Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants for Japanese Patients With Venous Thromboembolism　- The Primary Results From the KUROSIO Study.

BACKGROUND: Direct oral anticoagulants (DOACs) are recommended as the first-choice anticoagulation therapy in the acute phase of venous thromboembolism (VTE). However, there is limited real-world data for Japanese VTE patients. METHODS AND RESULTS: The KUROSIO study (UMIN000023747) was a prospective long-term observational study comprising 1,017 patients with concurrent acute symptomatic pulmonary thromboembolism and proximal deep vein thrombosis (DVT) or isolated calf DVT initially treated with DOACs. After excluding 24 patients, 993 (mean age, 66.3±15.1 years; 58.6% females) were analyzed. The incidences of recurrent symptomatic VTE and major bleeding for up to 52 weeks after diagnosis were 3.2% and 2.2%, respectively. Multivariate analyses revealed chemotherapy and anemia as significant risk factors associated with recurrent symptomatic VTE and major bleeding, respectively. CONCLUSIONS: The efficacy and safety of DOACs in Japanese patients with VTE were determined in this real-world observational study.

Effectiveness and Safety of Direct Oral Anticoagulants vs. Warfarin and Recurrence After Discontinuation in Patients With Acute Venous Thromboembolism in the Real World.

BACKGROUND: The efficacy of direct oral anticoagulants (DOACs) compared with warfarin for the treatment of venous thromboembolism (VTE), and the recurrence of VTE after discontinuation of anticoagulation therapy in research are limited.Methods and Results: This retrospective study enrolled 893 patients with acute VTE between 2011 and 2019. The cohort was divided into the transient risk, unprovoked, continued cancer treatment, and cancer remission groups. The following were compared between DOACs and warfarin: composite outcome of all-cause death, VTE recurrence, bleeding and composite outcome of VTE-related death, recurrence and bleeding. In the continued cancer treatment group, more bleeding was seen in warfarin-treated patients than in patients treated with DOACs (53.2% vs. 31.2%, [P=0.048]). In addition, composite outcome of VTE-related death and recurrence after discontinuation of anticoagulation therapy (n=369) was evaluated. The continued cancer treatment group (multivariate analysis: HR: 3.62, 95% CI: 1.84-7.12, P<0.005) and bleeding-related discontinuation of therapy (HR: 2.60, 95% CI: 1.32-5.13, P=0.006) were independent predictors of the event after discontinuation of anticoagulation therapy. VTE recurrence after discontinuation of anticoagulation therapy in the cancer remission group was 1.6% and a statistically similar occurrence was found in the transient risk group (12.4%) (P=0.754). CONCLUSIONS: DOACs may decrease bleeding incidence in patients continuing to receive cancer treatment. In patients with bleeding-related discontinuation of anticoagulation therapy, VTE recurrence may increase. Discontinuation of anticoagulant therapy might be a treatment option in patients who have completed their cancer treatment.

Atrial fibrillation type matters: greater infarct volume and worse neurological defects seen in acute cardiogenic cerebral embolism due to persistent or permanent rather than paroxysmal atrial fibrillation.

