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.

Rivaroxaban treatment for asymptomatic venous thromboembolism: insights from the J'xactly study.

BACKGROUND: An established treatment strategy for asymptomatic pulmonary embolism (PE) or deep vein thrombosis (DVT) remains uncertain in Japan; therefore, in this study, we clarify the characteristics and outcomes of symptomatic compared to asymptomatic patients with PE or DVT. METHODS: This prospective, multicenter sub-analysis of the J'xactly study in Japan included 1,016 patients (mean age, 68; 41% male) with venous thromboembolism (VTE) treated with rivaroxaban. RESULTS: Asymptomatic PE patients (47% of PE patients) were more likely to have active cancer and asymptomatic proximal DVT at lower severity than symptomatic PE patients, despite no differences in age, sex, or the proportion receiving intensive 30 mg/day-rivaroxaban. Patients with asymptomatic DVT (34% of DVT patients) were older, had higher rates of female sex, active cancer, and distal DVT, and received shorter, less intense rivaroxaban treatment. Incidences did not differ between asymptomatic and symptomatic PE patients for recurrent symptomatic VTE (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.22-1.62; P = 0.31) or major bleeding (HR, 0.68; 95% CI, 0.20-2.33; P = 0.58), nor between asymptomatic and symptomatic DVT patients for recurrent symptomatic VTE (HR, 0.56; 95% CI, 0.23-1.40; P = 0.21) and major bleeding (HR, 1.47; 95% CI, 0.54-3.97; P = 0.45). CONCLUSIONS: The real-world composite adverse event rate for treatment with rivaroxaban, as physician-adjusted for dose and duration, was similar for asymptomatic and symptomatic patients regardless of the presence of PE or DVT, suggesting a favorable safety profile for potential rivaroxaban treatment for asymptomatic VTE.

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.

Fake-news-free evidence-based communication for proper vein-lymphatic disease management.

Published scientific evidence demonstrate the current spread of healthcare misinformation in the most popular social networks and unofficial communication channels. Up to 40% of the medical websites were identified reporting inappropriate information, moreover being shared more than 450,000 times in a 5-year-time frame. The phenomenon is particularly spread in infective diseases medicine, oncology and cardiovascular medicine. The present document is the result of a scientific and educational endeavor by a worldwide group of top experts who selected and analyzed the major issues and related evidence-based facts on vein and lymphatic management. A section of this work is entirely dedicated to the patients and therefore written in layman terms, with the aim of improving public vein-lymphatic awareness. The part dedicated to the medical professionals includes a revision of the current literature, summing up the statements that are fully evidence-based in venous and lymphatic disease management, and suggesting future lines of research to fulfill the still unmet needs. The document has been written following an intense digital interaction among dedicated working groups, leading to an institutional project presentation during the Universal Expo in Dubai, in the occasion of the v-WINter 2022 meeting.

Association Between the Development of Thrombosis and Worsening of Disease Severity in Patients With Moderate COVID-19 on Admission　- From the CLOT-COVID Study.

BACKGROUND: The worsening of coronavirus disease 2019 (COVID-19) severity is a critical issue in current clinical settings and may be associated with the development of thrombosis.Methods and Results: This study used patient data obtained in the CLOT-COVID study, a retrospective multicenter cohort study. The demographics of patients with moderate COVID-19 on admission with and without worsened severity during hospitalization were compared and predictors were identified. Of 927 patients with moderate COVID-19 on admission, 182 (19.6%) had worsened severity during hospitalization. Patients with worsening of severity were older, more likely to have hypertension, diabetes, heart disease, and active cancer, and more likely to use pharmacological thromboprophylaxis. Patients with worsening of severity had higher D-dimer levels on admission and were more likely to develop thrombosis and major bleeding during hospitalization than those without worsening. Increased age (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.03, P=0.005), diabetes (OR: 1.63, 95% CI: 1.11-2.33, P=0.012), D-dimer levels >1.0 µg/mL on admission (OR: 2.10, 95% CI: 1.45-3.03, P<0.001), and thrombosis (OR: 6.28, 95% CI: 2.72-14.53, P<0.001) were independently associated with worsening of COVID-19 severity. CONCLUSIONS: Approximately 20% of patients with moderate COVID-19 had worsened severity during hospitalization. Increased age, diabetes, D-dimer levels >1.0 µg/mL on admission, and the development of thrombosis during hospitalization were significantly associated with worsened COVID-19 severity.

