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Background Endothelial dysfunction (ED) is associated with cardiovascular events in patients with atrial fibrillation (AF). However, the utility of ED as a prognostic marker after AF ablation supplementary to the CHA 2 DS 2 ‐VASc score is unclear. This study aimed to investigate the relationship between ED and 5‐year cardiovascular events in patients undergoing AF ablation. Methods and Results We conducted a prospective cohort study of patients who underwent a first‐time AF ablation and for whom the endothelial function was assessed by the peripheral vascular reactive hyperemia index (RHI) before ablation. We defined ED as an RHI of 2 DS 2 ‐VASc score ( P =0.004). The 5‐year incidence of cardiovascular events was higher among patients with ED than those without ED (98 [11.8%] versus 13 [6.2%]; log‐rank P =0.014). We found ED to be an independent predictor of cardiovascular events after AF ablation (hazard ratio [HR], 1.91 [95% CI, 1.04–3.50]; P =0.036) along with a CHA 2 DS 2 ‐VASc score of ≥2 (≥3 for women) (HR, 3.68 [95% CI, 1.89–7.15]; P Conclusions The prevalence of ED among patients with AF was high. Assessing the endothelial function could enable the risk stratification of cardiovascular events after AF ablation.

Background and Purpose: To assess the actual malignant core volume in endovascular therapy (EVT) eligible patients with large ischemic regions from the RESCUE-Japan LIMIT database. Methods: RESCUE-Japan LIMIT was a multicenter, open-label, randomized clinical trial in large vessel occlusion patients with large ischemic region indicated by an ASPECTS valued from 3 to 5. We assessed the volumetrically measured core volume which identifies an unfavorable outcome (modified Rankin Scale; mRS 4-6 at 90 days) by receiver operating characteristic (ROC) analysis in the endovascular therapy (EVT) group. Predictive marginal probabilities were also assessed to identify the unfavorable outcome. Symptomatic intracranial hemorrhages and death within 90 days in the EVT group and the medical management (MM) group were compared. Clinical characteristics and radiological values were also compared. Results: Of the 203 cases enrolled, 182 patients (92 in EVT group vs. 90 in MM group) had adequate core volume. The mean age was 75.6±10 years old and 46% of females in the EVT group and 77.0±10 years old and 42% of females in the MM group. Median core volume was 94 (IQR; 65.3-147.5) mL in EVT patients and 110 (IQR; 74.0-140.0) mL in those with MM group (P=0.84). ROC analysis identified a core volume of 120 mL as the unfavorable outcome (61/92) in the EVT group (51% sensitivity and 77% specificity, area under curve=0.65) and 99 mL in the MM group (77/91, 62% sensitivity and 54% specificity, area under curve=0.56). Predictive marginal probabilities indicated 132 mL as an overlay of the two groups for achieving the unfavorable functional outcome. Symptomatic intracranial hemorrhage was seen in 9.8% in the EVT group and 5.6% in the MM group (p=0.28), and death within 90 days was 17.4% in the EVT group and 23.3% in the MM group (p=0.32). Conclusions: The current analysis demonstrates that a core threshold of approximately 130 mL is the upper limit for identifying large ischemic region stroke patients treated with EVT who are unlikely to suffer from unfavorable outcomes. EVT-eligible patients under this threshold may benefit from EVT. Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT03702413.

Background We aimed to compare outcomes after stroke due to anterior circulation large vessel occlusion with initial imaging assessments using diffusion‐weighted imaging (DWI) or noncontrast computed tomography (NCCT). Methods Among 2399 patients with large vessel occlusion stroke in a prospective, multicenter registry, patients with (1) prestroke modified Rankin Scale scores 0 to 1, (2) occlusion of the internal carotid artery or M1 segment of the middle cerebral artery, and (3) onset‐to‐hospital‐arrival time Results A total of 343 patients (130 women [37.9%]; median age, 74 years [interquartile range, IQR, 66–82 years]) were analyzed. DWI‐based assessment was performed in 217 patients, and NCCT‐based assessment was performed in 126 patients. The DWI group showed a lower baseline National Institutes of Health Stroke Scale score ( P P P P =0.89), with similar rates of successful recanalization (77.6% versus 76.4%, respectively; P =0.88). Frequency of good functional outcome was 47.0% in the DWI group and 41.3% in the NCCT group (adjusted odds ratio, 1.32; 95% CI, 0.49–3.55). Symptomatic intracranial hemorrhage was encountered in 2.8% in the DWI group and 1.6% in the NCCT group ( P =0.71). Conclusions Potential difference in accuracy of ischemic damage assessment between the 2 modalities did not seem to affect outcomes of anterior circulation large vessel occlusion stroke. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.