Aims: Some studies have shown that the type of atrial fibrillation (AF), whether paroxysmal AF (PAF) or persistent or permanent AF (PeAF), affects the incidence of ischaemic stroke. This study sought to determine the relationship between the AF pattern and the severity and brain volume of infarction in an AF population including transient ischaemic attack (TIA) patients. Methods and results: This was a retrospective observational study. We studied 161 consecutive patients who were admitted to our stroke care unit with cardiogenic embolism or TIA related to non-valvular AF (age 79 ± 9.5, 78 females, and 87 PAF patients). We evaluated the differences in severity and infarct volume between the types of AF. Additionally, we divided the patients into three groups according to severe stroke (n = 38), TIA (n = 28), and those who were neither (stroke, n = 95) for the assessment of the predictors of severe stroke and TIA. Persistent or permanent atrial fibrillation patients with acute cardiogenic stroke or TIA had worse peak National Institute of Health Stroke Scale (NIHSS) scores [PAF median 4 (range 3-14), PeAF 17 (5.8-25); P < 0.0001] and worse NIHSS scores at discharge [PAF 2.0 (1-7), PeAF 11 (3-22); P < 0.0001]. Their infarct brain volume assessed by computed tomography or magnetic resonance imaging was also larger [PAF 4.4 (1.1-32) mL, PeAF 64 (6.9-170) mL; P < 0.0001]. Multivariate analysis of severe stroke vs. non-severe stroke patients showed that having PeAF was the only independent predictor of severe stroke [odds ratio (OR) 4.27, 95% confidence interval (CI) 1.91-10.2; P = 0.0003]. Comparison of TIA vs. non-TIA patients showed that PeAF (OR 0.120, 95% CI 0.0230-0.444; P = 0.0008) and anticoagulant use (OR 8.24, 95% CI 2.15-40.8; P = 0.0018) were independent predictors of TIA. Conclusion: Cardiogenic emboli due to non-valvular PeAF are associated with a worse acute clinical course and greater volume of infarction than those due to PAF.

Early Transfer of Patients with Acute Heart Failure from a Core Hospital to Collaborating Hospitals and Their Prognoses.

Japan is facing problems associated with "heart failure (HF) pandemics" and bed shortages in core hospitals that can accommodate patients with acute HF. The prognosis is currently unknown for acute HF patients who were transferred from core hospitals to collaborating hospitals during the very early treatment phase and whose treatment strategies are in place.We enrolled 166 acute HF patients who were hospitalized between January 1, 2015, and December 31, 2015, and compared the conditions of transferred patients (n = 53, median duration before transfer = 6 days) and nontransferred patients (n = 113). The transferred and nontransferred patients had similar one-year mortality rates (24.5% versus 19.5%, log-rank P = 0.27) and composite one-year mortality and HF readmission rates (35.8% versus 31.0%, log-rank P = 0.32). Multivariate analysis determined that patient transfers were not associated with a higher composite endpoint (hazard ratio, 1.08; 95% confidence interval, 0.58-1.99, P = 0.82). Transferred patients with low composite congestion scores (CCSs) had significantly lower composite endpoints than those with high CCSs (23.5% versus 57.9%, log-rank P = 0.005).Acute HF patients who were transferred did not have inferior prognoses compared with nontransferred patients when the treatment strategies were correctly assumed by cardiologists. The implementation of early and strict decongestion strategies before transfer may be important for reducing cardiovascular events.

Pulmonary embolism severity index and simplified pulmonary embolism severity index risk scores are useful to predict mortality in Japanese patients with pulmonary embolism.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) and simplified PESI (sPESI) have not been fully evaluated in Japan, so the present study aimed to evaluate these risk stratification models in the prediction of mortality of affected patients in Japan. METHODS AND RESULTS: We retrospectively analysed 302 PE patients (63.9±17.2 years of age; 42.4% male) from January 2011 to December 2012 using data from the Tokyo CCU Network. The areas under the receiver-operating characteristic curves were 0.92 (95% confidence interval (CI): 0.88-0.97) for the PESI and 0.88 (95% CI: 0.77-0.98) for the sPESI. CONCLUSIONS: Both scores can be used to predict PE mortality in Japan.

Administration of Direct Oral Anticoagulant Immediately after Unfractionated Heparin Bolus for the Treatment of Intermediate-High-Risk Pulmonary Thromboembolism.

