Background: Extracorporeal cardiopulmonary resuscitation (ECPR), an emerging resuscitative therapy following refractory cardiac arrests, is associated with hemorrhagic complications that potentially affect patient outcomes. Objectives: This study evaluated the risks and predictors of hemorrhagic complications among patients who underwent ECPR for out-of-hospital cardiac arrest (OHCA) from different causes. Methods: Using the SAVE-J II (Study of Advanced Cardiac Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan) study, we analyzed multicentric data of patients who underwent ECPR for OHCA from 2013 to 2018 in Japan. Based on the causes of OHCA, the participants were stratified into endogenous cardiac, endogenous noncardiac, and exogenous groups. The primary outcome was any bleeding. Results: Among 1,935 patients, 1,417, 305, and 213 patients had endogenous cardiac, endogenous noncardiac, and exogenous causes, respectively. For survivors, the median follow-up period was 36 days, and most of the bleeding events occurred within 1 week post-ECPR. The 30-day cumulative incidence of any bleeding significantly differed among the 3 groups (endogenous cardiac: n = 321 [25.9%]; endogenous noncardiac: n = 41 [18.9%]; and exogenous: n = 27 [13.7%]; P < 0.001). However, the risks for bleeding complications did not differ between the causes of OHCA after adjustment for confounders. Intra-aortic balloon pumping use was associated with higher risks of bleedings and lower risk for all-cause death. Conclusions: Underlying causes of OHCA did not significantly impact adjusted bleeding risks. Intra-aortic balloon pumping use was independently associated with higher bleeding risks and lower mortality, although this warrants cautious interpretation because of a potential selection bias. Vigilant monitoring for bleeding complications is crucial in ECPR patients, especially in those with additional circulatory support devices.

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.

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 <12g/dL for women and <13g/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.

Background: Previous randomized clinical trials did not support a benefit of screening for occult cancer after diagnosis of venous thromboembolism (VTE), although screening may be of potential benefit for selected high-risk patients. Methods and Results: The COMMAND VTE Registry-2 enrolled consecutive patients with acute symptomatic VTE between 2015 and 2020 from 31 centers across Japan. The 3,706 patients in the registry without known active cancer at the time of VTE diagnosis were divided into 2 groups: those with (n=250) and without (n=3,456) newly diagnosed cancer during the follow-up period. The cumulative incidence of newly diagnosed cancer was 1.5% at 30 days, 3.7% at 1 year, and 7.0% at 3 years. The multivariable Cox proportional hazard model demonstrated that older age (hazard ratio [HR] 1.02 per 1 year increase; 95% confidence interval [CI] 1.01-1.03; P<0.001), a history of cancer (HR 3.57; 95% CI 2.73-4.64; P<0.001), autoimmune disorders (HR 1.48; 95% CI 1.06-2.02; P=0.02), a history of major bleeding (HR 1.64; 95% CI 1.04-2.48; P=0.04), and the absence of transient provoking risk factors for VTE (HR 1.44; 95% CI 1.08-1.92; P=0.01) were independently associated with newly diagnosed cancer. Conclusions: The incidence of newly diagnosed cancer after VTE diagnosis was 3.7% at 1 year, and several independent risk factors for newly diagnosed cancer after VTE diagnosis were identified.

BACKGROUND:Right ventricular (RV) function is a key determinant of outcomes after transcatheter tricuspid interventions. The pulmonary artery pulsatility index (PAPI), an invasive hemodynamic index reflecting RV interaction with filling pressures and pulmonary circulation, has prognostic value in several cardiovascular conditions. However, its role in transcatheter tricuspid valve replacement (TTVR) remains unknown. OBJECTIVES:The aim of this study was to investigate the prognostic implications of PAPI in patients undergoing TTVR. METHODS:Patients with severe tricuspid regurgitation undergoing orthotopic TTVR with available preprocedural right heart catheterization data were retrospectively analyzed. The primary endpoint was a composite of all-cause mortality and heart failure hospitalization at 2-year follow-up. Patients were stratified according to an optimal PAPI cutoff derived from maximally selected rank statistics on the basis of the log-rank test. RESULTS:Among 94 patients (median age 78 years [Q1-Q3: 72-82 years], 59% women), 28 (30%) had low PAPI (≤1.13). The median duration of follow-up was 491 days (Q1-Q3: 227-879 days). Kaplan-Meier estimates of survival free from the composite endpoint, all-cause mortality, and heart failure hospitalization were 29.2% (95% CI: 13.6%-62.5%), 52.6% (95% CI: 30.2%-91.7%), and 49.1% (95% CI: 28.4%-85.1%) in the low PAPI group vs 70.0% (95% CI: 58.6%-83.5%), 87.6% (95% CI: 79.2%-96.9%), and 76.6% (95% CI: 65.4%-89.6%) in the high PAPI group (log-rank P < 0.001, log-rank P = 0.006, and log-rank P = 0.017, respectively). On multivariable Cox regression analysis with Firth's penalized likelihood, PAPI ≤1.13 was independently associated with the primary endpoint (HR: 2.50; 95% CI: 1.18-5.27; P = 0.018), irrespective of RV longitudinal function and age. CONCLUSIONS:In patients undergoing TTVR, low preprocedural PAPI identifies a high-risk phenotype, and it is independently associated with adverse outcomes. PAPI may represent a simple and valuable tool for risk stratification in TTVR patients.

