2496 patients with hemodynamically stable pulmonary embolism (2100 patients [84%] treated with direct oral anticoagulants), who were divided into 2 groups: sPESI scores of 0 and ≥1. We investigated the 30‐day mortality, home treatment prevalence, and factors predisposing to home treatment using the Kaplan‐Meier method and logistic regression model. Patients with an sPESI score of 0 accounted for 612 (25%) patients, and only 17% among 532 patients with out‐of‐hospital pulmonary embolism were treated at home. The cumulative 30‐day mortality was lower in patients with an sPESI score of 0 than the score of ≥1 (0% and 4.8%, log‐rank P

Background There have been limited data on the changes in clinical outcomes after the introduction of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) in real clinical practice. We evaluated the changes in management strategies and long‐term outcomes from the warfarin era to the DOAC era. Methods and Results We compared the 2 series of multicenter COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) registries in Japan enrolling consecutive patients with acute symptomatic VTE: Registry 1: 3027 patients in the warfarin era (2010–2014) and Registry 2: 5197 patients in the DOAC era (2015–2020). The prevalence of DOAC use increased more in Registry 2 than in the Registry 1 (Registry 1: 2.6% versus Registry 2: 79%, P

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.

Abstract 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

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of prior pulmonary thromboembolism (PE), caused by incomplete clot dissolution after PE. In patients with CTEPH, lifelong anticoagulation is mandatory to prevent recurrence of PE and secondary in situ thrombus formation. Warfarin, a vitamin K antagonist, is commonly used for anticoagulation in CTEPH based on historical experience and evidence. The anticoagulant activity of warfarin is affected by food and drug interactions, requiring regular monitoring of prothrombin time. The lability of anticoagulant effect often results in haemorrhagic and thromboembolic complications. Thus, lifelong warfarin is a handicap in terms of safety and convenience. Currently, the use of direct oral anticoagulants (DOACs) in CTEPH has increased with the advent of four DOACs. The safety of DOACs is superior to warfarin, with less intracranial bleeding in patients with non-valvular atrial fibrillation and venous thromboembolism. Edoxaban, the latest DOAC, also has proven efficacy and safety for those diseases in two large clinical trials; the ENGAGE-AF trial and HOKUSAI-VTE trial. The present trial seeks to evaluate whether edoxaban is non-inferior to warfarin in preventing worsening of CTEPH.Methods and analysis The KABUKI trial (is an investigator-initiated, multicentre, phase 3, randomised, single-blind, parallel-group, warfarin-controlled, non-inferiority trial to evaluate the efficacy and safety of edoxaban versus warfarin (vitamin K Antagonist) in subjects with chronic thromBoembolic pUlmonary hypertension taking warfarin (vitamin K antagonIst) at baseline) is designed to prove the non-inferiority of edoxaban to warfarin in terms of efficacy and safety in patients with CTEPH.Ethics and dissemination This study is approved by the Institutional Review Board of each participating institution. The findings will be published in a peer-reviewed journal, including positive, negative and inconclusive results.Trial registration number NCT04730037.Protocol version This paper was written per the study protocol V.4.0, dated 29 January 2021.

Abstract Balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary disease (CTEPD) is performed worldwide. High mean pulmonary arterial pressure (mPAP) during BPA is associated with aggravation of procedure‐related complications. Inhaled nitric oxide (NO) acts as a pulmonary vasodilator in CTEPH patients. The aim of this retrospective observational study was to evaluate the effects of inhaled NO in CTEPH/CTEPD patients during BPA. We assessed hemodynamic changes and the frequency of procedure‐related complications with or without NO inhalation. We performed 338 consecutive BPA in 72 CTEPH/CTEPD patients between April 2016 and November 2020. Since December 2019, all 16 patients (72‐BPA sessions) inhaled NO during the procedure as a routine. Inhaled NO significantly reduced mPAP from 31.3 ± 8.5 to 27.2 ± 6.8 mmHg (p

Abstract Recently, balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic pulmonary disease (CTEPD) has become an established procedure with stable results. The number of elderly CTEPH/CTEPD patients has also increased due to the widespread recognition of the disease concept. However, the reports of BPA in the elderly are limited. The aim of this study was to evaluate the efficacy and safety of BPA in elderly patients (>80 years). From April 2016 to December 2020, 344 BPA sessions (74 patients) were performed. The safety and efficacy of the BPA procedures were compared in the younger group (

Background: The relationship between hemoglobin A1c (HbA1c) levels and coronary artery disease (CAD) has previously been confirmed. Serum 1,5-anhydro-d-glucitol (1,5-AG) levels are a useful clinical marker for short-term glycemic status that reflect glycemic excursions with greater sensitivity compared with HbA1c, specifically in the postprandial state. Postprandial hyperglycemia is an important CAD risk factor. Thus, the aim of this study was to compare HbA1c with 1,5-AG as a CAD predictor. Methods: The subjects consisted of 336 consecutive patients who underwent their first coronary angiography between July 2011 and March 2013. The relationship between CAD prevalence and HbA1c as well as CAD prevalence and 1,5-AG levels was evaluated. The correlation between CAD complexity and HbA1c or 1,5-AG was also assessed. CAD complexity was evaluated by the SYNTAX score. Results: CAD patients presented with significantly lower 1,5-AG and higher HbA1c values than patients without CAD (11.6 µg/ml [6.1, 19.1] vs. 17.6 μg/ml [11.9, 25.0], p < 0.001, and 6.0% [5.6, 7.1] vs. 5.7% [5.4, 6.2], p < 0.001, respectively) (median [25th, 75th percentiles]). According to logistic regression analysis, 1,5-AG was a predictor of CAD prevalence (odds ratio 0.94, 95% confidence interval 0.90-0.97). However, HbA1c levels did not present a predictive value for CAD. Levels of 1,5-AG and HbA1c were significantly correlated with SYNTAX scores (ρ = -0.27, p < 0.001; and ρ = 0.23, p < 0.001, respectively). Conclusions: The use of 1,5-AG, may be superior to HbA1c in predicting CAD prevalence. Both 1,5-AG and HbA1c correlate with CAD complexity. [ABSTRACT FROM AUTHOR]

Preprocedural chronic kidney disease and contrast-induced acute kidney injury are predictors of in-hospital death and long-term mortality. However, neither the time course of kidney function after percutaneous coronary intervention (PCI) nor the relation between the time course of kidney function and prognosis has been adequately studied. We studied 531 patients who underwent PCI for acute coronary syndrome. The continuous deterioration of kidney function (CDKF) was defined as a >25% increase in serum creatinine level or serum creatinine >0.5 mg/dl above baseline at 6 to 8 months after PCI. CDKF was observed in 87 patients (16.4%). Independent risk factors for CDKF were contrast-induced acute kidney injury, preprocedural hemoglobin level, and proteinuria. Patients with CDKF exhibited significant higher 5-year mortality rate than patients without CDKF (25% vs 9.4%, log-rank p [ 0.0006). Independent risk factors for 5-year mortality were age >75 year, anemia, New York Heart Association class III or IV, low ejection fraction, and CDKF. CDKF is associated with an increased risk of all-cause mortality of 5 years in patients with acute coronary syndrome undergoing PCI. [ABSTRACT FROM AUTHOR]