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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 <0.001). There was no patient with 30-day mortality with an sPESI score of 0. Independent factors for home treatment among out-of-hospital pulmonary embolism patients with an sPESI score of 0 were no transient risk factors for venous thromboembolism, no cardiac biomarker elevation, and direct oral anticoagulants use in the acute phase., Conclusions: The 30-day mortality rate was notably low in an sPESI score of 0. Nevertheless, only a minority of patients with an sPESI score of 0 were treated at home between 2015 and 2020 after the introduction of direct oral anticoagulants for venous thromboembolismin Japan.

Background: There is no established risk score for anticoagulant-related bleeding during the acute phase in patients with pulmonary embolism (PE). The PE-Syncope, Anemia, and Renal Dysfunction (PE-SARD) bleeding score was developed to predict early major bleeding but has not yet been fully externally validated., Objectives: To externally validate the PE-SARD bleeding score., Methods: Using the COntemporary ManageMent AND outcomes in patients with Venous ThromboEmbolism (COMMAND VTE) Registry-2 database, which enrolled 5197 consecutive acute symptomatic venous thromboembolism patients among 31 centers in Japan between January 2015 and August 2020, we identified acute PE patients. We divided them into 3 groups by the score: high-risk (>2.5 points), intermediate-risk (1-2.5 points), and low-risk (0 points). The discriminating and calibration performances of the score for 30-day major bleeding were assessed. Subgroup analyses based on active cancer were also performed., Results: Of 2781 eligible patients, the high-risk group accounted for 557 patients (20%), intermediate-risk group for 1412 (51%), and low-risk group for 812 (29%). Major bleeding occurred in 121 patients within 30 days. The cumulative 30-day incidence of major bleeding substantially increased in the higher risk categories by the score (high-risk group, 8.2% [95% CI, 5.9%-10.5%]; intermediate-risk group, 4.6% [95% CI, 3.5%-5.7%]; and low-risk group, 1.8% [95% CI, 0.8%-2.7%]). The discriminating power of the score was modest with a C statistic of 0.65 (95% CI, 0.61-0.70), with a good calibration performance with a score of <4 points, except for that in active cancer patients., Conclusion: The PE-SARD bleeding score had a modest discriminating performance with a limited calibration performance in acute PE patients without active cancer., Competing Interests: Declaration of competing interests Y.N. received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo. Y.Y. received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. T.M. reports lecturer’s fees from Bristol Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol Myers Squibb and Kowa; advisory board for Sanofi. K. Kaneda received lecture fees from Bristol Myers Squibb, Pfizer, and Daiichi Sankyo. N.I. received lecture fees from Bayer Healthcare, Bristol Myers Squibb, and Daiichi Sankyo. S.I. received lecture fees from Bayer Healthcare, Bristol Myers Squibb, and Daiichi Sankyo. Y.O. received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Bayer Healthcare and Daiichi Sankyo. N.K. received lecture fees from Bayer Healthcare and grant support from Pfizer. All other authors declare that they have no conflict of interest., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: There is a scarcity of data evaluating the effect of peripheral artery disease (PAD) on long-term mortality after percutaneous coronary intervention (PCI) relative to coronary artery bypass grafting (CABG) in patients with severe coronary artery disease in real-world practice., Methods: Among 14,867 consecutive patients who underwent their first coronary revascularization with PCI or isolated CABG between 2011 and 2013 in the CREDO-Kyoto PCI/CABG registry Cohort-3, the current study population consisted of 3380 patients with three-vessel coronary artery disease or left main coronary artery disease. Long-term clinical outcomes were compared between PCI and CABG stratified by the presence or absence of PAD. Median clinical follow-up was 5.9 (IQR: 5.1-6.8) years., Results: There were 461 patients with PAD (PCI: N = 307, CABG: N = 154), and 2919 patients without PAD (PCI: N = 1823, CABG: N = 1096). The cumulative 5-year mortality after coronary revascularization was 31.2 % in patients with PAD and 16.2 % in those without PAD (p < 0.0001). There was a higher risk of PCI relative to CABG for all-cause death in patients with and without PAD (adjusted HR, 1.59; 95%CI, 0.99-2.53; p = 0.054, and HR, 1.25; 95%CI, 1.01-1.56; p = 0.04) without interaction (p interaction p = 0.48); Nevertheless, there was no excess risk of PCI relative to CABG for cardiovascular death regardless of PAD., Conclusions: The long-term mortality after coronary revascularization was significantly higher in severe CAD patients with PAD than those without PAD. There was a higher mortality risk of PCI relative to CABG in patients with and without PAD without interaction, which was mainly driven by excess non-cardiovascular deaths., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The