Background and Purpose— The treatment and prognosis of acute large vessel occlusion with mild symptoms have not been sufficiently studied. The present study aimed to investigate the clinical or radiological predictors of clinical outcome in patients with stroke with mild symptoms due to acute large vessel occlusion. Methods— Of 2420 patients with acute large vessel occlusion in the RESCUE-Japan Registry 2 (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Registry 2), a multicenter prospective registry in Japan, patients with modified Rankin Scale scores of 0 to 2 before onset and initial National Institutes of Health Stroke Scale (NIHSS) scores of 0 to 5 were examined in post hoc analysis. We examined the clinical and radiological characteristics associated with a favorable outcome (modified Rankin Scale score, 0–2 at 90 days) using multivariate analysis, as well as the factors associated with a favorable outcome in patients treated with endovascular therapy. Results— We analyzed 272 patients (median age, 73 years; median NIHSS score on admission, 3). Eighty-six (31.6%) patients were treated with intravenous recombinant tissue-type plasminogen activator, 54 (19.9%) underwent endovascular therapy, and 208 (76.5%) showed a favorable outcome. In multivariate analysis, age P Conclusions— Younger age, lower initial NIHSS score, intravenous recombinant tissue-type plasminogen activator, and absence of hyperglycemia were independently associated with a favorable outcome in patients with acute large vessel occlusion with low NIHSS scores. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.

Background: Many studies have reported that dipeptidyl peptidase (DPP)-4 inhibitors do not significantly reduce cardiovascular events (CVE). We sought to evaluate whether DPP-4 inhibitors effected the incidence of CVE in diabetic patients with no history of atherosclerotic events. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; heart failure requiring hospitalization; aortic disease; and peripheral artery disease. JPAD patients were divided into a DPP-4 Group and a non-DPP-4 Group based on whether or not they were taking DPP-4 inhibitors at the 2013 follow-up. We investigated the incidence of CVE in 1,107 JPAD patients who had had at least one follow-up by 2019. Results: During the observation period from 2013 to 2019, there were 37 (7%) CVE in the DPP-4 Group (n=520) and 66 (11%) in the non-DPP-4 Group (n=587). The incidence of CVE was significantly lower in the DPP-4 Group than in the non-DPP-4 Group (Log-Rank P=0.0074, Figure). Cox proportional hazards model analysis revealed that use of DPP-4 inhibitors (HR, 0.65: 0.43-0.98, P=0.04) was an independent factor after adjustment for age ≥65 years, hypertension, dyslipidemia, and, insulin usage (Figure). Conclusions: Our study demonstrated that the use of DPP-4 inhibitors was associated with a reduced incidence of CVE after adjustment in diabetic patients without a history of atherosclerotic events. It is necessary to be aware of the cardiovascular event-suppressing effect of DPP-4 inhibitors on diabetic patients.

Background: We sought to evaluate whether there was a difference in the incidence rate of cardiovascular event (CVD) among different hemoglobin (Hb) A1c levels in diabetic patients without a history of atherosclerotic events. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; aortic disease; and peripheral artery disease. Among 2,535 JPAD patients, HbA1c levels of the JPAD patients were recorded on average 8 times. Based on the mean value of HbA1c, we divided the patients into three groups: a High HbA1c Group (n=899, HbA1c ≥7.5%); a Moderate HbA1c Group (n=581, 7.5% >HbA1c ≥7.0 %); or, a Low HbA1c Group (n=1055, 7.0% >HbA1c). We compared the incidence of CVD among the three groups. Results: The mean HbA1c (%) was 8.6 in the High HbA1c Group, 7.4 in the Moderate HbA1c Group, and 6.6 in the Low HbA1c Group on registration. During an 11.56-year follow-up, the incidence of CVD was significantly higher in the High HbA1c Group (P2 , duration of diabetes ≥7.0% years, medications, eGFR ≥60 ml/min/1.73m 2 , and systolic blood pressure ≥140 mm Hg (Figure). Conclusions: Our study demonstrated that HbA1c ≥7.5% was independently associated with the incidence of CVD in diabetic patients without a history of atherosclerotic events while 7.5% >HbA1c ≥7.0 % was not.