Effectiveness and safety of rivaroxaban in patients with venous thromboembolism and active cancer: A subanalysis of the J'xactly study.

BACKGROUND: Data on the effectiveness and safety of rivaroxaban for the treatment of patients with venous thromboembolism (VTE) and active cancer are limited in the Japanese real-world setting. METHODS: In this subanalysis of the J'xactly study, which was a multicenter, prospective, observational study, we evaluated the effectiveness and safety of rivaroxaban in patients with acute VTE and active cancer (n = 193) versus those without active cancer (n = 823). RESULTS: Compared with patients without active cancer, those with active cancer demonstrated a significantly different age distribution, with fewer aged <65 and ≥75 years; a lower proportion of women; a lower mean body mass index; and a lower proportion of physical inactivity, injury, thrombophilia, and heart failure. There was no difference in the initial dose distribution of rivaroxaban between patients with and without active cancer. The incidences of recurrence or aggravation of symptomatic VTE and major bleeding were not significantly different [VTE: 1.44 % vs. 2.80 % per patient-year, hazard ratio (HR) 0.50, 95 % confidence interval (CI) 0.18-1.39, p = 0.172; major bleeding: 4.49 % vs. 2.55 % per patient-year, HR 1.80, 95 % CI 0.82-3.95, p = 0.137]. Approximately 10 % of patients with active cancer died at 6 months, with a significantly higher cumulative all-cause mortality rate than those without active cancer (23.29 % vs. 2.03 % per patient-year, HR 11.31, 95 % CI 7.30-17.53, p < 0.001). CONCLUSIONS: In patients with VTE and active cancer, rivaroxaban showed acceptable effectiveness, although clinically significant bleeding remains a concern. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry number, UMIN000025072.

Mortality-associated Risk Factors in Hospitalized COVID-19 Patients in Japan: Findings of the CLOT-COVID Study.

BACKGROUND: Reports of mortality-associated risk factors in patients with the novel coronavirus disease 2019 (COVID-19) are limited. METHODS: We evaluated the clinical features that were associated with mortality among patients who died during hospitalization (n = 158) and those who were alive at discharge (n = 2,736) from the large-scale, multicenter, retrospective, observational cohort CLOT-COVID study, which enrolled consecutively hospitalized COVID-19 patients from 16 centers in Japan from April to September 2021. Data from 2,894 hospitalized COVID-19 participants of the CLOT-COVID study were analyzed in this study. RESULTS: Patients who died were older (71.1 years vs 51.6 years, P < 0.001), had higher median D-dimer values on admission (1.7 µg/mL vs 0.8 µg/mL, P < 0.001), and had more comorbidities. On admission, the patients who died had more severe COVID-19 than did those who survived (mild: 16% vs 63%, moderate: 47% vs 31%, and severe: 37% vs 6.2%, P < 0.001). In patients who died, the incidence of thrombosis and major bleeding during hospitalization was significantly higher than that in those who survived (thrombosis: 8.2% vs 1.5%, P < 0.001; major bleeding: 12.7% vs 1.4%, P < 0.001). Multivariable logistic regression analysis revealed that age >70 years, high D-dimer values on admission, heart disease, active cancer, higher COVID-19 severity on admission, and development of major bleeding during hospitalization were independently associated with a higher mortality risk. CONCLUSION: This large-scale observational study in Japan identified several independent risk factors for mortality in hospitalized patients with COVID-19 that could facilitate appropriate risk stratification of patients with COVID-19.

Clinical Outcome After Discontinuation of Anticoagulation Therapy in Japanese Patients With Venous Thromboembolism　- Insights From the J'xactly Study.