impact of very low baseline levels of low-density lipoprotein cholesterol (LDL-C) on patients with coronary artery disease remains unclear., Method: We enrolled 39,439 patients of the pooled population from the CREDO-Kyoto registries Cohorts 1, 2, and 3. The study population consisted of 33,133 patients who had undergone their first coronary revascularization. We assessed the risk for mortality and cardiovascular events according to quintiles of the baseline LDL-C levels., Results: Patients in the very low LDL-C quintile (<85 mg/dL) had more comorbidities than those in the other quintiles. Lower LDL-C levels were strongly associated with anemia, thrombocytopenia, and end-stage renal disease. The cumulative 4-year incidence of all-cause death increased as LDL-C levels decreased (very low: 19.4 %, low: 14.5 %, intermediate: 11.1 %, high: 10.0 %, and very high: 9.2 %; p < 0.001), which was driven by both the early and late events. After adjusting for baseline characteristics, the adjusted risks of the very low and low LDL-C quintiles relative to the intermediate LDL-C quintile remained significant for all-cause death (very low: HR 1.29, 95 % CI 1.16-1.44, p < 0.001; low: HR 1.15, 95 % CI 1.03-1.29, p = 0.01). The excess adjusted risks of the lowest LDL-C quintile relative to the intermediate LDL-C quintile were significant for clinical outcomes such as cardiovascular death (HR 1.17, 95 % CI 1.01-1.35), non-cardiovascular death (HR 1.35, 95 % CI 1.15-1.60), sudden death (HR 1.44, 95 % CI 1.01-2.06), and heart failure admission (HR 1.11 95 % CI 1.01-1.22), while there was no excess risk for the lowest LDL-C quintile relative to the intermediate LDL-C quintile for myocardial infarction and stroke., Conclusions: Lower baseline LDL-C levels were associated with more comorbidities and a significantly higher risk of death, regardless of cardiovascular or non-cardiovascular causes, in patients who underwent coronary revascularization., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) have become widely used for cancer-associated venous thromboembolism (VTE). However, DOAC-associated bleeding complications remain challenging, especially in patients with gastrointestinal (GI) cancer. This study aimed to compare the bleeding outcomes between patients with upper or lower GI cancers and those without GI cancer., Methods: Using the COMMAND VTE Registry-2 database, which is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020, we identified 1149 active cancer patients with DOACs (upper GI cancer: N = 88; lower GI cancer: N = 114; non-GI cancer: N = 947). The primary outcome was major bleeding during anticoagulation therapy, which was evaluated in the competing risk regression model., Results: The upper GI cancer group had a lower mean body weight, and most often had anemia. The cumulative 5-year incidence of major bleeding was higher in the upper GI cancer group (upper GI cancer: 22.4 %, lower GI cancer: 15.4 %, and non-GI cancer: 11.6 %, P = 0.015). The most frequent major bleeding site in the upper GI cancer group was the upper GI (53 %), followed by the lower GI (24 %). After adjusting for the confounders, the excess risk in upper GI cancer relative to non-GI cancer remained significant for major bleeding (adjusted subhazard ratio, 2.25; 95 %CI, 1.31-3.87, P = 0.003), but that in lower GI cancer was insignificant., Conclusions: Upper GI cancer, but not lower GI cancer, as compared to non-GI cancer was associated with a higher risk for major bleeding during anticoagulation therapy with DOACs., Clinical Trial Registration: URL: http://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000044816., Competing Interests: Declaration of competing interest Dr. Nishimoto received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. Dr. Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Morimoto reports lecturer's fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; advisory board for Sanofi. Dr. Kaneda received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. Dr. Ikeda N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi Sankyo. Dr. Ikeda S. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb and Daiichi Sankyo. All other authors declare that they have no conflict of interest., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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 <0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in Registry 2 than in Registry 1 (10.5% versus 9.5%, P =0.02), and the risk reduction of recurrent VTE in Registry 2 remained significant even after adjusting the confounders (hazard ratio [HR], 0.78 [95% CI, 0.65-0.93]; P =0.005). The cumulative 5-year incidence of major bleeding was not significantly different between the 2 registries (12.1% versus 13.7%, P =0.26), and the risk of major bleeding between the 2 registries was not significantly different even after adjusting the confounders (HR, 1.04 [95% CI, 0.89-1.21]; P =0.63)., Conclusions: Along with the shift from warfarin to DOACs, there was a lower risk of recurrent VTE in the DOAC era than in the warfarin era, whereas there was no apparent change in the risk of major bleeding, which might still be an unmet need even in the DOAC era.