Objective: This study aims to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) after unfractionated heparin (UFH) bolus for the treatment of intermediate-high-risk pulmonary embolism. Materials and Methods: On the basis of initial treatment, 81 patients were divided into two groups: DOAC after UFH bolus infusion group (group D; n=32) and conventional therapy group (group C; n=49). The frequency of recurrence of venous thromboembolism (VTE) and bleeding within 6 months were compared. In addition, hospitalization length and thrombus reduction rate in the pulmonary artery on computed tomography (CT) at the chronic phase were assessed. Results: Recurrence of VTE was found in one (3.1%) and three patients (6.1%) (P=1.00) in groups D and C, respectively, whereas no bleeding events was found in group D and 8.2% of patients in group C (P=0.15). Group D showed shorter hospitalization (7.2±2.3 days) than group C (15.7±9.9 days; P<0.001). In the subset of patients with serial CT assessment (group D, n=20; group C, n=38), almost all thrombus of pulmonary artery were disappeared and the thrombus reduction rates were similar between the two groups (group D, 99.5%; group C, 97.1%; P=0.59). Conclusion: DOAC administration immediately after UFH bolus treatment has the same efficacy and safety, whereas hospitalization days were significantly shorter than the conventional treatment group.

Gender Differences Among Patients With Acute Pulmonary Embolism.

Gender differences in patients with acute pulmonary embolism (APE) remain unclear and controversial. We aimed to understand the gender differences in patients with APE treated in the cardiovascular care units. The registry database of 1,428 patients with APE treated at the Tokyo cardiovascular care unit Network institutions from 2010 to 2014 was retrieved for analysis. In all, 795 women (55.7%) and 633 men (44.3%) were included in this study. The women were older than men (68.0 ± 16.1 vs 60.9 ± 15.6 years, p < 0.0001). Compared with men, women had more complaints of dyspnea and disturbed consciousness, lesser complaints of leg symptoms, and chest pain. Pulmonary arterial systolic pressure (51.5 ± 22.2 mm Hg vs 47.4 ± 22.4 mm Hg, p = 0.012) and the serum B-type natriuretic peptide level (180.4 [50.7 to 526.1] pg/ml vs 107.0 [25.0 to 306.8] pg/ml, p < 0.0001) on admission, was higher in women than in men. Severe cases with massive embolism were seen more in women compared with men (14.6% vs 9.2%, p = 0.0002). The use of inferior vena cava filters were lower in women than in men (31.9% vs 37.3%, p = 0.029). Furthermore, 30-day PE-related mortality was higher in women than in men significantly (5.0% vs 2.8%, p = 0.043). In conclusion, women APE patients were older with higher severity than men APE patients, resulting in poor prognosis.

Treatment Outcomes of Anticoagulant Therapy and Temporary Inferior Vena Cava Filter Implantation for Pregnancy Complicated by Venous Thrombosis.

Objective: Although deep vein thrombosis (DVT) followed by pulmonary thromboembolism (PE) is a critical complication during pregnancy, there have been few reports about its intrapartum management. We evaluated intrapartum management by using a temporary inferior vena cava filter (IVCF) in pregnant women with PE/DVT. Materials and Methods: Eleven women with PE/DVT during pregnancy between January 2004 and December 2016 were included. The patients were hospitalized for intravenous unfractionated heparin infusion after acute PE/DVT onset. Seven patients were discharged and continued treatment with subcutaneous injection of heparin at the outpatient unit. IVCF was implanted 1-3 days before delivery in 10 patients. Anticoagulant therapy was discontinued 6-12 h before delivery. We retrospectively analyzed rates of maternal or perinatal death, and recurrence of symptomatic PE/DVT. Results: One patient was diagnosed as having PE/DVT and 10 had DVT alone. One patient suffered hemorrhagic shock during delivery; however, maternal or perinatal death and recurrence of symptomatic PE/DVT did not occur in any patient. Conclusion: Maternal or perinatal death and recurrence of symptomatic PE/DVT was not seen in women diagnosed as having PE/DVT during pregnancy and treated with anticoagulant therapy and IVCF.

Cardiac Magnetic Resonance Imaging of Very Late Intrapericardial Hematoma 8 Years after Coronary Artery Bypass Grafting.

