Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069.

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.

Association between tranexamic acid administration and mortality based on the trauma phenotype: a retrospective analysis of a nationwide trauma registry in Japan.

BACKGROUND: In trauma systems, criteria for individualised and optimised administration of tranexamic acid (TXA), an antifibrinolytic, are yet to be established. This study used nationwide cohort data from Japan to evaluate the association between TXA and in-hospital mortality among all patients with blunt trauma based on clinical phenotypes (trauma phenotypes). METHODS: A retrospective analysis was conducted using data from the Japan Trauma Data Bank (JTDB) spanning 2019 to 2021. RESULTS: Of 80,463 patients with trauma registered in the JTDB, 53,703 met the inclusion criteria, and 8046 (15.0%) received TXA treatment. The patients were categorised into eight trauma phenotypes. After adjusting with inverse probability treatment weighting, in-hospital mortality of the following trauma phenotypes significantly reduced with TXA administration: trauma phenotype 1 (odds ratio [OR] 0.68 [95% confidence interval [CI] 0.57-0.81]), trauma phenotype 2 (OR 0.73 [0.66-0.81]), trauma phenotype 6 (OR 0.52 [0.39-0.70]), and trauma phenotype 8 (OR 0.67 [0.60-0.75]). Conversely, trauma phenotypes 3 (OR 2.62 [1.98-3.47]) and 4 (OR 1.39 [1.11-1.74]) exhibited a significant increase in in-hospital mortality. CONCLUSIONS: This is the first study to evaluate the association between TXA administration and survival outcomes based on clinical phenotypes. We found an association between trauma phenotypes and in-hospital mortality, indicating that treatment with TXA could potentially influence this relationship. Further studies are needed to assess the usefulness of these phenotypes.

Prevalence of bleeding events in real-world Japanese registry for Percutaneous Ventricular Assist Device.

PURPOSE: Bleeding complication is a critical risk factor for outcomes of acute heart failure patients requiring mechanical circulatory support (MCS), including percutaneous catheter-type heart pumps (Impella). The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) is an ongoing, large-scale, real-world registry to characterize Japanese patients requiring Impella. Here we analyzed bleeding complication profiles in patients who received Impella. METHODS: All consecutive Japanese patients who received Impella from October 2017 to January 2020 were enrolled. The 30-day survival and bleeding complications were analyzed. RESULTS: A total of 1344 patients were included: 653 patients received Impella alone, 685 patients received a combination of veno-arterial extracorporeal membrane oxygenation and Impella (ECPELLA), and 6 patients had failed Impella delivery. Overall 30-day survival was 67.0%, with Impella alone at 81.9% and ECPELLA at 52.7%. Overall bleeding/hematoma adverse events with a relation or not-excluded relation to Impella was 6.92%. Among them, the rates of hematoma and bleeding from medical device access sites were 1.41% and 4.09%, respectively. There was no difference between etiologies for these events. CONCLUSION: This study represents the first 3-year survival and the safety profile focused on bleeding adverse events from the J-PVAD registry. The results show that the real-world frequency of bleeding adverse events for patients who received Impella was an expected range from previous reports, and future real-world studies should aim to expand this data set to improve outcomes and adverse events.

Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) have been a hot topic since the Japan EPA Lipid Intervention Study (JELIS), the first landmark study using a highly purified eicosapentaenoic acid (EPA), indicated that EPA could decrease the incidence of cardiovascular events. Over 20 years have passed since the JELIS was conducted, and the standard treatment for dyslipidemia has altered significantly since then. The JELIS subjects did not undertake the current risk management especially current standard statins and did not exclusively target secondary prevention patients. In addition, the subjects included are relatively high EPA population. Furthermore, the clinical implication of the plasma EPA/arachidonic acid (AA) ratio as a biomarker has not yet been validated. Therefore, the Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and EPA (RESPECT-EPA) was planned and is currently underway in Japan. METHODS: The RESPECT-EPA comprises two parts: the open-label randomized controlled trial (RCT) and biomarker study (prospective cohort study design). The RCT included patients with a low EPA/AA ratio. These patients were then randomized to highly purified EPA (1800 mg/day) or control groups. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, unstable angina pectoris, and clinically indicated coronary revascularization. The biomarker study assesses the EPA/AA ratio's usefulness as a biomarker for cardiovascular events prediction. RESULTS: In the RCT, a total of 2,460 patients were enrolled in 95 sites in Japan. Patients' baseline characteristics were similar between intervention and control groups in the RCT. The baseline median EPA/AA ratio was 0.243 and 0.235, respectively. A total of 1,314 patients were participated in the observational part, and the baseline median EPA/AA ratio was 0.577. CONCLUSIONS: After this study is completed, we will have further evidence on whether a highly purified EPA is effective in reducing cardiovascular events for secondary prevention or not, as well as whether if EPA/AA ratio is a predictor for future cardiovascular events. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012069).

