Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis (ONCO DVT Study): An Open-Label, Multicenter, Randomized Clinical Trial.

BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

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.

Statins use and recurrent venous thromboembolism in the direct oral anticoagulant era: insight from the COMMAND VTE Registry-2.

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.

Left Ventricular End-Systolic Diameter May Predict Persistent Heart Failure with Reduced Ejection Fraction.

Patients with persistent heart failure (HF) with reduced ejection fraction (HFrEF) have a poorer prognosis than those with HF with improved ejection fraction (HFimpEF). However, data on the predictive value of echocardiographic parameters for persistent HFrEF are lacking. We retrospectively studied 443 patients who were diagnosed with HFrEF (EF ≤ 40%) during hospitalization and underwent echocardiography at the 1-year follow-up. We divided them into the 2 groups: HFimpEF (EF > 40%) and persistent HFrEF group at 1-year follow-up, and assessed the predictive value of echocardiographic parameters at discharge for persistent HFrEF. In total, 301/443 patients (68%) were diagnosed with persistent HFrEF and 142/443 (32%) with HFimpEF at the 1-year follow-up. Kaplan-Meier analysis revealed that the persistent HFrEF group had a poorer prognosis than the HFimpEF group (log-rank, P < 0.001). Receiver operating characteristic curve analysis revealed that left ventricular end-systolic diameter (LVESD) had the highest area under the curve (AUC) (0.70; 95% confidence interval [CI]: 0.64-0.75; cutoff value: 55 mm) among various echocardiographic parameters. LVESD was an independent predictor of persistent HFrEF at the 1-year follow-up (odds ratio: 1.07, 95%CI: 1.02-1.12) upon multivariable logistic regression analysis. The incidence of persistent HFrEF was higher in patients with an LVESD ≥ 55 mm than in those with an LVESD < 55 mm (81% versus 55%, Fisher's exact test, P < 0.001). In conclusion, an LVESD (≥ 55 mm) was associated with persistent HFrEF. Focusing on LVESD in daily practice may help clinicians with risk stratification for decision-making regarding management in patients with advanced HF refractory to guideline-directed medical therapy.

Functional Evaluation of Human Bioengineered Cardiac Tissue Using iPS Cells Derived from a Patient with Lamin Variant Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is caused by various gene variants and characterized by systolic dysfunction. Lamin variants have been reported to have a poor prognosis. Medical and device therapies are not sufficient to improve the prognosis of DCM with the lamin variants. Recently, induced pluripotent stem (iPS) cells have been used for research on genetic disorders. However, few studies have evaluated the contractile function of cardiac tissue with lamin variants. The aim of this study was to elucidate the function of cardiac cell sheet tissue derived from patients with lamin variant DCM. iPS cells were generated from a patient with lamin A/C (LMNA) -mutant DCM (LMNA p.R225X mutation). After cardiac differentiation and purification, cardiac cell sheets that were fabricated through cultivation on a temperature-responsive culture dish were transferred to the surface of the fibrin gel, and the contractile force was measured. The contractile force and maximum contraction velocity, but not the maximum relaxation velocity, were significantly decreased in cardiac cell sheet tissue with the lamin variant. A qRT-PCR analysis revealed that mRNA expression of some contractile proteins, cardiac transcription factors, Ca2+-handling genes, and ion channels were downregulated in cardiac tissue with the lamin variant.Human iPS-derived bioengineered cardiac tissue with the LMNA p.R225X mutation has the functional properties of systolic dysfunction and may be a promising tissue model for understanding the underlying mechanisms of DCM.

Predictors of neo-aortic valve regurgitation in the long term after arterial switch operation.