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patients with unprovoked venous thromboembolisms (VTEs) can be sub-classified based on the different phenotypes using a latent class analysis (LCA), which might be useful for selecting individual management strategies., Methods: In the COMMAND VTE Registry-2 database enrolling 5197 VTE patients, the current derivation cohort consisted of 1556 patients with unprovoked VTEs. We conducted clustering with an LCA, and the patients were classified into subgroups with the highest probability. We compared the clinical characteristics and outcomes among the developed subgroups., Results: This LCA model proposed 3 subgroups based on 8 clinically relevant variables, and classified 592, 813, and 151 patients as Class I, II, and III, respectively. Based on the clinical features, we named Class I the younger, Class II the older with a few comorbidities, and Class III the older with many comorbidities. The cumulative 3-year anticoagulation discontinuation rate was highest in the older with many comorbidities (Class III) (39.9 %, 36.1 %, and 48.4 %, P = 0.02). There was no significant difference in the cumulative 5-year incidence of recurrent VTEs among the 3 classes (12.8 %, 11.1 %, and 4.0 % P = 0.20), whereas the cumulative 5-year incidence of major bleeding was significantly higher in the older with many comorbidities (Class III) (7.8 %, 12.7 %, and 17.8 %, P = 0.04)., Conclusion: The current LCA revealed that patients with unprovoked VTEs could be sub-classified into further phenotypes depending on the patient characteristics. Each subclass phenotype could have different clinical outcomes risks especially a bleeding risk, which could have a potential benefit when considering the individual anticoagulation strategies., Clinical Trial Registration: URL: http://www.umin.ac.jp/ctr/index.htm COMMAND VTE Registry-2: Unique identifier, UMIN000044816 COMMAND VTE Registry: Unique identifier, UMIN000021132., Competing Interests: Declaration of competing interest Dr. Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and grant support from Bayer Healthcare and Daiichi-Sankyo. Dr. Morimoto reports lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb, and Kowa, and the advisory board for Sanofi. Dr. Kaneda received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Dr. Nishimoto received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Dr. Ikeda N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Dr. Ikeda S. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Dr. Ogihara received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and research funds from Bayer Healthcare and Daiichi-Sankyo. Dr. Koitabashi received lecture fees from Bayer Healthcare and grant support from Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background:  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., Methods:  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., Results:  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., Conclusion:  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., Competing Interests: Y.Y. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and grant support from Bayer Healthcare and Daiichi-Sankyo. T.M. reports lecturer's fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; advisory board for Sanofi. Y.N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. K.K. received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. N.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. S.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Y.O. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and research funds from Bayer Healthcare and Daiichi-Sankyo. K.T. received significant research grant from AMI Co., Ltd., Bayer Yakuhin, Ltd., Bristol-Myers K.K., EA Pharma Co., Ltd., MOCHIDA PHARMACEUTICAL CO., LTD., and scholarship fund from AMI Co., Ltd., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Edwards Lifesciences Corporation, Johnson & Johnson K.K., ONO PHARMACEUTICAL CO., LTD., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and honoraria from Amgen K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and belongs to the endowed departments donated by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., NIPRO CORPORATION, TERUMO Co, Ltd., Abbott Medical Co., Ltd., Cardinal Health Japan, Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Medical Appliance Co., Ltd., Medtronic Japan Co., Ltd. All other authors have reported that they have no relationships relevant to the contents of this article to disclose., (Thieme. All rights reserved.)