Impact of glycated hemoglobin on 2-year clinical outcomes in elderly patients with atrial fibrillation: sub-analysis of ANAFIE Registry, a large observational study.

BACKGROUND: This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). METHODS: The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%). RESULTS: Of 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA2DS2-VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11-1.93]) and net clinical outcome (aHR 1.33 [1.05-1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs. CONCLUSIONS: Among elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level. TRIAL REGISTRATION: UMIN000024006; date of registration: September 12, 2016.

Short-Term Outcomes of Impella Support in Japanese Patients With Cardiogenic Shock Due to Acute Myocardial Infarction　- Japanese Registry for Percutaneous Ventricular Assist Device (J-PVAD).

BACKGROUND: The Impella®percutaneous left ventricular assist device has been available in Japan since 2017. This is the first large-scale registry study to analyze the efficacy and safety of Impella in Japanese patients with acute myocardial infarction with cardiogenic shock (AMICS).Methods and Results: The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) has registered all consecutive Japanese patients treated with Impella. We extracted data for 593 AMICS patients from J-PVAD and analyzed 30-day survival and safety profiles. Overall 30-day survival was 63.1%. The 30-day survival of the Impella alone and Impella plus venoarterial extracorporeal membrane oxygenation (ECPELLA) groups was 80.9% and 45.7%, respectively. The Impella alone group was older and had a lower rate of cardiac arrest, milder consciousness disturbance, less inotrope use, lower serum lactate concentrations, higher B-type natriuretic peptide concentrations, and higher left ventricular ejection fraction (LVEF) than the ECPELLA group. Cox regression analysis revealed that older age and comorbid renal disturbance were common risk factors affecting 30-day mortality in both groups. Major adverse events were hemolysis (10.8%), hemorrhage/hematoma (7.6%), peripheral ischemia (4.4%), stroke (1.3%), and thrombosis (0.7%). LVEF improved in both groups during support. CONCLUSIONS: AMICS treatment with Impella showed favorable 30-day survival and safety profiles. The survival rate of patients treated with Impella alone was particularly high. Further studies are needed to improve outcomes of patients with ECPELLA support.

Safety Profile and Effectiveness of Rivaroxaban for Patients With Venous Thromboembolism in Japan　- Results From Post-Marketing Surveillance (XASSENT).

BACKGROUND: The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period. CONCLUSIONS: XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

Relationship Between Direct Oral Anticoagulant Doses and Clinical Outcomes in Elderly Patients With Non-Valvular Atrial Fibrillation　- ANAFIE Registry Sub-Analysis.

