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BACKGROUND: Data on thrombosis and current real-world management strategies for anticoagulation therapy are scarce but important for understanding current issues and unmet needs of an optimal management of patients with coronavirus disease 2019 (COVID-19). METHOD: The CLOT-COVID Study (thrombosis and antiCoaguLatiOn Therapy in patients with COVID-19 in Japan Study: UMIN000045800) was a retrospective, multicenter cohort study enrolling consecutive hospitalized patients with COVID-19 among 16 centers in Japan from April 2021 to September 2021, and we tried to capture the status of the patients in the fourth and fifth waves of the COVID-19 infections in Japan. We enrolled consecutive hospitalized patients who were diagnosed with COVID-19 and had a positive polymerase chain reaction test obtained from the hospital databases. RESULTS: Among 2894 patients with COVID-19, 1245 (43%) received pharmacological thromboprophylaxis. The proportion of pharmacological thromboprophylaxis increased according to the severity of the COVID-19 in 9.8% with mild COVID-19, 61% with moderate COVID-19, and 97% with severe COVID-19. The types and doses of anticoagulants varied widely across the participating centers. During the hospitalization, 38 patients (1.3%) and 126 (4.4%) underwent ultrasound examinations for the lower extremities and contrast-enhanced computed tomography examinations, respectively, and 55 (1.9%) developed thrombosis, mostly venous thromboembolism (71%). The incidence of thrombosis increased according to the severity of the COVID-19 in 0.2% with mild COVID-19, 1.4% with moderate COVID-19, and 9.5% with severe COVID-19. Major bleeding occurred in 57 patients (2.0%) and 158 (5.5%) died, and 81% of them were due to respiratory failure from COVID-19 pneumonia. CONCLUSIONS: In the present large-scale observational study, pharmacological thromboprophylaxis for hospitalized patients with COVID-19 was common especially in patients with severe COVID-19, and management strategies varied widely across the participating centers. The overall incidence of thrombosis was substantially low with an increased incidence according to the severity of the COVID-19.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) need anticoagulant therapy for life. Conventionally, vitamin K antagonists (VKAs) have been used and data about direct oral anticoagulants (DOACs) in CTEPH patients are lacking. Recently, balloon pulmonary angioplasty (BPA) has emerged as a treatment option for CTEPH. However, there are no reports examining the effects of DOACs and VKAs on the hemodynamics of patients after BPA. The aim of this study was to compare DOACs and VKAs regarding the hemodynamic changes in patients with CTEPH treated by BPA. Patients who were treated by BPA and underwent follow-up right heart catheterization 6 ± 1 months after the final BPA procedure were included in this study. The subjects were divided into two groups based on the anticoagulant administered, and hemodynamic changes (mean pulmonary artery pressure, mPAP; pulmonary vascular resistance, PVR; cardiac index, CI) were assessed. Of the 65 consecutive patients, 29 met the inclusion criteria (DOAC-group n = 14, VKA-group n = 15). Compared to pre-BPA, post-BPA hemodynamic parameters were improved in both groups. There was no significant difference between the two groups regarding pre-BPA, post-BPA, 6Mo-f/u and Δhemodynamic parameters (difference between 6Mo-f/u and post-BPA, ΔmPAP, − 0.7 ± 3.3 vs. − 2.7 ± 5.4 mmHg, p = 0.24; ΔPVR, − 41.9 ± 80.9 vs. − 16.4 ± 74.1 dyne s/cm5, p = 0.38; ΔCI, − 0.06 ± 0.35 vs. − 0.10 ± 0.35 L/min/m2, p = 0.80; DOAC-group vs. VKA-group, respectively). Hemodynamic improvement by BPA was maintained over 6 months of follow-up irrespective of the type of anticoagulant administered in CTEPH patients.

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 levels1.0 μg/mL on admission (OR: 2.10, 95% CI: 1.45-3.03, P0.001), and thrombosis (OR: 6.28, 95% CI: 2.72-14.53, P0.001) were independently associated with worsening of COVID-19 severity.Approximately 20% of patients with moderate COVID-19 had worsened severity during hospitalization. Increased age, diabetes, D-dimer levels1.0 μg/mL on admission, and the development of thrombosis during hospitalization were significantly associated with worsened COVID-19 severity.