Background: Rivaroxaban, a direct oral anticoagulant, is used as first-line treatment to prevent venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). However, the frequency of rivaroxaban discontinuation and the subsequent clinical outcomes remain unclear. Methods and Results: The study was a subanalysis of the prospective, multicenter, observational J'xactly study, conducted in Japan, and included patients who underwent anticoagulant discontinuation without major bleeding and recurrent VTE. The modified intention-to-treat population (n=1,016) included 579 patients (57%) who underwent anticoagulant discontinuation during a mean follow-up period of 20.2 months (mean [±SD] anticoagulation period 6.9±6.2 months). Patients were divided into 3 groups: those with active cancer, those without active cancer and a transient risk factor for VTE, and those without active cancer or a transient risk factor and/or with previous VTE (unprovoked group). After discontinuation, VTE recurrence occurred in 4.1% of patients, with an annual incidence of 4.6%/year and an increased tendency in the unprovoked group; major bleeding occurred in 8 patients (1.4%; annual incidence 1.1%/year), of whom half were in the cancer group. Conclusions: This analysis of a real-world observational study provides data on VTE recurrence after rivaroxaban discontinuation, which will facilitate anticoagulant discontinuation according to individual risk-benefit considerations.

Safety and Effectiveness of Apixaban in Japanese Patients With Venous Thromboembolism in Clinical Practice　- A Post-Marketing Surveillance.

BACKGROUND: A post-marketing surveillance study (STANDARD-VTE) evaluated the real-world safety and effectiveness of apixaban in Japanese patients prescribed for either the treatment of venous thromboembolism (VTE) or prevention of recurrent VTE.Methods and Results:Patients newly initiated on apixaban were followed up for 52 weeks or 28 days post-discontinuation. Subgroup analysis was performed on patients with and without active cancer, and on patients with provoked VTE and with unprovoked VTE. A total of 1,119 patients were enrolled. Of these, 43.1% were aged ≥75 years, 46.4% had body weight ≤60 kg, and 21.3% had active cancer; mean serum creatinine was 0.76 mg/dL. The incidence of adverse drug reactions (ADRs) was 8.85%, and that of severe ADRs was 3.22%. Incidence of any bleeding, major bleeding, and recurrent VTE was 6.70%, 3.40%, and 0.80%, respectively. In patients starting apixaban 10 mg twice daily, THE incidence of any bleeding and major bleeding was 7.72% and 3.86%, respectively. In patients with active cancer, THE incidence of any bleeding and major bleeding was 16.81% and 9.24%, respectively. CONCLUSIONS: No new safety signals of apixaban were identified in Japanese patients with VTE. In this study, the safety and effectiveness of apixaban in real-world practice was consistent with the results of the apixaban phase III trial.

Supplement of Clinical Practice Guidelines for Endovenous Thermal Ablation for Varicose Veins: Overuse for the Inappropriate Indication.

While endovenous thermal ablation (ETA) become first choice of treatment for varicose veins, overuse of ETA for the inappropriate indication is growing problem. ETA is performed not only on varicose cases without symptom but also non diseased cases with segmental reflux of saphenous veins or no reflux. Indications of ETA was demonstrated in "the Clinical Practice Guidelines for ETA for Varicose Veins 2019" by Japanese Society of Phlebology. Purpose of this supplement is description of basics of correct indication for ETA. We also demonstrate the typical case of overuse of ETA for wrong indication. (This is a translation of Jpn J Phlebol 2020; 31: 39-43.).

A Multicenter Prospective Observational Cohort Study to Investigate the Effectiveness and Safety of Rivaroxaban in Japanese Venous Thromboembolism Patients (The J'xactly Study).

BACKGROUND: There is insufficient real-world data on the current status of Japanese patients with venous thromboembolism (VTE) or its treatment and prevention with rivaroxaban.Methods and Results:In this multicenter, prospective, observational study conducted in Japan, 1,039 patients with acute symptomatic/asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) with or without DVT prescribed rivaroxaban were enrolled at 152 institutions and observed for a median of 21.3 months. Mean age was 68.0±14.7 years, mean body weight was 60.3±14.1 kg, 59.0% were females, and 19.0% had active cancer. Incidences of recurrence or aggravation of symptomatic VTE (primary effectiveness outcome) and major bleeding (principal safety outcome) were 2.6% and 2.9% per patient-year, respectively. These outcomes did not differ between patients with DVT and those with PE (primary effectiveness outcome: 2.6% vs. 2.5% per patient-year, P=0.810; principal safety outcome: 3.5% vs. 2.4% per patient-year, P=0.394). The incidence of composite clinically relevant events, including recurrence or aggravation of symptomatic VTE, acute coronary syndrome, ischemic stroke, all-cause death, or major bleeding events, was 9.2% per patient-year. Multivariate analysis revealed that male sex, being underweight, having active cancer, chronic heart and lung disease, and previous stroke were independent determinants for composite clinically relevant events. CONCLUSIONS: In Japanese clinical practice, a single-drug approach with rivaroxaban was demonstrated to be a valuable treatment for a broad range of VTE patients.