Background: Polypharmacy was reported to be associated with major bleeding in various populations. However, there are no data on polypharmacy and its association with bleeding in patients undergoing percutaneous coronary intervention (PCI)., Methods and results: Among 12,291 patients in the CREDO-Kyoto PCI Registry Cohort-3, we evaluated the number of medications at discharge and compared major bleeding, defined as Bleeding Academic Research Consortium Type 3 or 5 bleeding, across tertiles (T1-3) of the number of medications. The median number of medications was 6, and 88.0% of patients were on ≥5 medications. The cumulative 5-year incidence of major bleeding increased incrementally with increasing number of medications (T1 [≤5 medications] 12.5%, T2 [6-7] 16.5%, and T3 [≥8] 20.4%; log-rank P<0.001). After adjusting for confounders, the risks for major bleeding of T2 (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.08-1.36; P=0.001) and T3 (HR 1.27; 95% CI 1.12-1.45; P<0.001) relative to T1 remained significant. The adjusted risks of T2 and T3 relative to T1 were not significant for a composite of myocardial infarction or ischemic stroke (HR 0.95 [95% CI 0.83-1.09; P=0.47] and HR 1.06 [95% CI 0.91-1.23; P=0.48], respectively)., Conclusions: In a real-world population of patients undergoing PCI, approximately 90% were on ≥5 medications. Increasing number of medications was associated with a higher adjusted risk for major bleeding, but not ischemic events.

Background: Recent large clinical trials have revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes not only in patients with heart failure with reduced ejection fraction, but also in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). However, the effect of SGLT2 inhibitors on left ventricular (LV) diastolic function is still controversial., Methods and Results: The TOP-HFPEF trial (Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus) is a multicenter, double-arm, open-label, confirmatory, investigator-initiated clinical study to investigate the effect of SGLT2 inhibitor on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus. The participants are randomly assigned (1:1) to the tofogliflozin group (20 mg once daily) or the control group (administration or continuation of antidiabetic drugs other than SGLT2 inhibitors). The estimated number of patients to be enrolled in this trial is 90 in total (45 in each group). The participants are followed up for 52 weeks with tofogliflozin or control drugs. The primary endpoint is the change in E/e' assessed by echocardiography from the baseline to the end of this study (52 weeks). This trial will also evaluate the effects of tofogliflozin on cardiovascular events, biomarkers, other echocardiographic parameters, the occurrence of atrial fibrillation, and renal function., Conclusions: The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Data on concomitant mitral regurgitation (MR) in patients with severe aortic stenosis (AS) are scarce.Methods and Results: We investigated the risk of concomitant MR in patients with severe AS in the CURRENT AS Registry-2 according to initial treatment strategy (transcatheter aortic valve implantation [TAVI], surgical aortic valve replacement [SAVR], or conservative). Among 3,365 patients with severe AS, 384 (11.4%) had moderate/severe MR (TAVI: n=126/1,148; SAVR: n=68/591; conservative: n=190/1,626). The cumulative 3-year incidence for death or heart failure (HF) hospitalization was significantly higher in the moderate/severe than no/mild MR group in the entire population (54.6% vs. 34.3%, respectively; P<0.001) and for each treatment strategy (TAVI: 45.0% vs. 31.8% [P=0.006]; SAVR: 31.9% vs. 18.7% [P<0.001]; conservative: 67.8% vs. 41.6% [P<0.001]). The higher adjusted risk of moderate/severe MR relative to no/mild MR for death or HF hospitalization was not significant in the entire population (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.95-1.39; P=0.15); however, the risk was significant in the SAVR (HR 1.92; 95% CI 1.04-3.56; P=0.04) and conservative (HR 1.30; 95% CI 1.02-1.67; P=0.04) groups, but not in the TAVI group (HR 1.03; 95% CI 0.70-1.52; P=0.86), despite no significant interaction (P interaction =0.37)., Conclusions: Moderate/severe MR was associated with a higher risk for death or HF hospitalization in the initial SAVR and conservative strategies, while the association was less pronounced in the initial TAVI strategy.