Although arterial switch operations (ASOs) have been performed globally to repair d-transposition of the great arteries (d-TGA) in neonates and infants, few studies have been reported regarding the influence of the hemodynamics of patients with d-TGA who have undergone ASO on the development of neo-aortic valve regurgitation (AR). We aimed to investigate the relationship between the hemodynamics and development of AR after ASO in patients with d-TGA by catheter evaluation. This observational study screened 114 consecutive patients who underwent ASO for d-TGA or Taussig-Bing anomaly and who subsequently underwent catheter evaluations in our institution. We reviewed their records for the past 20 years and collected their first catheterization data post-ASO in early childhood. Thirty-six post-ASO patients who underwent catheter evaluations in both the early surgical and long-term phases were finally analyzed. Patients were divided into the following groups according to the presence of significant AR in the long-term phase: the AR group (n = 9 with AR ≥ grade II by the Sellers classification) and the non-AR group (n = 27 with AR < grade II). In the long-term phase, the diastolic blood pressure was significantly lower and the ascending aortic diameter was significantly larger in the AR group than in the non-AR group (p = 0.004 and p = 0.006, respectively). The systolic blood pressure (SBP) and pulse pressure (PP) were similar in both groups. Meanwhile, in the early surgical phase, SBP and PP were significantly higher in the AR group than in the non-AR group (p = 0.029 and p = 0.002, respectively). The receiver operating characteristic curve for late AR showed that the area under the curve for SBP and PP in the early surgical phase were 0.746 and 0.853, respectively. Even though sensitivity analysis was performed, SBP or PP greater than the cutoff value in the early surgical phase was identified as predictors for late AR. Our results suggested that high SBP or PP in the early surgical phase could influence the development of AR in the long term after ASO.

Impact of Late Ventricular Arrhythmias on Cardiac Mortality in Patients with Acute Myocardial Infarction.

OBJECTIVES: This study investigated the relationship between the timing of ventricular tachycardia or ventricular fibrillation (VT or VF) and prognosis in patients undergoing primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: It is unknown whether the timing of VT/VF occurrence affects the prognosis of patients with AMI. METHODS: From January 2004 to December 2014, 1004 patients with AMI underwent primary PCI. Of these patients, 888 did not have VT/VF (non-VT/VF group) and 116 had sustained VT/VF during prehospitalization or hospitalization. Patients with VT/VF were divided into two groups: early VT/VF (VT/VF occurrence before and within 2 days of admission, 92 patients) and late VT/VF (VT/VF occurrence >2 days after admission; 24 patients) groups. RESULTS: The frequency of VT/VF occurrence was high between the day of admission and the 2nd day and between days 6 and 10 of hospitalization. The late VT/VF group had a significantly longer onset-to-balloon time, lower ejection fraction, poorer renal function, and higher creatine phosphokinase (CK)-MB level on admission (p< 0.001). They also had a lower 30-day cardiac survival rate than the early VT/VF and non-VT/VF groups (42% vs. 76% vs. 96%, p < 0.001). Moreover, independent predictors of in-hospital cardiac mortality among patients with AMI who had sustained VT/VF were higher peak CK-MB [Odds ratio (OR: 1.001, 95%confidence interval (CI): 1.000-1.002, p= 0.03)], higher Killip class (OR: 1.484, 95%CI 1.017-2.165, p= 0.04), and late VT/VF (OR: 3.436, 95%CI 1.115-10.59, p= 0.03). CONCLUSIONS: The timing of VT/VF occurrences had a bimodal peak. Although late VT/VF occurrence after primary PCI was less frequent than early VT/VF occurrence, patients with late VT/VF had a very poor prognosis.

Clinical experience of idarucizumab use in cases of cardiac tamponade under uninterrupted anticoagulation of dabigatran during catheter ablation of atrial fibrillation.