The influence of obesity on the development of thrombosis and severity of coronavirus disease 2019 (COVID-19) remains unclear.The CLOT-COVID study was a retrospective multicenter cohort study enrolling 2894 consecutive hospitalized patients with COVID-19 between April 2021 and September 2021 among 16 centers in Japan. The present study consisted of 2690 patients aged over 18 years with available body mass index (BMI), who were divided into an obesity group (BMI ≥30) (N = 457) and a non-obesity group (BMI30) (N = 2233).The obesity group showed more severe status of COVID-19 at admission compared with the non-obesity group. The incidence of thrombosis was not significantly different between the groups (obesity group: 2.6 % versus non-obesity group: 1.9 %, p = 0.39), while the incidence of a composite outcome of all-cause death, or requirement of mechanical ventilation or extracorporeal membrane oxygenation during hospitalization was significantly higher in the obesity group (20.1 % versus 15.0 %, p 0.01). After adjusting confounders in the multivariable logistic regression model, the risk of obesity relative to non-obesity for thrombosis was not significant (adjusted OR, 1.39; 95 % CI, 0.68-2.84, p = 0.37), while the adjusted risk of obesity relative to non-obesity for the composite outcome was significant (adjusted OR, 1.85; 95 % CI, 1.39-2.47, p 0.001).In the present large-scale observational study, obesity was not significantly associated with the development of thrombosis during hospitalization; however, it was associated with severity of COVID-19.

There has been limited data on the influence of sex on development of thrombosis in patients with coronavirus disease 2019 (COVID-19).The CLOT-COVID Study was a retrospective, multicenter cohort study enrolling 2894 consecutive hospitalized patients with COVID-19 among 16 centers in Japan from April 2021 to September 2021. We divided the entire cohort into the men (N = 1885) and women (N = 1009) groups.There were no significant differences in D-dimer levels at admission between men and women. Men had more severe status of the COVID-19 at admission compared with women (Mild: 57% versus 66%, Moderate: 34% versus 29%, and Severe: 9.1% versus 5.7%, P 0.001). Men more often received pharmacological thromboprophylaxis than women (47% versus 35%, P 0.001). During the hospitalization, men more often developed thrombosis than women (2.5% [95%CI, 1.9-3.3%] versus 0.8% [95%CI, 0.4-1.6%], P = 0.001). Men had numerically higher incidences of thrombosis than women in all subgroups of the worst severity of COVID-19 during the hospitalization (Mild: 0.3% versus 0.0%, Moderate: 1.6% versus 1.0%, and Severe: 11.1% versus 4.3%). Even after adjusting confounders in the multivariable logistic regression model, the excess risk of men relative to women remained significant for thrombosis (adjusted OR, 2.51; 95%CI, 1.16-5.43, P = 0.02).In the current large observational study of patients with COVID-19, men had more severe status of the COVID-19 than women, and the risk of development of thrombosis was higher in men compared with women, which could be helpful in determining the patient-specific optimal management strategies for COVID-19.

The serum 1,5-anhydro-d-glucitol (1,5-AG) level rapidly decreases concomitantly with urinary glucose excretion in hyperglycemia. 1,5-AG is a sensitive clinical marker of short-term glycemic control, postprandial hyperglycemia and glucose fluctuation. Increasing evidence about the relationship between cardiovascular disease (CVD) and glucose fluctuations have been published. In this review, we summarize the possibilities and limitations of 1,5-AG as a marker of CVD. Research showed that 1,5-AG level is associated with prevalence of CVD and is also a predictive value for cardiovascular (CV) events. Especially in a high risk population, the predictive value of 1,5-AG for CV events becomes more effective. Besides, 1,5-AG is an effective glycometabolic marker that complements HbA1c in terms of glucose fluctuation. Appropriate use of 1,5-AG might lead to improved prognosis for patients or decrease medical financial burden of the population through early detection of glucose disorder and quality glucose control.

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 (80 years; 278 sessions) and the elderly group (≥80 years; 66 sessions). The hemodynamic parameters were significantly improved in both groups (mean pulmonary arterial pressure: 34.4 ± 9.9 → 21.2 ± 6.2 mmHg

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.

Balloon pulmonary angioplasty (BPA) has improved the survival rate of patients with chronic thromboembolic pulmonary hypertension (CTEPH). The resolution of symptoms is one of the remaining goals of BPA. Frailty affects the outcome of cardiovascular diseases or treatments. The aim of this study is to assess the association between frailty and outcome of BPA. The resolution of symptoms is evaluated by the post-BPA World Health Organization functional class (WHO-FC). A total of 54 patients with CTEPH were divided into 2 groups by post-BPA WHO-FC (WHO-FC I group; n = 34 vs. WHO-FC ≥ II group; n = 20). Frailty was assessed by physicians using the clinical frailty scale (CFS) at the point of patient admission for their first BPA sessions. Compared to the WHO-FC ≥ II group, the WHO-FC I group was younger (65.6 ± 13.9 years vs. 74.3 ± 8.0 years) and had a lower CFS (3 [3, 4] vs. 4 [4, 6]) (median [25th, 75th percentiles]). The WHO-FC I achievement rates for each CFS score were CFS 3: 82.8%; 4: 53.8%; 5: 25.0%; 6: 33.3%; and 7: 20.0%. Logistic regression analysis showed that CFS was an independent predictor of WHO-FC I achievement (odds ratio 0.50, p = 0.012), but pre-BPA hemodynamic parameters and age were not independent predictors. Whether WHO-FC I can be achieved is predicted by pre-BPA patient frailty but not by pre-BPA hemodynamic parameters and age.