BACKGROUND: This sub-analysis of the ANAFIE Registry, a prospective, observational study of >30,000 Japanese non-valvular atrial fibrillation (NVAF) patients aged ≥75 years, assessed the prevalence of direct oral anticoagulant (DOAC) under-dose prevalence, identified the factors of under-dose prescriptions, and examined the relationship between DOAC dose and clinical outcomes.Methods and Results: Patients, divided into 5 groups by DOAC dose (standard, over-, reduced, under-, and off-label), were analyzed for background factors, cumulative incidences, and clinical outcome risk. Endpoints were stroke/systemic embolic events (SEE), major bleeding, and all-cause death during the 2-year follow-up. Of 18,497 patients taking DOACs, 20.7%, 3.8%, 51.6%, 19.6%, and 4.3%, were prescribed standard, over-, reduced, under-, and off-label doses. Factors associated with under-dose use were female sex, age ≥85 years, reduced creatinine clearance, history of major bleeding, polypharmacy, antiplatelet agents, heart failure, dementia, and no history of catheter ablation or cerebrovascular disease. After confounder adjustment, under-dose vs. standard dose was not associated with the incidence of stroke/SEE or major bleeding but was associated with a higher mortality rate. Patients receiving an off-label dose showed similar tendencies to those receiving an under-dose; that is, they showed the highest mortality rates for stroke/SEE, major bleeding, and all-cause death. CONCLUSIONS: Inappropriate low DOAC doses (under- or off-label dose) were not associated with stroke/SEE or major bleeding but were associated with all-cause death.

Causes of Death in Elderly Patients With Non-Valvular Atrial Fibrillation　- Results From the ANAFIE Registry.

BACKGROUND: Previous studies on mortality in atrial fibrillation (AF) included a limited number of elderly patients receiving direct oral anticoagulants (DOACs). This subanalysis of the ANAFIE Registry evaluated 2-year mortality according to causes of death of elderly non-valvular AF (NVAF) patients in the DOAC era.Methods and Results: The ANAFIE Registry was a multicenter prospective observational study. Mean patient age was 81.5 years and 57.3% of patients were male. Of the 32,275 patients completing the study, 2,242 died. The most frequent causes of death were cardiovascular (CV) death (32.4%), followed by infection (17.1%) and malignancy (16.1%). Incidence rates of CV-, malignancy-, and infection-related death were 1.20, 0.60, and 0.63 per 100 person-years, respectively. Patients aged ≥85 years showed increased proportions of non-CV and non-malignancy deaths and a decreased proportion of malignancy deaths compared with patients aged <85 years. The incidence of death due to congestive heart failure/cardiogenic shock, infection, and renal disease was higher in patients aged ≥85 than those aged <85 years. Compared with warfarin, DOACs were associated with a significantly lower risk of death by intracranial hemorrhage, ischemic stroke, and renal disease. CONCLUSIONS: This subanalysis described the mortality according to causes of death of Japanese elderly NVAF patients in the DOAC era. Our results imply that a more holistic approach to comorbid conditions and stroke prevention are required in these patients.

Echocardiographic Parameters of Left Atrial Structure and Function and Clinical Outcomes at 2 Years in Elderly Patients With Atrial Fibrillation　- The ANAFIE Echocardiographic Substudy.

BACKGROUND: This prospective ANAFIE Registry substudy investigated the relationship between the echocardiographic parameters of left atrial (LA) structure and function and clinical outcomes at 2 years among atrial fibrillation (AF) patients aged ≥75 years.Methods and Results: Outcomes of 1,474 elderly non-valvular AF (NVAF) patients who underwent transthoracic echocardiography at baseline were analyzed by categories of maximum LA volume index (max. LAVi) and LA emptying fraction (LAEF) total. Baseline mean±standard deviation LAEF total and max. LAVi were 28.2±14.9% and 54.2±25.9 mL/m2, respectively. Proportions of oral anticoagulant (OAC), direct OAC, and warfarin use were 92.7%, 68.7%, and 24.0%, respectively. Patients with LAEF total ≤45.0% (n=1,213) vs. >45.0% (n=224) were at higher risk of cardiovascular events (hazard ratio [HR]: 2.19, P=0.021) and heart failure (HF) hospitalization (HR: 2.25, P=0.045). Risk of all-cause death was higher with max. LAVi >48.0 mL/m2(n=656) vs. ≤48.0 mL/m2(n=621) (HR: 1.69, P=0.048). Subgroups with abnormal LA function and structure had increased incidence of cardiac/cardiovascular events and HF hospitalization. No significant interaction was observed between echocardiographic parameters and OAC type. CONCLUSIONS: Elderly Japanese patients with NVAF and LAEF total ≤45.0% were at higher risk of cardiovascular events and HF hospitalization, and those with max. LAVi >48.0 mL/m2were at higher risk of all-cause death.