The ONCO DVT study demonstrated the benefit of extended anticoagulation therapy with edoxaban in patients with cancer-associated isolated distal deep vein thrombosis (DVT). However, it remains unclear whether these results can be applied regardless of the number of thrombosed venous segments. In this post-hoc subgroup analysis of the ONCO DVT study, 601 patients were stratified into the single-site (N=268) and multiple-sites (N=333) DVT subgroups based on the number of thrombosed venous segments at diagnosis. We compared 12-month and 3-month edoxaban treatment groups in each subgroup for the primary endpoint of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death and the major secondary endpoint of major bleeding at 12 months. The cumulative 12-month incidence of the primary endpoint was significantly lower in the 12-month edoxaban group than in the 3-month edoxaban group both in the single-site (0.8

Background:The impact of coexisting malnutrition and sarcopenia on survival after transcatheter aortic valve replacement (TAVR) has not been fully studied. Methods and Results:Among 513 consecutive patients undergoing TAVR between February 2014 and June 2023, 340 with available preoperative Geriatric after Nutritional Risk Index (GNRI) and Short Physical Performance Battery (SPPB) data were categorized into 4 groups based on malnutrition (GNRI <98) and sarcopenia (SPPB ≤9) status: malnutrition and sarcopenia (N=98); malnutrition without sarcopenia (N=69); no malnutrition with sarcopenia (N=83); neither malnutrition nor sarcopenia (N=90, reference). The primary outcome measure was all-cause death. Patients with both malnutrition and sarcopenia were older and had a higher prevalence of anemia compared with the reference group. The cumulative 5-year mortality rate was significantly higher in this group. After adjusting for confounders, coexistence of malnutrition and sarcopenia had a significantly higher risk for all-cause death (hazard ratio [HR] 3.15; 95% confidence interval [CI]: 1.68-5.89; P<0.001). In contrast, malnutrition without sarcopenia (HR 1.36; 95% CI 0.64-2.90; P=0.42) and no malnutrition with sarcopenia (HR 1.86; 95% CI 0.92-3.79; P=0.08) were not associated with increased mortality. Conclusions:The coexistence of malnutrition and sarcopenia significantly increased mortality risk after TAVR, which highlights the importance of integrating both nutritional and sarcopenia assessments into preoperative risk stratification to optimize outcomes in patients undergoing TAVR.

Background: Data on the association of weekend vs. weekday diagnosis with clinical outcomes of venous thromboembolism (VTE) in the direct oral anticoagulant (DOAC) era are limited. Methods and Results: The COMMAND VTE Registry-2 is a multicenter registry that enrolled 5,197 consecutive acute symptomatic VTE patients from 31 centers in Japan between January 2015 and August 2020. Baseline characteristics, anticoagulation strategies, and 30-day outcomes were compared between patients diagnosed on weekends (n=537; 10.3%) and those diagnosed on weekdays (n=4,660, 89.7%). Compared with patients diagnosed on weekdays, those diagnosed on weekends more frequently presented with pulmonary embolism (PE; 74.7% vs. 51.2%; P<0.001) and more often received thrombolysis and cardiopulmonary support. The cumulative 30-day incidence of all-cause death in PE patients was significantly higher in patients diagnosed on weekends than in those diagnosed on weekdays (7.5% vs. 4.1%; P=0.003), but the difference was not significant after multivariable adjustment (hazard ratio 1.51; 95% confidence interval [CI] 0.99-2.30; P=0.056). The 30-day risk of major bleeding was significantly higher in weekend PE patients after multivariable adjustment (hazard ratio 1.79; 95% CI 1.11-2.88; P=0.02). Conclusions: VTE patients diagnosed on weekends presented more often with PE and with greater severity. Although the higher crude 30-day mortality in weekend PE patients was attenuated after adjustment, a weekend diagnosis remained associated with higher 30-day major bleeding risk.