Background: No clinical studies have focused on the factors associated with discharge destination in patients with acute decompensated heart failure. Methods and Results: Of 4,056 consecutive patients hospitalized for ADHF in the KCHF registry, we analyzed 3,460 patients hospitalized from their homes and discharged alive. There were 3009 and 451 patients who were discharged to home (home discharge) and non-home (non-home discharge), respectively. We investigated the factors associated with non-home discharge and compared the outcomes between home discharge and non-home discharge. Factors independently and positively associated with non-home discharge were age ≥80 years (odds ratio [OR]:1.76, 95% confidence interval [CI]:1.28-2.42), body mass index ≤22 kg/m 2 (OR:1.49, 95%CI:1.12-1.97), poor medication adherence (OR:2.08,95%CI:1.49-2.88), worsening heart failure (OR:2.02, 95%CI:1.46-2.82), stroke during hospitalization (OR:3.74, 95%CI:1.75-8.00), functional decline (OR:12.24, 95%CI:8.74-17.14) and length of hospital stay >16 days (OR:4.14, 95%CI:3.01-5.69), while those negatively associated were diabetes mellitus (OR:0.69, 95%CI:0.51-0.94), cohabitants (OR:0.62, 95%CI:0.46-0.85), and ambulatory state before admission (OR:0.25, 95%CI:0.18-0.36). The cumulative 1-year incidence of all-cause death was significantly higher in the non-home discharge group than in the home discharge group. The non-home discharge group compared with the home discharge group was associated with a higher adjusted risk for all-cause death (HR:1.66, P Conclusions: The discharge destination of acute decompensated heart failure patients is influenced by factors such as pre-hospital social background, age, body mass index, low self-care ability, events during hospitalization (worsening heart failure, stroke, etc.), functional decline, and length of hospital stay; moreover, the prognosis of non-home discharge patients is worse than that of home discharge patients.

Background: Rapid and accurate diagnosis of acute coronary syndrome (ACS) is critical to prevent the fatal complication accompanied with the delay of the treatment. However, the diagnosis of non-ST-segment elevation ACS (NSTE-ACS), especially shortly after the onset, is not straightforward because even high-sensitivity cardiac troponin (hs-cTn) is sometimes not elevated at that phase. We previously reported in a retrospective study that serum nardilysin is a potential biomarker for the early detection of NSTE-ACS. Here, we present the results of the Nardi-ACS study, a multicenter prospective study conducted at six centers in Japan to clarify the significance of nardilysin for the early detection of ACS. Methods and Results: We analyzed serum nardilysin and hs-cTnI (Architect; Abbott) in the sequential 2 independent cohorts; phase I primary cohort (435 patients with chest pain who consecutively visited to the emergency room (ER)) and phase II validation cohort (486 patients with a strong suspicion of ACS who underwent coronary angiography). The frequency of non-ACS, STEMI and NSTE-ACS was 64.4, 22.5, and 13.1 (%) in the phase I, and 14.0, 60.0, and 25.9 (%) in the phase II cohort, respectively. The cutoff value of serum nardilysin was set at 1350.9 pg/ml (mean +2SD) obtained in 246 healthy volunteers, while the cutoff of hs-cTnI was set at 52 pg/ml. The initial blood test in the phase I cohort revealed that nardilysin was significantly elevated in ACS patients, compared to non-ACS patients (p Conclusion: Nardilysin could be a potential biomarker for the early diagnosis of troponin-negative NSTE-ACS.

Background Heart failure might be an important determinant in choosing coronary revascularization modalities. There was no previous study evaluating the effect of heart failure on long‐term clinical outcomes after percutaneous coronary intervention (PCI) relative to coronary artery bypass grafting (CABG). Methods and Results Among 14 867 consecutive patients undergoing first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013 in the CREDO‐Kyoto PCI/CABG registry Cohort‐3, we identified the current study population of 3380 patients with three‐vessel or left main coronary artery disease, and compared clinical outcomes between PCI and CABG stratified by the subgroup based on the status of heart failure. There were 827 patients with heart failure (PCI: N=511, and CABG: N=316), and 2553 patients without heart failure (PCI: N=1619, and CABG: N=934). In patients with heart failure, the PCI group compared with the CABG group more often had advanced age, severe frailty, acute and severe heart failure, and elevated inflammatory markers. During a median 5.9 years of follow‐up, there was a significant interaction between heart failure and the mortality risk of PCI relative to CABG (interaction P =0.009), with excess mortality risk of PCI relative to CABG in patients with heart failure (HR, 1.75; 95% CI, 1.28–2.42; P P =0.77). Conclusions There was a significant interaction between heart failure and the mortality risk of PCI relative to CABG with excess risk in patients with heart failure and neutral risk in patients without heart failure.