Background: There have been still limited data on the transition of management strategies and clinical outcomes after introduction of direct oral anticoagulant (DOAC) for cancer-associated venous thromboembolism (VTE) in the real-world clinical practice., Methods: Using the 2 series of multicenter COMMAND VTE registries in Japan enrolling consecutive patients with acute symptomatic VTE, we compared 695 patients with cancer-associated VTE in the Registry-1 of the warfarin era and 1507 patients in the Registry-2 of the DOAC era., Results: Regarding oral anticoagulation therapy, 576 patients (82.9 %) in the Registry-1 received warfarin, whereas 1119 patients (79.6 %) in the Registry-2 received DOACs. The cumulative 3-year incidence of discontinuation of anticoagulation was not significantly different between the 2 registries (56.7 % vs. 62.7 %, P = 0.11). The cumulative 5-year incidence of recurrent VTE was significantly lower in the Registry-2 than in the Registry-1 (17.7 % vs. 10.1 %, P < 0.001). The cumulative 5-year incidence of major bleeding was significantly lower in the Registry-2 than in the Registry-1 (26.6 % vs. 20.4 %, P = 0.045). The proportion of gastrointestinal bleeding numerically increased from the Registry-1 to the Registry-2 (46.7 % and 49.5 %), whereas that of intracranial bleeding numerically decreased from the Registry-1 to the Registry-2 (17.1 % and 14.1 %)., Conclusions: In the current historical comparison of cancer-associated VTE between the 2 large real-world registries, there was a striking change in the treatment strategies with decreased risks of recurrent VTE and major bleeding in the DOAC era compared with those in the warfarin era, while there seemed to be unmet needs of DOAC-related gastrointestinal bleeding., Clinical Trial Registration: URL: http://www.umin.ac.jp/ctr/index.htm UNIQUE IDENTIFIER: UMIN000044816., Competing Interests: Declaration of competing interest Dr. Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo and grant support from Bayer Healthcare and Daiichi-Sankyo. Dr. Morimoto reports lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; advisory board for Sanofi. Dr. Kaneda received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Dr. Nishimoto received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Dr. Ikeda N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Dr. Ikeda S. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb and Daiichi-Sankyo. All other authors report that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Introduction: There is limited data on the safety of direct oral anticoagulants (DOACs) in fragile patients with venous thromboembolism (VTE)., Materials and Methods: We used the COMMAND VTE Registry-2 enrolling patients with acute symptomatic VTE. The study population consisted of 3928 patients receiving DOACs, who were divided into fragile (2136 patients) and non-fragile groups (1792 patients). Fragility was defined as patients of age ≥ 75 years, creatinine clearance level ≤ 50 ml/min, and/or body weight ≤ 50 kg., Results: The fragile group significantly more often received reduced doses of DOACs compared to the non-fragile group (51 % and 19 %, P < 0.001). The cumulative 5-year incidence of major bleeding was numerically higher in the fragile group than the non-fragile group (15.0 % and 11.1 %, P = 0.052), even with no significant excess risk after adjusting for confounders (HR 1.03, 95%CI 0.81-1.31, P = 0.78). The cumulative 5-year incidence of clinically relevant bleeding was significantly higher in the fragile group than the non-fragile group (28.6 % and 19.6 %, P < 0.001), even after adjusting for confounders (HR 1.28, 95%CI 1.08-1.53, P = 0.005). There was no significant difference in cumulative 5-year incidence of recurrent VTE between the groups (9.6 % and 8.9 %, P = 0.68), which was consistent after adjusting for confounders (HR 1.13, 95%CI 0.84-1.51, P = 0.41)., Conclusions: Among VTE patients receiving DOACs, fragile patients were associated with a numerically higher rate of major bleeding and a significantly increased risk of clinically relevant bleeding, but not an increased risk of recurrent VTE., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshito Ogihara reports a relationship with Bayer Healthcare that includes: funding grants and speaking and lecture fees. Yoshito Ogihara reports a relationship with Daiichi Sankyo Co Ltd. that includes: funding grants and speaking and lecture fees. Yoshito Ogihara reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Yoshito Ogihara reports a relationship with Pfizer that includes: speaking and lecture fees. Yugo Yamashita reports a relationship with Bayer Healthcare that includes: funding grants and speaking and lecture fees. Yugo Yamashita reports a relationship with Daiichi-Sankyo that includes: funding grants and speaking and lecture fees. Yugo Yamashita reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Yugo Yamashita reports a relationship with Pfizer that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Bristol-Myers Squibb that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Daiichi