Anticoagulants are prescribed for prevention of thromboembolic events (TE) of atrial fibrillation (AF), however, their effects have a negative impact on disastrous bleeding outcomes. Idarucizumab was developed to reverse the anticoagulation effects of dabigatran. This study aimed to retrospectively investigate the clinical efficacy and safety of idarucizumab in the setting of progressive emergent bleeding events associated with catheter ablation (CA). Dabigatran is given uninterruptedly as an anticoagulant in patients undergoing CA of AF. The capacity of idarucizumab to reverse the anticoagulant effects of dabigatran in patients with cardiac tamponade associated with CA was examined by measuring the activated partial thromboplastin time (aPTT), active clotting time (ACT), and prothrombin international normalizing ratio (PT-INR). The primary endpoint was effective hemostasis. This analysis included 21 patients receiving idarucizumab, given for restoration of hemostasis. In all 21 patients, hemostasis was restored at a median of 205.6 ± 14.8 min. Normal intraoperative cessation of bleeding was reported in 16 patients, and completion of hemostasis was also ascertained in the remaining four within 5 h. No TEs occurred within 72 h after the idarucizumab administration. Despite a significant reduction in the aPTT and ACT, no significant change was observed in PT-INR after administering idarucizumab. In emergency situations, idarucizumab was able to reverse dabigatran within a relatively short period without any serious adverse events.

Initial and Long-Term Results of a Microcatheter-Based Retrograde Approach for the Endovascular Treatment of Chronic Total Occlusion in Iliac or Femoropopliteal Arteries.

BACKGROUND: Initial and long-term outcomes of the retrograde endovascular approach using a microcatheter for the treatment of chronic total occlusion (CTO) in the iliac or femoropopliteal (FP) arteries have not been fully elucidated. METHODS: From 2012 to 2014, 20 consecutive patients (21 limbs) underwent endovascular therapy (EVT) for CTO in the iliac or FP arteries using the microcatheter-based retrograde approach. An analysis of the initial and long-term outcomes was conducted. RESULTS: All procedures were successful. The mean follow-up duration was 27.4 ± 11.3 months. The mean patient age was 75.8 ± 9.1 years. Eighteen (85.7%) target lesions were located in the superficial femoral artery, 1 (4.8%) in the popliteal artery, and 2 (9.5%) in the iliac artery. All lesions were de novo. The mean occlusion length was 183.3 ± 95.4 mm. A stent was used in 19 (94.5%) lesions and balloon angioplasty was performed for 2 (5.5%) lesions. Retrograde puncture site complication (hematoma in popliteal artery) was reported in 1 (4.8%) patient. Postprocedure primary patency rates at 1, 2, and 3 years were 89.5%, 72.0%, and 41.2%, respectively, and the secondary patency rates at the corresponding time points were 100%, 77.2%, and 48.6%, respectively. CONCLUSIONS: Initial and long-term outcomes of EVT for CTO in iliac and FP arteries using the microcatheter-based retrograde approach are promising.

Edoxaban for 12 Versus 3 Months in Cancer-associated Isolated Distal Deep Vein Thrombosis According to Different Doses: Insights from the ONCO DVT study.

BACKGROUND: 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. METHODS: 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-month and 3-month treatments. RESULTS: 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% 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 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), signaling there was a potential interaction (P=0.07). CONCLUSIONS: 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.

The impact of renal function on clinical outcomes of patients with cancer-associated isolated distal deep vein thrombosis: Insights from the ONCO DVT study.

BACKGROUND: The multicenter, open-label, randomized clinical trial ONCO DVT compared 3-month and 12-month edoxaban treatment regimens for isolated distal deep vein thrombosis (DVT) and suggested potential benefits of prolonged edoxaban treatment in terms of thrombotic risk. However, the risk-benefit balance of prolonged edoxaban treatment in patients with renal function remains unclear. OBJECTIVES: To compare the safety and efficacy of 3-month and 12-month edoxaban treatment regimens in patients with cancer-associated isolated distal DVT and different renal functions. METHODS: This pre-specified subgroup analysis of the ONCO DVT study included 601 patients divided into subgroups according to renal function using a 50 mL/min creatinine clearance (Ccr) cutoff. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) and VTE-related death at 12 months and the major secondary endpoint was major bleeding at 12 months. RESULTS: Among the 601 patients, 131 (21.8 %) comprised the renal dysfunction subgroup. The primary endpoint occurred in 6 (9.7 %) and 1 (1.4 %) patients in the 3-month and 12-month edoxaban groups in the renal dysfunction subgroup, respectively, and in 16 (6.6 %) and 2 (0.9 %) patients in the no renal dysfunction subgroup, respectively. The major secondary endpoint occurred in 9 (14.5 %) and 7 (10.1 %) patients in the 12-month and 3-month edoxaban groups in the renal dysfunction subgroup, and in 13 (5.3 %) and 21 (9.3 %) patients in the no renal dysfunction subgroup, respectively. CONCLUSIONS: A 12-month edoxaban regiment was superior to a 3-month treatment in terms of thrombotic risk irrespective of renal function. A higher bleeding risk was not identified in patients with renal dysfunction who received prolonged edoxaban treatment.