Background Outcomes after stroke as a result of large‐vessel occlusion in patients with prestroke disability were compared between endovascular therapy (EVT) and medical management. Methods and Results Of 2420 patients with acute stroke with large‐vessel occlusion in a prospective, multicenter, nationwide registry in Japan, patients with prestroke modified Rankin Scale scores 2 to 4 with occlusion of the internal carotid artery, or M1 of the middle cerebral artery were analyzed. The primary effectiveness outcome was the favorable outcome, defined as return to at least the prestroke modified Rankin Scale score at 3 months. Safety outcomes included symptomatic intracranial hemorrhage. A total of 339 patients (237 women; median 85 [interquartile range (IQR), 79–89] years of age; median prestroke modified Rankin Scale score of 3 [IQR, 2–4]) were analyzed. EVT was performed in 175 patients (51.6%; mechanical thrombectomy, n=139). The EVT group was younger ( p p p p =1.00). Conclusions Patients who underwent EVT showed better functional outcomes than those with medical management. Given proper patient selection, withholding EVT solely on the basis of prestroke disability might not offer the best chance of favorable outcome. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.

Background and Purpose— Sex differences in the management and outcomes of acute ischemic stroke with large vessel occlusion are unknown in the era of endovascular therapy (EVT). This study investigated these differences in the RESCUE (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism)-Japan Registry 2 patient database. Methods— RESCUE-Japan Registry 2 registered patients with large vessel occlusion who were admitted within 24 hours of onset were enrolled in this study. We estimated the likelihood to receive EVT according to sex. The primary outcome was good outcome defined as a modified Rankin Scale score of 0 to 2 at 90 days after onset. Secondary outcomes were mortality within 90 days, any or symptomatic intracranial hemorrhage within 72 hours, and recurrence of stroke or transient ischemic attack within 90 days. Results— Among 2399 patients, 1087 patients were female and 1312 were male; 47.9% of females and 57.7% of males received EVT (adjusted odds ratio, 0.71; 95% CI, 0.59–0.86). Good outcome was observed in 27.3% and 44.2% of the females and males, respectively ( P< 0.0001). The adjusted odds ratio of a good outcome in females was 0.80 (95% CI, 0.65–0.99). Mortality was 12.3% and 9.9% in females and males, respectively ( P =0.06); the adjusted odds ratio was 0.78 (95% CI, 0.58–1.05). Conclusions— Females with acute ischemic stroke with large vessel occlusion showed poor functional outcome compared to males. Females were less likely to receive EVT; lower utilization of EVT accounted for a portion of the poor outcome.

Background: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting. Methods: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months. Results: Mean age was 75.0±7.6 years, and 85.2% of patients were men. OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS 2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79–1.72; P =0.20 for noninferiority, P =0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71–1.39; P =0.016 for noninferiority, P =0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively. Conclusions: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

Background: Safety and efficacy of clopidogrel monotherapy after very short dual antiplatelet therapy (DAPT) is uncertain in patients undergoing complex percutaneous coronary intervention (PCI). Methods: We conducted a post hoc subgroup analysis based on the complexity of PCI in the STOPDAPT-2 trial (Short and Optimal Duration of Dual Antiplatelet Therapy-2), which randomly compared 1-month DAPT followed by clopidogrel monotherapy with 12-month DAPT after cobalt-chromium everolimus-eluting stent implantation. Complex PCI was defined as any of the following: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents, >60 mm total stent lengths, and target of chronic total occlusion. The primary end point was the composite of cardiovascular (cardiovascular death/myocardial infarction/definite stent thrombosis/stroke) and bleeding (TIMI [Thrombolysis in Myocardial Infarction] major/minor) end points. The major secondary end points were the cardiovascular and bleeding end points. Results: Among the 3009 study patients, there were 509 patients (16.9%) with complex PCI (1-month DAPT: N=245, and 12-month DAPT: N=264) and 2500 patients (83.1%) without complex PCI (1-month DAPT: N=1255, and 12-month DAPT: N=1245). There were no significant interactions between the complexity of PCI and the effects of 1-month DAPT versus 12-month DAPT on the primary end point (complex PCI: 1.67% versus 5.32%, hazard ratio, 0.30 [95% CI, 0.10–0.92], P =0.04, and noncomplex PCI: 2.50% versus 3.35%, hazard ratio, 0.75 [95% CI, 0.47–1.20], P =0.23; P interaction =0.14), and on the major secondary cardiovascular end point (complex PCI: 1.67% versus 3.04%, hazard ratio, 0.54 [95% CI, 0.16–1.79], P =0.31, and noncomplex PCI: 2.02% versus 2.39%, hazard ratio, 0.86 [95% CI, 0.50–1.47], P =0.58; P interaction =0.49). The cumulative 1-year incidence of the major secondary bleeding end point was significantly lower in the 1-month DAPT group than in the 12-month DAPT group regardless of the complexity of PCI (complex PCI: 0% versus 2.29%, log-rank P =0.02, and noncomplex PCI: 0.48% versus 1.38%, log-rank P =0.02). Conclusions: The effects of clopidogrel monotherapy after 1-month DAPT relative to 12-month DAPT for the primary and major secondary end points were comparable in complex PCI and noncomplex PCI without significant interactions. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02619760.