A 55-year-old man presented with dyspnea, edema, and appetite loss. He had undergone coronary artery bypass grafting 8 years previously. He had jugular venous distention and Kussmaul's sign. Contrast-enhanced cardiac magnetic resonance imaging (CMRI) demonstrated an intrapericardial mass compressing the right ventricular (RV) cavity. T1- and T2-weighted black-blood images showed a mass with heterogeneous high signal intensity and a thick and dark rim. The mass was considered to be a chronic hematoma. After pericardiotomy with surgical removal of the hematoma, CMRI showed the marked improvement of the RV function. Late intrapericardial hematoma is rare and CMRI is useful for making a differential diagnosis.

Prognosis of super-elderly healthy Japanese patients after pacemaker implantation for bradycardia.

BACKGROUND: The prognosis of super-elderly patients (age≥85 years) who undergo bradycardia pacemaker (PM) implantation remains unknown. METHODS: We retrospectively enrolled 868 patients (men 49.0%, 76.6±10.6 years) who could walk unassisted and whose expected life expectancy was more than 1 year, receiving their first bradycardia PM implantation between January 1, 2006, and June 30, 2013. Clinical outcomes were compared between super-elderly patients (n=201, mean age 88.6±3.2 years) and younger patients (n=667, 73.0±9.3 years). RESULTS: At the end of a median 1285-day follow-up, 128 patients (14.7%) died, of which 54 were cardiac deaths (42.2%). Mortality rates were similar between the groups (16.4% vs. 14.2%, log-rank p=0.56) and across different indications for implantation (atrio-ventricular conduction disturbance or sick sinus syndrome, p=0.59), initial rhythms (sinus rhythm or persistent atrial fibrillation, p=0.62), pacing modes (dual chamber pacing or VVI pacing, p=0.26), and ventricular lead positions (septum or apex, p=0.52). On Cox proportional hazard model analysis, hypertension [hazard ratio (HR)=1.74, 95% confidence interval (CI)=1.19-2.54, p=0.004], diabetes mellitus (HR=2.18, 95% CI=1.51-3.14, p<0.001), history of myocardial infarction (HR=3.59, 95% CI=2.49-5.16, p<0.001), and history of stroke (HR=2.26, 95% CI=1.51-3.37, p<0.001) were independent predictors for mortality. CONCLUSIONS: The mortality rate of super-elderly patients who had no critical illnesses and were healthy enough to walk unassisted at the time of PM implantation was not inferior to that of younger patients. Prognosis was determined by comorbidities, but not by age, PM indication, initial rhythm, pacing leads, or mode.

Assessment of the Safety and Efficacy of Edoxaban for the Treatment of Venous Thromboembolism Secondary to Active Malignancy.

Objective: To assess the safety and efficacy of edoxaban for the treatment of venous thromboembolism (VTE) secondary to active malignancy. Materials and Methods: We enrolled 48 patients with newly diagnosed VTE secondary to active malignancy that was treated with oral edoxaban for 1 year between September 2014 and August 2015. We retrospectively examined the presence or absence of recurrent symptomatic VTE, VTE-related mortality, and bleeding events. Results: No recurrent symptomatic VTE or VTE-related deaths were recorded, enabling efficient assessment. Treatment safety was determined based on the reports of bleeding. Bleeding was reported in two patients, with serious bleeding in one of them. Conclusion: Edoxaban is safe and effective for the treatment of VTE secondary to active malignancy.

Predictive value of biomarkers for the prognosis of acute pulmonary embolism in Japanese patients: Results of the Tokyo CCU Network registry.