IntroductionChronic 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 analysisThe 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 disseminationThis 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 numberNCT04730037.Protocol versionThis paper was written per the study protocol V.4.0, dated 29 January 2021.

Chronic thromboembolic pulmonary hypertension (CTEPH) is group 4 pulmonary hypertension caused by organized thrombi in the pulmonary arteries. Balloon pulmonary angioplasty (BPA) is an emerging treatment option for patients with inoperable CTEPH but needs contrast media. Therefore, management can be very difficult in patients who have severe iodine allergies. We present a case of a 61-year-old female with CTEPH. Right heart catheterization showed that the mean pulmonary arterial pressure (mPAP) was 47 mmHg. Her organized thrombi were not surgically accessible, so we performed BPA to improve her hemodynamic status. One session of BPA was performed, but the second session was halted because of iodine-induced anaphylactic shock. Despite the administration of pulmonary arterial hypertension-specific drugs for 3 months, the patient's mPAP was still 33 mmHg. CTEPH patients with mPAP ≥30 mmHg have a poor prognosis, so we decided to perform BPA using gadolinium contrast media. A total of six sessions of gadolinium contrast BPA (Gd-BPA) improved the patient's mPAP to the normal range. Gadolinium contrast media could also be used for visualizing pulmonary arteries during BPA. Our report is the first successful case of Gd-BPA, which improved the patient's hemodynamic status to the almost normal range. Gd-BPA may be an attractive treatment option for patients with inoperable CTEPH and severe iodine allergy.

At present, there is consensus that prolonged dual antiplatelet therapy (DAPT) is effective to reduce cardiovascular events at the expense of bleeding complication events. A causal relationship of prolonged DAPT with an increase in mortality remains debatable, however, it appears to be obvious that bleeding complications are associated with an increase in cardiac events. Thus, individualized optimal DAPT duration balancing the risk and benefit of DAPT should be applied. In addition, strategy to minimize bleeding complications is highly recommended. Several risk scores have been reported to discriminate the risk and benefits of DAPT. However, in general, bleeding risk and event risk are correlated with each other, thus predictability of these scores is limited to moderate. Therefore, interpretation of previous trials is important to overcome the shortcome in outcomes. In this review, we provide an overview of DAPT trials and clarify the shortfalls to consider in Japan. Finally, possible future trends with reference to the results of recent clinical trials will be presented.

Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as Group-4 pulmonary hypertension caused by organized thrombi in pulmonary arteries. Pulmonary endarterectomy (PEA) has been shown to improve the symptoms and prognoses of patients with proximal CTEPH. The soluble guanylate cyclase stimulator (riociguat) is the sole FDA-licensed drug for the treatment of CTEPH, and guidelines recommend its use for patients with inoperable CTEPH or residual or recurrent pulmonary hypertension following PEA. Balloon pulmonary angioplasty (BPA) is a new procedure, but it is a promising alternative to PEA, especially in patients with inoperable CTEPH. This review summarizes the history, indications, procedures and complications of BPA. Finally, we discuss the future perspective of BPA for better management of CTEPH.

Objectives The aims of this study were to (1) evaluate risk factors of complications of balloon pulmonary angioplasty (BPA) and (2) assess the mechanism of the complications. Background BPA represents a promising treatment option in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the complication ratio differs across reports, and the causes remain controversial. Methods All complications found by angiography and non-contrasted computerized tomography (CT) immediately after BPA were recorded. New emergences of a ground-glass pattern or consolidation in CT after BPA that were not recognized on CT images before BPA were counted as pulmonary bleeding. Lesion morphologies were classified into four types (web, ring, abrupt narrowing and occlusive lesions) according to selective pulmonary angiography. Results Thirty patients consented to analysis of the BPA-related images, and 879 lesions (112 sessions) were evaluated. One hundred and twenty-two (99.2%) of 123 complications were confirmed to be associated with BPA procedures at the local area. In the multivariate analysis, occlusive lesions were the sole independent predictor of procedure-related complications (adjusted odds ratio 5.83, 95%CI [1.94-17.47], p = 0.002). Hemodynamic parameters were not predictors of complications. CT images after BPA presented the predictive value for the occurrence of hemoptysis. Conclusions Almost all complications were attributed to operators' procedures. Lesion morphology was the sole predictor of BPA-related complications, while hemodynamic parameters were not associated with the frequency of complications. CT scan images after BPA were useful to identify bleeding complications and to predict hemoptysis.