Background Patients with cancer-associated venous thromboembolism (VTE) are at a high risk of major bleeding during anticoagulant therapy, emphasizing the need for bleeding risk assessment in the era of direct oral anticoagulants (DOACs). However, few bleeding risk scores have been specifically developed and validated for this population. Objectives The aim of this study was to develop and validate a novel bleeding risk score (ONCO-DOAC BLEED score) for patients with cancer-associated VTE receiving DOAC therapy. Methods We derived the bleeding risk prediction score using 1,166 patients with cancer-associated VTE treated with DOAC therapy from the COMMAND VTE (Contemporary Management and Outcomes in Patients with Venous Thromboembolism) Registry-2 and externally validated its performance in an independent cohort from the ONCO deep vein thrombosis and ONCO pulmonary embolism studies. Results Over a median follow-up of 163 days, 127 patients (10.9%) experienced major bleeding. In multivariable analysis, a history of major bleeding, chronic kidney disease, nonsteroidal anti-inflammatory drug use, distant metastatic cancer, terminal cancer, upper gastrointestinal cancer, pancreatic cancer, and uterine cancer were independently associated with major bleeding. Based on these risk factors, the ONCO-DOAC BLEED score was constructed. This score demonstrated moderate discrimination for major bleeding in the derivation cohort (Harrell's C-index 0.68; Uno's C-index 0.67) and validation cohort (Harrell's C-index 0.62; Uno's C-index 0.63), with higher discrimination in the derivation cohort and comparable performance in the validation cohort compared with the VTE-BLEED, RIETE, CAT-BLEED, and Perform scores. Conclusions The ONCO-DOAC BLEED score provides clinically relevant stratification of major bleeding risk in patients with cancer-associated VTE receiving DOAC therapy and may support individualized therapeutic decision-making in routine practice. (Optimal Duration of Anticoagulation Therapy for Isolated Distal Deep Vein Thrombosis in Patients With Cancer Study [ONCO DVT]; NCT03895502 and Optimal Duration of Anticoagulation Therapy for Low-risk Pulmonary Embolism Patients With Cancer [ONCO PE]; NCT04724460)

BACKGROUND:Low body weight (BW) is reportedly associated with an increased risk of bleeding and mortality in venous thromboembolism (VTE). However, there are limited data on the impact of low BW on clinical outcomes among patients with cancer-associated VTE in the direct oral anticoagulants (DOACs) era. METHODS AND RESULTS:We analyzed 1,484 patients with symptomatic VTE and active cancer from the COMMAND VTE Registry-2, and divided the cohort into low (≤60 kg) and non-low (>60 kg) BW groups (n=969 and 515, respectively). The cumulative 3-year incidence of major bleeding was significantly higher in the low than non-low BW group (13.1% vs. 10.2%; Gray's P=0.04). However, after adjustment, the risk of major bleeding in the low BW was no longer significantly different to that in the non-low BW group (hazard ratio [HR] 1.36; 95% confidence interval [CI] 0.96-1.92). The cumulative 3-year incidence of recurrent VTE did not differ significantly between the low and non-low groups (5.2% vs. 5.4%, respectively; Gray's P=0.46; adjusted HR 0.71; 95% CI 0.42-1.18). The cumulative 3-year incidence of all-cause death was significantly higher in the low than non-low BW group (65.0% vs. 50.8%; log-rank P<0.001; adjusted HR 1.47; 95% CI 1.25-1.73). CONCLUSIONS:Low BW in cancer-associated VTE was not associated with major bleeding or recurrent VTE, but was associated with all-cause death, possibly reflecting cancer-related prognostic factors.

Cancer-associated isolated distal deep vein thrombosis (IDDVT) is a common complication in patients with cancer. The Optimal Duration of Anticoagulation Therapy for Isolated Distal Deep Vein Thrombosis in Patients with Cancer study revealed the superiority of 12- over 3-month edoxaban treatment with respect to thrombotic risk. However, it remains unclear whether D-dimer levels during anticoagulation influence the efficacy of extended anticoagulation. In this post hoc subgroup analysis, we stratified 519 patients into the low D-dimer (<1.0 μg/mL) (n = 308) and high D-dimer (≥1.0 μg/mL) (n = 211) subgroups based on D-dimer levels at 3 months. The cumulative incidence of a composite of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death was lower in the 12-month edoxaban group than in the 3-month edoxaban group in both the low D-dimer (0.8% vs 5.6%; P = .02; odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01-0.66) and high D-dimer (0.9% vs 10.2%; P = .01; OR, 0.11; 95% CI, 0.01-0.62) subgroups without interaction. Furthermore, there was no significant difference in the cumulative incidence of major bleeding between the 12- and 3-month groups in both the low D-dimer (3.6% vs 1.8%; P = .64; OR, 1.96; 95% CI, 0.47-9.67) and high D-dimer (18.3% vs 14.6%; P = .29; OR, 1.27; 95% CI, 0.60-2.75) subgroups without interaction. In conclusion, a 12-month edoxaban treatment for cancer-associated IDDVT was superior to a 3-month treatment in reducing thrombotic events, irrespective of D-dimer levels after 3 months of anticoagulation therapy. There was no significant increased risk of major bleeding in the 12-month edoxaban group relative to the 3-month edoxaban group regardless of the D-dimer levels at 3 months. This trial was registered at www.clinicaltrials.gov as #NCT03895502.