Cancer-associated venous thromboembolism in the direct oral anticoagulants era: Insight from the COMMAND VTE Registry-2.

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.

Edoxaban, Rivaroxaban, or Apixaban for Cancer-Associated Venous Thromboembolism in the Real World: Insights from the COMMAND VTE Registry-2.

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.

External validation of the PE-SARD bleeding score for early major bleeding in patients with acute pulmonary embolism: From the COMMAND VTE Registry-2.

BACKGROUND: There is no established risk score for anticoagulant-related bleeding during the acute phase in patients with pulmonary embolism (PE). The Syncope, Anemia, 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. PATIENTS/METHODS: Using the 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 those 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 in active cancer patients. CONCLUSIONS: The PE-SARD bleeding score had a modest discriminating performance with a limited calibration performance in acute PE patients without active cancer.

Fragility and long-term clinical outcomes in patients with venous thromboembolism receiving direct oral anticoagulants: From the COMMAND VTE REGISTRY-2.

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.

Subclass phenotypes in patients with unprovoked venous thromboembolisms using a latent class analysis.

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.

Prognostic impact of guideline-directed medical therapy in patients with heart failure on regular hemodialysis.

BACKGROUND: Renin-angiotensin system inhibitor (RASi) and ß-blocker provide prognostic benefits as guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). However, there is limited data for the favorable effects in such patients receiving regular hemodialysis. We aimed to evaluate the prognostic impact of RASi and ß-blocker in patients with HFrEF who receive regular hemodialysis. METHODS: In this retrospective, single-center, observational study, from 2110 consecutive patients hospitalized for HF and who survived to discharge, 97 with HFrEF who received regular hemodialysis were included for analysis. They were classified into three groups according to prescribed medication at discharge following index hospitalization: both RASi and ß-blocker (Dual-GDMT group: n = 55), either RASi or ß-blocker (Mono-GDMT group: n = 34), and neither RASi nor ß-blocker (No-GDMT group: n = 8). The primary endpoint was a composite of all-cause death and rehospitalization for heart failure. RESULTS: The mean age was 66 years and 79% of the patients were men. During the median follow-up of 501 days, the primary endpoint occurred in 43 patients (44%). Kaplan-Meier analysis revealed that the Dual-GDMT group had the lowest rates of the primary endpoint (log-rank test for trend: p < 0.001). Even after adjustment for diverse covariates (multivariate Cox regression), the Dual-GDMT (hazard ratio [HR]: 0.04, 95% confidence interval (CI): 0.005-0.32) and Mono-GDMT (HR: 0.08, 95% CI: 0.01-0.50) groups had better prognoses than the No-GDMT group. CONCLUSIONS: The prescription of RASi and/or ß-blocker was associated with a lower adverse-event rate after discharge in patients with HFrEF who were on regular hemodialysis.

Renin-angiotensin system inhibitor exerts prognostic effects in HFpEF patients with low baseline chloride level.