Venous thromboembolism complications after endovenous laser ablation for varicose veins and role of duplex ultrasound scan.

OBJECTIVE: A nationwide survey was conducted in Japan to determine the incidence of venous thromboembolism (VTE) after endovenous thermal ablation for varicose veins and to investigate its pathogenic background. METHODS: The survey targeted all cases of endovenous thermal ablation between January 2011 and December 2013. Based on this survey, a retrospective study of patients who developed endovenous heat-induced thrombosis (EHIT) of classes 2 to 4, no EHIT-related deep venous thrombosis (DVT), and pulmonary embolism (PE) was conducted. Lower extremity venous ultrasound was performed within 72 hours and at 1 to 3 months postoperatively in all institutions. We investigated factors associated with the occurrence of complications and the usefulness of postoperative ultrasound. RESULTS: Survey responses were collected from 213 institutions. Endovenous laser ablation was performed for 43,203 patients (EHIT 2 in 318 patients, EHIT 3 in 50 patients, EHIT 4 in 7 patients, other DVTs in 24 patients, and PE in 3 patients). The incidence of VTE complications was 1.0% for EHIT 2, 0.11% for EHIT 3, 0.013% for EHIT 4, 0.063% for other DVTs, and 0.0067% for PE based on the adjusted population. Sex, age, obesity, origin of the varicose vein, vein diameter, and preoperative Caprini score were not strong indicators of VTE complications. Of 50 patients with EHIT 3, there were 35 patients who had EHIT 3 during the first postoperative ultrasound session. In one patient, EHIT 3 progressed to EHIT 4 despite initiation of anticoagulant therapy. Of seven patients with EHIT 4, only one patient had EHIT 4 at the first postoperative ultrasound examination. Because ultrasound performed before the occurrence of EHIT 4 revealed that three patients had EHIT 2 or EHIT 3, EHIT 4 could have possibly been predicted by ultrasound. Of three patients with PE, two developed PE before ultrasound, and EHIT was not detected by ultrasound in one of those patients before PE developed. Anticoagulant therapy was administered in most patients with EHIT 3 and all patients with EHIT 4 and PE, with favorable outcomes. CONCLUSIONS: The incidence of VTE complications after endovenous laser ablation was low. Furthermore, the value of performing postoperative ultrasound for VTE management seems to be low because the occurrence of severe VTE complications could not be predicted by lower extremity venous ultrasound. Although the perioperative detection of VTE complications by this modality resulted in the early administration of anticoagulant therapy and may have contributed to improved prognosis, the number of those patients was limited.

Stanford type B aortic dissection is more frequently associated with coronary artery atherosclerosis than type A.

BACKGROUND: The relationship between aortic dissection and coronary artery disease is not clear. The purpose of this study was to clarify the difference in the rate of coronary artery atherosclerosis between Stanford type A and type B aortic dissection by reviewing our institutional database. METHODS: One hundred and forty-five patients (78 males, 67 females; mean age: 60 ± 12 years) admitted to our hospital with acute aortic dissection who underwent coronary angiography during hospitalization from 2000 through 2002 were enrolled in this study. The background characteristics, coronary risk factors, and coronary angiography findings (number of significant stenoses, stenoses according to Bogaty standards, extent index) of patients were compared between type A (Group A; n = 71) and type B dissection (Group B; N = 74). RESULTS: Significantly more patients had prior histories of complications from ischemic heart disease in Group B than in Group A (P = 0.04), with no significant differences in comparison to other risk factors observed except for hypertension. Significantly (p = 0.005) more stenoses were observed in Group B (1.54 ± 0.04) than in Group A (0.38 ± 0.1). A significantly higher (P < 0.05) index score indicating the severity of coronary atherosclerosis was observed in Group B (1.49 ± 0.09) than in Group A (0.72 ± 0.07). CONCLUSIONS: Stanford type B acute aortic dissection was significantly more frequently associated with coronary artery atherosclerosis than type A.