BACKGROUND: Several studies from Western countries have reported associations between cardiac troponin and B-type natriuretic peptide (BNP) levels and acute pulmonary embolism prognosis; however, the number of such reports from Asian countries, including Japan, is limited. Thus, we evaluated the relationship between blood biochemical findings and acute-phase pulmonary embolism prognosis in Japanese patients. METHODS: The subjects included 441 patients with acute pulmonary embolism (191 men, 250 women; average age, 65.8±16.0 years) treated at Tokyo CCU Network Institutions from 2009 to 2011 and registered via survey forms. The association between blood biochemical findings at admission and 30-day mortality was investigated. RESULTS: The median BNP value was 186.5pg/mL (25th to 75th interquartile range: 49.8-500pg/mL) of 210 cases. No deaths were recorded among those with BNP levels <90pg/mL (n=70), whereas significantly higher mortality (10 deaths/140 cases, 7.1%; p=0.033) was observed among those with BNP levels ≥90pg/mL. A qualitative cardiac troponin test was positive in 58 of the 204 cases (28.4%), with a significantly higher mortality incidence (p=0.017) among the troponin-positive cases [6 (10.3%) versus 3 (2.1%) deaths among the 146 troponin-negative cases]. The overall mean blood glucose level at admission of 331 cases was 152.0±74.0mg/dL, and 30-day mortality significantly increased with blood glucose values (p=0.048). CONCLUSIONS: Troponin, BNP, and blood glucose levels are useful prognostic biomarkers for acute pulmonary embolism in Japanese patients.

Seasonal Changes in Hospital Admissions for Pulmonary Embolism in Metropolitan Areas of Tokyo (from the Tokyo Cardiovascular Care Unit Network).

Although several studies have shown the relation between temperature/atmospheric pressure and pulmonary embolism (PE), their results are inconsistent. Furthermore, diurnal temperature range (DTR) and diurnal pressure range (DPR) were not fully evaluated for their associations with hospital admissions for PE. Study subjects comprised cases of 1,148 PE treated at institutions belonging to the Tokyo Cardiovascular Care Unit Network from January 2005 to December 2012. Patient data were combined with a variety of daily local climate parameters obtained from the Japan Meteorological Agency. Every 1°C increase in the DTR at lag0 corresponded to an increased relative risk of hospital admission for PE (odds ratio [OR] 1.036, 95% confidence interval [CI] 1.003 to 1.070). In the cooler season (November to April), an increase of 1 hPa (barometric pressure) in the DPR at lag4 and lag5 was associated with an increased relative risk of hospital admission for PE (OR 1.042, 95% CI 1.007 to 1.077 and OR 0.952, 95% CI 0.914 to 0.992, respectively). An increase in the PE hospitalization rate was seen only in the cool season. Using a metropolitan database, we showed that DTR and DPR have different impacts on hospital admissions for PE. In conclusion, we found that an increase in the DTR increases the PE hospitalization rate, especially during the cooler season. The impact of DTR and DPR on PE incidence and related hospitalizations needs to be further evaluated.

Current status of the use of inferior vena cava filters in cases of pulmonary embolism in CCUs: From the Tokyo CCU Network.

OBJECTIVE: To elucidate the current status of use of inferior vena cava filters (IVCFs) in cases of pulmonary embolism at institutions belonging to the Tokyo CCU Network. METHODS: We conducted a retrospective investigation of 832 consecutive cases of pulmonary embolism reported on survey forms to the Tokyo CCU Network between 2005 and 2010. RESULTS: Of 832 cases of pulmonary embolism, IVCFs were used in 338 (40.6%) and not used in 415 (49.9%). Their use was unclear in 79 (9.5%) cases. The use rate gradually increased each year from 2005 until 2008 but decreased from 2009 onward. Moreover, 68.9% of the IVCFs used in cases were non-permanent types. In terms of pulmonary embolism severity, the rate of use was 37.2% in non-massive cases, 49.4% in sub-massive cases, 46.9% in massive cases, and 31.9% in collapse cases. Thirty-day mortality in cases of collapse in which IVCFs were not used was extremely high at 75.8%, suggesting that in many cases, rapid deterioration may occur with insufficient time for IVCF insertion. The differences in IVCF usage rate among institutions were large in the range of 12.5-90% from 2005 to 2008, which slightly declined to the range of 25.0-72.2% from 2009 to 2010. CONCLUSIONS: We elucidated the current IVCF use status in cases of pulmonary embolism at institutions belonging to the Tokyo CCU Network. Since the status of use differed among institutions, future studies of effective methods of use are required.