BACKGROUND: Few interventions have shown improved prognosis in patients with heart failure and preserved ejection fraction (HFpEF). Serum chloride levels, which are affected by serum renin secretion, are associated with the prognosis of HFpEF patients. However, the relationship between serum chloride levels and the effects of renin-angiotensin system inhibitors (RASi) in HFpEF patients remains unclear. We investigated whether the prognostic benefit of RASi depends on baseline serum chloride levels in HFpEF patients. METHODS: This observational study included 506 hospitalized patients with HFpEF (ejection fraction ≥50%) who were discharged. They were divided into two categories based on serum chloride levels at admission (cutoff level: 101 mEq/L) according to previous reports. In each chloride category, all-cause mortality, the primary endpoint, was compared between patients who received RASi and those who did not. RESULTS: Patients who received RASi had a significantly lower mortality rate after discharge than those who did not, but only in the lower chloride category (log-rank, P = 0.001). Multivariable Cox regression analysis confirmed the effect of risk reduction by RASi on all-cause mortality in the lower chloride category (adjusted hazard ratio: 0.31, 95% confidence interval: 0.11-0.84). The prognostic advantages of RASi were evident in the lower chloride category, but not in the higher chloride category, at admission (P for interaction = 0.027). CONCLUSION: RASi administration was associated with an improved prognosis only in HFpEF patients with a low baseline serum chloride level. Clinicians should consider RASi administration if patients' serum chloride levels are low, to improve the long-term prognosis of HFpEF patients.

Anticoagulation strategies and long-term recurrence in patients with venous thromboembolism in the era of direct oral anticoagulants.

BACKGROUND: There has been limited data on anticoagulation strategies and long-term recurrence in patients with venous thromboembolism (VTE) in the era of direct oral anticoagulant (DOAC). METHODS: The COMMAND VTE Registry-2 is a multicenter retrospective cohort study enrolling 5197 consecutive patients with acute symptomatic VTE between January 2015 and August 2020 among 31 centers in Japan. In this primary report, the entire cohort was divided into 5 groups; major transient risk factors (N = 475, 9.1%), minor transient risk factors (N = 788, 15%), unprovoked (N = 1913, 37%), non-malignant persistent risk factors (N = 514, 9.9%), and active cancer (N = 1507, 29%) groups. RESULTS: DOACs were administered in 79% of patients who received oral anticoagulants. Discontinuation of anticoagulant at 1 year was most frequent in the major transient risk factors group (57.2%, 46.3%, 29.1%, 32.0%, and 45.6%). The cumulative 5-year incidence of recurrent VTE was lowest in the major transient risk factors group (2.6%, 6.4%, 11.0%, 12.1%, and 10.1%, P < 0.001). The cumulative 5-year incidence of major bleeding was highest in the active cancer group (9.8%, 11.4%, 11.0%, 15.5%, and 20.4%, P < 0.001). After discontinuation of anticoagulation therapy, the cumulative 5-year incidence of recurrent VTE was highest in the unprovoked group (3.3%, 11.0%, 24.9%, 17.5%, and 11.8%, P < 0.001). CONCLUSIONS: In this large real-world VTE registry, anticoagulation strategies and long-term recurrence widely differed depending on the baseline characteristics. Detailed risk stratifications of recurrent VTE could be useful for decision-making of anticoagulation strategies, whereas the bleeding-risk assessment might be especially important in the era of DOAC. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000044816.

Prognosis and diastolic dysfunction predictors in patients with heart failure and recovered ejection fraction.

There is limited data on whether diastolic dysfunction in patients with heart failure (HF) and recovered ejection fraction (HFrecEF) is associated with worse prognosis. We retrospectively assessed 96 patients diagnosed with HFrecEF and created ROC curve of their diastolic function at the 1-year follow-up for the composite endpoint of cardiovascular death and HF readmission after the follow-up. Eligible patients were divided into two groups according to the cutoff value of E/e' ratio (12.1) with the highest AUC (0.70). Kaplan-Meier analysis showed that HFrecEF with high E/e' group had a significantly poorer prognosis than the low E/e' group (log-rank, p = 0.01). Multivariate Cox regression analysis revealed that the high E/e' group was significantly related to the composite endpoint (hazard ratio 5.45, 95% confidence interval [CI] 1.23-24.1). The independent predictors at discharge for high E/e' ratio at the 1-year follow-up were older age and female sex after adjustment for covariates (odds ratio [OR] 1.07, 95% CI 1.01-1.13 and OR 4.70, 95% CI 1.08-20.5). In conclusion, HFrecEF with high E/e' ratio might be associated with a poor prognosis. Older age and female sex were independent predictors for a sustained high E/e' ratio in patients with HFrecEF.