[Effectiveness of the Waffle Procedure for Constrictive Pericarditis].

A 66-year-old woman was referred to our hospital with dyspnea. Right-sided congestive pleural effusion of an unknown etiology was detected and she was diagnosed with constrictive pericarditis. Pericardiectomy was performed via median sternotomy under extracorporeal circulation because severe adhesion was observed. However, hemodynamics did not improve after pericardial resection because of thickend epicardium in front of the right ventricle. Hence, the waffle procedure was additionally performed on the anterior surface of the right ventricle after coming-off the extracorporeal circulation. Although significant cardiac dilatation was achieved, hemodynamics did not change markedly. The symptoms gradually alleviated postoperatively and cardiac catheterization performed 3 weeks later revealed marked improvement in hemodynamics. Although improvement in hemodynamics takes time, the waffle procedure appears to be effective.

[Surgical Repair of Coronary-pulmonary Artery Fistulae with Giant Coronary Aneurysm].

A 69-year-old woman was referred to our hospital due to dyspnea on exertion and a heart murmur. A chest X-ray showed a bulge at the left 3rd arch and chest computed tomography( CT) revealed a giant mass adjacent to the right ventricular outflow. Multidetector-row CT and coronary angiography showed a giant coronary aneurysm (55×45 mm) and fistulae arising from the left main coronary trunk and entering into the main pulmonary artery (PA). The pulmonary to systemic flow ratio was 1.84. She was diagnosed with coronary-pulmonary artery fistulae with giant coronary aneurysm. Aneurysmorrhaphy and closure of the fistula outlet from the PA were performed under cardiopulmonary bypass with cardiac arrest. After declamping the aorta, residual shunt flow was found at several sites of abnormal vessels in the right ventricular outflow using a Doppler flowmeter. The vessels were ligated with pledgeted sutures, but did not disappear completely. Postoperative coronary angiography and transthoracic echocardiogram showed a small residual shunt flow into the PA. The postoperative course was uneventful;she was discharged on postoperative day 18. Six months later, the residual shunt flow had disappeared. No recurrence has been detected for 7 years.

Frequency of deep vein thrombosis among hospitalized non-surgical Japanese patients with congestive heart failure.

PURPOSE: Congestive heart failure (CHF) is one of the risk factors for deep vein thrombosis (DVT) according to the Japanese guidelines for DVT treatment and prevention. The purpose of this study is to estimate the frequency of DVT among hospitalized CHF patients, since there have been only limited DVT data in Japanese CHF patients. METHODS: Patients enrolled in the study were with risk factors for DVT listed in the guidelines as well as with acute exacerbation of CHF, bed rest for at least 4 days, and aged 60 or above. Patients treated by physical prophylaxis or anti-platelet medication were included, while patients treated by any anticoagulant medicines were excluded. Patients with surgery or injury within 3 months before the hospitalization or diagnosed clinically or with obvious past history as having DVT at hospitalization were excluded. The presence of DVT in the eligible patients was determined by ultrasonography and the images were evaluated by an independent central evaluation committee. RESULTS: Forty-four patients were enrolled in the study including 19 males and 25 females. The mean age was 79.0±10.6 years, and the mean duration of bed rest was 8.9±3.2 days. Out of these 44 patients, DVT was detected in 15 (34%) patients. Eight patients were on treatment with physical prophylaxis but DVT was still detected in two patients. Furthermore, 12 out of the rest of the patients were treated by anti-platelet agents and were still with DVT in 3 patients. CONCLUSION: When evaluated ultrasonographically, the frequency of DVT in hospitalized non-surgical Japanese patients with CHF was approximately 35%. DVT occurred in 25% of patients treated by physical prophylaxis or anti-platelet agents. The results suggest that Japanese hospitalized patients with CHF have a high risk of DVT and thus can be recognized to have potential benefit by preventing and treating DVT according to the guidelines.