Associated organs and system with COVID-19 death with information of organ support: a multicenter observational study.

BACKGROUND: The organ dysfunction that is associated with death in COVID-19 patients has not been determined in multicenter epidemiologic studies. In this study, we evaluated the major association with death, concomitant organ dysfunction, and proportion of multiple organ failure in deaths in patients with COVID-19, along with information on organ support. METHODS: We performed an observational cohort study using the Japanese multicenter research of COVID-19 by assembling a real-world data (J-RECOVER) study database. This database consists of data on patients discharged between January 1 and September 31, 2020, with positive SARS-CoV-2 test results, regardless of intensive care unit admission status. These data were collected from the Diagnosis Procedure Combination and electronic medical records of 66 hospitals in Japan. The clinician identified and recorded the organ responsible for the death of COVID-19. RESULTS: During the research period, 4,700 patients with COVID-19 were discharged from 66 hospitals participating in the J-RECOVER study; of which, 272 patients (5.8%) from 47 institutions who died were included in this study. Respiratory system dysfunction (87.1%) was the leading association with death, followed by cardiovascular (4.8%), central nervous (2.9%), gastrointestinal (2.6%), and renal (1.1%) dysfunction. Most patients (96.7%) who died of COVID-19 had respiratory system damage, and about half (48.9%) had multi-organ damage. Of the patients whose main association with death was respiratory dysfunction, 120 (50.6%) received mechanical ventilation. CONCLUSION: This study showed that although respiratory dysfunction was the most common association with death in many cases, multi-organ dysfunction was associated with death due to COVID-19.

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.

Three-year experience of catheter-based micro-axial left ventricular assist device, Impella, in Japanese patients: the first interim analysis of Japan registry for percutaneous ventricular assist device (J-PVAD).

Catheter-based micro-axial ventricular assist device Impella® (Abiomed, Danvers, MA) has been used in Japanese patients with drug-refractory acute heart failure (AHF) since 2017. This is the first interim analysis of the ongoing Japan Registry for Percutaneous Ventricular Assist Device (J-PVAD) to investigate the safety and efficacy of Impella support. Between October 2017 and January 2020, 823 Japanese patients, who were treated with the Impella 2.5, CP, or 5.0 pump, were enrolled. The primary endpoints were safety profiles and cumulative 30-day survival. Among them, 44.8% of patients were acute myocardial infarction with cardiogenic shock. The Impella pumps were unable to implant in 4 patients. The Impella 2.5, CP, and 5.0 pumps were used in 72.4%, 6.2%, and 16.6%, respectively, and mean support duration was 8.1 ± 10.2 days. Combination use of Impella and venoarterial extracorporeal membrane oxygenation (VA-ECMO) was applied for 387 patients (47.3%). Pump stop occurred 22 patients (2.7%). Major adverse events included hemolysis (11.2%), hemorrhage/hematoma (6.1%), peripheral ischemia (1.6%), and stroke (1.6%). The overall 30-day survival was 62.2%. Survival of patients with single Impella support was significantly higher than patients with Impella combined with VA-ECMO support (81.1% vs 49.6%; p < 0.01), who had lower blood pressure, lower left ventricular ejection fraction, and higher degree of inotropic support. Results suggest that short-term outcome of Impella support for Japanese patients was favorable with acceptable safety profiles.

Impact of Previous Stroke on Clinical Outcome in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Registry.