Background: The prognostic implications of very low body mass index (BMI) values remain unclear in patients with acute decompensated heart failure (ADHF). This study aimed to investigate the prognostic impact of BMI classification based on the World Health Organization criteria in patients with ADHF. Methods and Results: Using data from 4056 consecutive patients with ADHF hospitalized in 19 participating hospitals in Japan between October 2014 and March 2016, we analyzed 3509 patients with available BMI data at discharge. The patients were divided into five groups; (1) Severely underweight: BMI2 , (2) Underweight: BMI≥16 kg/m 2 and 2 , (3) Normal weight: BMI≥18.5 kg/m 2 and 2 , (4) Overweight: BMI≥25 kg/m 2 and 2 (5) Obese: BMI≥30 kg/m 2 . The primary outcome measure was all-cause death. The median follow-up duration was 471 days, with 96.4% follow up at 1-year. The cumulative 1-year incidence of all-cause death was higher in underweight groups, and lower in overweight groups (Severely underweight: 36.3%, Underweight: 23.9%, Normal weight: 14.4%, Overweight: 7.9%, and Obese: 9.0%, P Conclusions: Lower BMI, not obesity, was associated with a higher risk for all-cause death after discharge in patients with ADHF.

Background: Heart failure (HF) is the leading cause of death in patients with atrial fibrillation (AF). Radiofrequency catheter ablation (RFCA) of AF is effective for maintaining sinus rhythm though its impact on heart failure still remains controversial. Purpose: We sought to elucidate whether AF recurrence following RFCA was associated with subsequent HF hospitalizations. Methods: We conducted a large-scale, prospective, multicenter, observational study. A total of 4931 consecutive patients who underwent an initial RFCA for AF with longer than 1-year of follow-up in 26 centers were enrolled (average age, 64±10 years; non-paroxysmal AF, 35.7%). The median follow-up duration was 2.9 years. The primary endpoint was an HF hospitalization more than 1-year after the index RFCA. We compared the patients without AF recurrences (group A) to those with AF recurrences within 1-year post RFCA (group B). Results: The 1-year cumulative incidence of AF recurrences after a single procedure was 30.7% (group A=3418, group B=1513 patients). Group B had a lower body mass index (group A vs. group B,24.1±3.6 vs. 23.8±3.4 kg/m 2 , p=0.014), longer history of AF (1.9 vs. 3.1 years, p Conclusions: Among AF patients receiving RFCA, those with AF recurrences were at a greater risk of subsequent heart failure hospitalizations than those without AF recurrences. Recognition that AF recurrence following RFCA is a risk factor for a subsequent HF-related hospitalization is appropriate in clinical practice.

Introduction: Blood pressure (BP) is a significant predictor for chronic kidney disease (CKD). Hypothesis: We sought to evaluate whether the progression of CKD in diabetic patients, without a history of atherosclerotic events, is dependent on BP control. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019. We defined late-stage kidney disease (LSKD) as estimated glomerular filtration rate (eGFR) 2 or hemodialysis. Among 2,536 JPAD patients, 27 patients were excluded for eGFR 2 on registration. BP of the JPAD patients was recorded on average 8 times. Based on the mean value of systolic BP (SBP), we divided the patients into three groups: a High BP Group (n=607, SBP≥140 mm Hg); a Moderate BP Group (n=989, 140>SBP≥130 mm Hg); or a Low BP Group (n=913, SBP Results: The mean eGFR (ml/min/1.73m 2 ) was 75.1 in the High BP Group, 72.6 in the Moderate BP Group, and 75.7 in the Low BP Group on registration. During a 11.2-year follow-up, the incidence of LSKD was significantly higher in the High BP and Moderate BP Groups than in the Low BP Group (P2 , duration of diabetes ≥7.0 years, statin usage, aspirin usage, eGFR≥60 ml/min/1.73m 2 , and hemoglobin A1c ≥7.2 % (Figure). Conclusions: Our study demonstrated that SBP was independently associated with the progression to LSKD in diabetic patients, without a history of atherosclerotic events. SBP less than 130 mm Hg is recommended for diabetic patients to prevent progression to LSKD.

