Takuma Takada

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most serious long‐term complication of acute pulmonary embolism (PE). Balloon pulmonary angioplasty (BPA) has been an effective treatment for improving the prognosis of CTEPH patients. Aims: This study aimed to evaluate the impact of BPA at each institution on the rate of CTEPH diagnosis based on the observations suggesting that the emergence of effective treatments could draw attention to targeted diseases. Methods: The COMMAND VTE Registry‐2 is a multicenter, retrospective cohort study of 5197 patients diagnosed with venous thromboembolism (VTE) at 31 medical centers in Japan. The study included 2787 patients with acute PE, who were divided into the BPA‐capable facility group (BPA centers) and the non‐BPA‐capable facility group (non‐BPA centers). We investigated the difference in the rate of CTEPH diagnosis after acute PE between the two groups. Results: Among patients with acute PE, 723 patients (25.9%) and 2064 patients (74.1%) were diagnosed at BPA centers and non‐BPA centers, respectively. There were 48 patients who were diagnosed with CTEPH, with a median follow‐up period of 747 days. The cumulative 3‐year incidence of CTEPH diagnosis was 5.0% in the BPA centers and 1.4% in the non‐BPA centers (crude hazard ratio [HR]: 3.80; 95% CI: 2.15–6.72; p < 0.001). Conclusion: The cumulative 3‐year incidence of CTEPH diagnosis after acute PE was significantly greater in BPA centers than in non‐BPA centers, which suggests the importance of appropriate awareness of CTEPH and BPA.

Aims: Doxorubicin (Dox) is an effective chemotherapeutic agent, but its clinical use is limited by cardiotoxicity. Cellular senescence contributes to Dox-induced cardiac dysfunction; however, the underlying molecular mechanism mediating the effect of senescence remains poorly understood. This study aimed to identify senescence-associated factors secreted from cardiomyocytes in Dox-treated hearts and define their functional significance in Dox-induced cardiotoxicity. Methods: Mice with cardiomyocyte-specific expression of the endoplasmic reticulum BioID secretome profiling system were used to identify Dox-induced secreted factors. Functional analyses were performed in neonatal rat ventricular myocytes (NRVMs). The effects of plasminogen activator inhibitor-1 (PAI-1) inhibition were evaluated in Dox-treated mice by assessing senescence markers, apoptotic responses, and cardiac structure and function. p21High-tdTomato reporter mice were used to examine the fate of senescent cardiomyocytes in vivo. Results: PAI-1 was identified as a major component of the senescence-associated secretory phenotype and was robustly upregulated in Dox-treated cardiomyocytes. In NRVMs, PAI-1 promoted senescence and maintained the senescent phenotype, in part by conferring resistance to apoptosis. Pharmacological inhibition of PAI-1 reduced senescence markers, enhanced apoptotic responses, and preserved cardiac structure and function in Dox-treated mice. Fate mapping analyses with p21High-tdTomato mice revealed that PAI-1 inhibition decreased the number of p21High senescent cardiomyocytes in Dox-treated hearts. Notably, PAI-1 inhibition did not attenuate Dox cytotoxicity in EO771 murine breast cancer cells. Conclusion: PAI-1 is a key mediator of Dox-induced cardiac dysfunction. PAI-1 inhibition shifts the fate of cardiomyocytes from senescence toward apoptosis and preserves cardiac structure and function without compromising the antitumor function of Dox, highlighting PAI-1 as a potential therapeutic target for chemotherapy-associated cardiotoxicity.

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.

Objective: Renin-angiotensin-aldosterone system inhibitors (RAASi) and beta-blockers decrease cardiovascular (CV) mortality in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) as the dose increases. Mineralocorticoid receptor antagonists (MRA) can also minimize CV mortality. This study aimed to investigate the potential of early administration of additional MRA to insufficient doses of RAASi and beta-blockers. Methods: Among 609 hospitalized patients with HFrEF, we analyzed 401 patients who received either or both <50% target dose of RAASi and beta-blockers at discharge. They were divided into two groups based on the prescription of MRA: MRA (n = 287) and non-MRA (n = 114). We performed propensity score (PS) matching using diverse parameters at discharge.CV death was the primary endpoint. Results: Among 401 unmatched patients with HFrEF, Kaplan–Meier analysis for the unmatched population did not show a statistical difference between the MRA and non-MRA groups (log-rank, p = 0.34). However, in the 160 PS-matched population, patients in the MRA group had a significantly lower CV mortality rate than those in the non-MRA group (hazard ratio: 0.29 [95% confidence interval: 0.10–0.79]). Conclusions: Early administration of additional MRA in patients with HFrEF, even those who received insufficient target doses of RAASi and beta-blockers, may be a therapeutic option.

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 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 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.

The ONCO DVT study revealed the superiority of 12-month relative to 3-month edoxaban treatment for cancer-associated isolated distal deep vein thrombosis (DVT) regarding the thrombotic risk. In this pre-specified subgroup analysis of the ONCO DVT study, we stratified the patients into those with a standard edoxaban dose (60 mg/day; N = 151) and those with a reduced edoxaban dose (30 mg/day; N = 450) and evaluated the clinical outcomes for the 12- and 3-month treatments. The cumulative 12-month incidence of symptomatic recurrent venous thromboembolism was lower in the 12-month than 3-month group for both the 60 mg (1.3% vs. 11.6%, P = 0.02; odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01–0.97) and 30 mg (1.1% vs. 7.6%, P = 0.002; OR, 0.14; 95% CI, 0.03–0.60) edoxaban subgroups, which was consistent across the edoxaban doses without a significant interaction (P = 0.90). The 12-month cumulative incidence of major bleeding was higher in the 12-month group than in the 3-month group for the 60 mg edoxaban subgroup (14.3% vs. 4.4%, P = 0.046; OR, 3.61; 95% CI, 0.97–13.52), whereas it did not significantly differ between the two groups for the 30 mg edoxaban subgroup (8.7% vs. 8.6%, P = 0.89; OR, 0.97; 95% CI, 0.49–1.91), signalling there was a potential interaction (P = 0.07). A 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However, caution was suggested for the standard dose of edoxaban due to the potential for an increased risk of bleeding with prolonged anticoagulation therapy. NCT03895502 (ONCO DVT Trial): https://classic.clinicaltrials.gov/ct2/show/NCT03895502