BACKGROUND: We determined the long-term event incidence among elderly patients with nonvalvular atrial fibrillation in terms of history of stroke/transient ischemic attack (TIA) and oral anticoagulation. METHODS: Patients aged ≥75 years with documented nonvalvular atrial fibrillation enrolled in the prospective, multicenter, observational All Nippon Atrial Fibrillation in the Elderly Registry between October 2016 and January 2018 were divided into 2 groups according to history of stroke/TIA. The primary end point was the occurrence of stroke/systemic embolism within 2 years, and secondary end points were major bleeding and all-cause death within 2 years. Cox models were used to determine whether there was a difference in the hazard of each end point in patients with/without history of stroke/TIA, and in ischemic stroke/TIA survivors taking direct oral anticoagulants versus those taking warfarin. RESULTS: Of 32 275 evaluable patients (13 793 women [42.7%]; median age, 81.0 years), 7304 (22.6%) had a history of stroke/TIA. The patients with previous stroke/TIA were more likely to be male and older and had higher hazard rates of stroke/systemic embolism (adjusted hazard ratio, 2.25 [95% CI, 1.97-2.58]), major bleeding (1.25, 1.05-1.49), and all-cause death (1.13, 1.02-1.24) than the other groups. Of 6446 patients with prior ischemic stroke/TIA, 4393 (68.2%) were taking direct oral anticoagulants and 1668 (25.9%) were taking warfarin at enrollment. The risk of stroke/systemic embolism was comparable between these 2 groups (adjusted hazard ratio, 0.90 [95% CI, 0.71-1.14]), while the risk of major bleeding (0.67, 0.48-0.94), intracranial hemorrhage (0.57, 0.39-0.85), and cardiovascular death (0.71, 0.51-0.99) was lower among those taking direct oral anticoagulants. CONCLUSIONS: Patients aged ≥75 years with nonvalvular atrial fibrillation and previous stroke/TIA more commonly had subsequent ischemic and hemorrhagic events than those without previous stroke/TIA. Among patients with previous ischemic stroke/TIA, the risk of hemorrhagic events was lower in patients taking direct oral anticoagulants compared with warfarin. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: UMIN000024006.

Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease.

BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease. METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority. RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority). CONCLUSIONS: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).

The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial.

BACKGROUND: The success of antithrombotic therapies is assessed based on thrombotic and bleeding events. Simultaneously assessing both kinds of events might be challenging, and recurrent bleeding events are often ignored. We tried to confirm the effects of kidney function on outcome events in patients undergoing antithrombotic therapy. METHODS: As a post hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, a randomized clinical trial with a median follow-up of 36 months, patients were divided into high and low estimated glomerular filtration rate (eGFR) groups with a cutoff value of 50 mL/min. The cumulative incidence of bleeding and crude incidence of recurrent bleeding per 100 patient-years were calculated. We used the Cox regression model with multiple failure time data for recurrent bleeding events. RESULTS: Among 2092 patients, 1386 (66.3%) showed high eGFR. The cumulative bleeding events per 100 patients at 1 year were 5.4 and 6.2 in the high and low eGFR groups, respectively. The difference continued to increase over time. The hazard ratio for time to the first bleeding event in the high eGFR group was 0.875 (95% confidence interval 0.701-1.090, p = .234) and that for the first composite event was 0.723 (95% confidence interval 0.603-0.867, p < .000). The recurrent bleeding events per 100 person-years were 11.3 and 15.3 in the high and low eGFR groups, respectively, with a rate ratio of 0.738 (95% confidence interval 0.615-0.886, p = .001). During the observation period, the risk of bleeding changed with time. It peaked soon after the study enrollment in both groups. It decreased continuously in the high eGFR group but remained high in the low eGFR group. CONCLUSIONS: We reaffirmed that kidney function affects bleeding events in patients on antithrombotic therapy, considering recurrent events. Patients should have detailed discussions with physicians regarding the possible bleeding events when continuing antithrombotic therapy, especially in patients with decreased kidney function. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000016612 . ClinicalTrials.gov, NCT02642419 . Registered on 21 October 2015.

Edoxaban Monotherapy in Nonvalvular Atrial Fibrillation Patients with Coronary Artery Disease.