Sankyo that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Japan Lifeline that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Kowa that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Kyocera that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Novartis that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Toray that includes: speaking and lecture fees. Takeshi Morimoto reports a relationship with Sanofi that includes: consulting or advisory. Kazuhisa Kaneda reports a relationship with Bristol-Myers Squibb that includes: speaking and lecture fees. Kazuhisa Kaneda reports a relationship with Pfizer that includes: speaking and lecture fees. Kazuhisa Kaneda reports a relationship with Daiichi-Sankyo that includes: speaking and lecture fees. Yuji Nishimoto reports a relationship with Bayer Healthcare that includes: speaking and lecture fees. Yuji Nishimoto reports a relationship with Bristol-Myers Squibb that includes: speaking and lecture fees. Yuji Nishimoto reports a relationship with Pfizer that includes: speaking and lecture fees. Yuji Nishimoto reports a relationship with Daiichi-Sankyo that includes: speaking and lecture fees. Nobutaka Ikeda reports a relationship with Bayer Healthcare that includes: speaking and lecture fees. Nobutaka Ikeda reports a relationship with Bristol-Myers Squibb that includes: speaking and lecture fees. Nobutaka Ikeda reports a relationship with Daiichi-Sankyo that includes: speaking and lecture fees. Satoshi Ikeda reports a relationship with Bayer Healthcare that includes: speaking and lecture fees. Satoshi Ikeda reports a relationship with Bristol-Myers Squibb that includes: speaking and lecture fees. Satoshi Ikeda reports a relationship with Daiichi-Sankyo that includes: speaking and lecture fees. Norimichi Koitabashi reports a relationship with Bayer Healthcare that includes: speaking and lecture fees. Norimichi Koitabashi reports a relationship with Pfizer that includes: funding grants. Kaoru Dohi reports a relationship with Bayer Healthcare that includes: speaking and lecture fees. Kaoru Dohi reports a relationship with Bristol-Myers Squibb that includes: speaking and lecture fees. Kaoru Dohi reports a relationship with Pfizer that includes: speaking and lecture fees. Kaoru Dohi reports a relationship with Daiichi Sankyo that includes: funding grants and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There 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., Objectives: To investigate the status of cancer-associated VTE in the DOAC era., Methods: This 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., Results: The 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)., Conclusions: The 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., Competing Interests: Declaration of competing interest Dr. Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo and grant support from Bayer Healthcare and Daiichi-Sankyo. Dr. Morimoto reports lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray and manuscript fees from Bristol-Myers Squibb and Kowa; he was on the advisory board for Sanofi. Dr. Kaneda received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Dr. Nishimoto received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Dr. Ikeda N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Dr. Ikeda S. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb and Daiichi-Sankyo. Dr. Ogihara received research funding from Bayer Healthcare. Dr. Koitabashi received lecture fees from Bayer Healthcare and grant support from Pfizer. All other authors reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There were no data comparing the in-hospital outcomes after transcatheter aortic valve implantation (TAVI) with those after surgical aortic valve replacement (SAVR) in Japan. Among consecutive patients with severe AS between April 2018 and December 2020 in the CURRENT AS Registry-2, we identified 1714 patients who underwent aortic valve replacement (TAVI group: 1134 patients, and SAVR group: 580 patients). Patients in the TAVI group were much older (84.4 versus 73.6 years, P < 0.001) and more often had comorbidities than those in the SAVR group. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group (0.6% versus 2.2%). After excluding patients with dialysis, in-hospital death rate was very low and comparable in the TAVI and SAVR groups (0.6% versus 0.8%). The rates of major bleeding and new-onset atrial fibrillation during index hospitalization were higher after SAVR than after TAVI (72% versus 20%, and 26% versus 4.6%, respectively), while the rate of pacemaker implantation was higher after TAVI than after SAVR (8.1% versus 2.4%). Regarding the echocardiographic data at discharge, the prevalence of patient-prosthesis mismatch was lower in the TAVI group than in the SAVR group (moderate: 9.0% versus 26%, and severe: 2.6% versus 4.8%). In this real-world data in Japan, TAVI compared with SAVR was chosen in much older patients with more comorbidities with severe AS. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group., (© 2023. The Author(s).)