Background: Current guidelines recommend an oral anticoagulant (OAC) monotherapy in patients with nonvalvular atrial fibrillation (NVAF) and stable coronary artery disease (CAD) 1 year postpercutaneous coronary intervention (PCI). It might be possible to shorten the time for de-escalation from a dual therapy to monotherapy, but data regarding de-escalation to an edoxaban monotherapy are lacking. This study aimed to assess the clinical safety of an edoxaban monotherapy in patients with NVAF and stable CAD. Methods: A multicenter, prospective, randomized, open-label, and parallel group study was established to investigate the safety of an edoxaban monotherapy in patients with NVAF and stable CAD including over 6 months postimplantation of a third-generation DES and 1 year postimplantation of other stents (PRAEDO AF study). Between March 2018 and June 2020, 147 patients from 8 institutions in Japan were randomized to receive either an edoxaban monotherapy (n = 74) or combination therapy (edoxaban plus clopidogrel, n = 73). The primary study endpoint was the composite incidence of major bleeding and clinically significant bleeding, defined according to the ISTH criteria. Results: Major or clinically significant bleeding occurred in 2 patients in the monotherapy group (1.67% per patient-year) and in 5 patients in the combination therapy group (4.28% per patient-year) (hazard ratio, 0.39; 95% confidence interval, 0.08-2.02). There was no incidence of a myocardial infarction, stent thrombosis, unstable angina requiring revascularization, ischemic stroke, systemic stroke, or hemorrhagic stroke in either of the groups. Conclusions: The edoxaban monotherapy was shown to have acceptable clinical safety in patients with NVAF and stable CAD. The study was registered with the Japan Registry of Clinical Trials (jRCTs031180119).

Clinical Outcomes After Percutaneous Coronary Intervention in East Asian Patients　- 30-Month Results of the PENDULUM Registry.

BACKGROUND: The 12-month results of the PENDULUM registry showed that after implantation of second-generation drug-eluting stents (DES), high P2Y12reaction unit (HPR) were independently associated with ischemic but not bleeding events.Methods and Results: This study analyzed cumulative incidences of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding (Bleeding Academic Research Consortium type 3 and 5) at 30 months after index percutaneous coronary intervention (PCI) (primary endpoints). Of 6,422 patients undergoing PCI with DES, 5,796 completed the 30-month follow up. The continuation rate of dual antiplatelet therapy decreased to 59.3% at 12 months and 26.4% at 30 months. At 30 months, the cumulative incidence of MACCE increased linearly and reached 9.5% (95% confidence interval 8.8-10.2) and that of major bleeding had the inflection point at 12 months and was 4.4% (3.9-5.0). MACCE and bleeding events were higher in HPR patients (unadjusted P value). After covariate adjustment, P2Y12reactivity units measured immediately after index PCI was not an independent risk factor for MACCE or major bleeding at 30 months. CONCLUSIONS: MACCE consistently increased after 12 months post-PCI, whereas the increase in major bleeding events slowed down after 12 months in Japanese PCI patients in a real-world clinical setting. HPR patients had increased MACCE and bleeding complications, but HPR was not an independent risk factor of events at 30 months.

Early P2Y12 Inhibitor Single Antiplatelet Therapy for High-Bleeding Risk Patients After Stenting　- PENDULUM Mono 24-Month Analysis.

BACKGROUND: In PENDULUM mono, Japanese patients with high bleeding risk (HBR) received short-term dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) with prasugrel after percutaneous coronary intervention (PCI). One-year data from PENDULUM mono showed better outcomes with prasugrel monotherapy after short-term DAPT compared with matched patients in the PENDULUM registry with longer DAPT durations according to guidelines at that time. This study presents 2-year results.Methods and Results: We compared 24-month data from PENDULUM mono (n=1,107; de-escalation strategy group) and the PENDULUM registry (n=2,273; conventional strategy group); both were multicenter, non-interventional, prospective registry studies, using the inverse probability of treatment weighting (IPTW) method. In the PENDULUM mono group, the cumulative incidence of clinically relevant bleeding (CRB) at 24 months post-PCI (primary endpoint) was 6.8%, and that of major adverse cardiac and cerebrovascular events (MACCE) was 8.9%. After IPTW adjustment, the cumulative incidence of CRB was 5.8% and 7.2% in PENDULUM mono and the PENDULUM registry, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.57-1.04; P=0.086), and that of MACCE was 8.0% and 9.5%, respectively (HR 0.77; 95% CI 0.59-1.01; P=0.061). CONCLUSIONS: Japanese PCI patients with HBR prescribed prasugrel SAPT after short-term DAPT had a lower ischemic event risk than those prescribed long-term DAPT, and this was particularly relevant for ischemic events after 1 year.