Background and Purpose: Diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch was well recognized as an early sign of acute ischemic stroke lesions. In the era of mechanical thrombectomy (MT), DWI-FLAIR mismatch could be a good marker for candidates of MT. We thus investigated the association between DWI-FLAIR mismatch and functional outcomes in patients who received MT for acute large vessel occlusion (LVO). Methods: We conducted historical cohort study in consecutive patients who were evaluated by MRI for suspected stroke at single stroke center. We enrolled patients with occlusion of the ICA or M1 or M2 segment of MCA who were underwent MT within 24 hours after the last known to be well. FLAIR negative was defined when a visible acute ischemic lesion was present on DWI without traceable parenchymal hyperintensity on FLAIR. We estimated the adjusted OR of FLAIR negative for moderate outcome defined as mRS 0-3 at 90 days after onset. We also estimated the adjusted OR for symptomatic intracranial hemorrhage within 72 hours and mortality at 90 days. Results: Among 380 patients who received MT for acute LVO, 202 patients were included in this study. Patients with FLAIR negative was 146 (72%), and the rest were FLAIR positive. Patients with FLAIR negative had significantly higher baseline NIHSS (median 16 vs 13, p=0.01), more transferred-in (78% vs 63%, p=0.02), more intravenous thrombolysis (IVT) (45% vs 18%, P=0.0003), more cardioembolism (69% vs 54%, p=0.03), and shorter times from the onset to hospital door (median 175 vs 371 minutes, p Conclusions: DWI-FLAIR mismatch was associated with better functional outcome in patients received MT for acute LVO at 90 days. DWI-FLAIR mismatch should be a good marker for the candidate of MT for acute LVO. Future randomized trial to evaluate the effectiveness of MRI-based MT using DWI-FLAIR mismatch should be considered.

Background and Purpose: Prehospital prediction models to estimate the likelihood of several types of stroke (large vessel occlusion [LVO], intracranial hemorrhage [ICH], and subarachnoid hemorrhage [SAH], and other strokes) should be useful to transfer those with suspected stroke to appropriate facilities. Japan Urgent Stroke Triage score with 21 items had excellent predictive abilities, but we tried to simplify the score with parsimonious items and comparable predictive abilities. Methods: We conducted historical and prospective multicenter cohort studies from June 2015 to July 2017. We developed the prediction rule with select variables from JUST score for LVO, ICH, SAH and other strokes using historical cohort study with 2236 patients and validated the developed score using prospective cohort study with 964 patients. We used multivariable logistic regression models to develop the prediction models using the same variables for each stroke type. Result: In the historical cohort, there were 1150 stroke, including 235 LVO, 352 ICH, 107 SAH and 456 other stroke. We developed the score with 7 items (high blood pressure, arrhythmia, conjugate deviation, headache, dysarthria, disturbance of consciousness, paralysis of upper limbs) which showed area under the receiver operating curve (AUC) of 0.84 for any type of stroke, 0.89 for LVO, 0.79 for ICH, and 0.90 for SAH in the historical cohort. The score was validated with good predictive ability in the prospective cohort (AUC of 0.76 for any type of stroke; 0.81 for LVO, 0.73 for ICH, and 0.85 for SAH). Conclusions: The simplified 7-item JUST (JUST-7) score had good predictive ability and can help paramedics or primary care physicians to estimate the likelihood of different type of stroke and decide the referral hospital.

Introduction: Antiplatelet (APT) therapy is challenging in patients on oral anticoagulants (OACs) for nonvalvular atrial fibrillation (NVAF) who have coronary artery diseases (CAD). Analyzing large scale registry of consecutive patients with NVAF should provide further guide for the safety and efficacy of combination therapy. Methods: We conducted historical multicenter registry at 71 centers in Japan between March 2017 and March 2018. The eligibility criteria were patients on OACs for NVAF on February 2013. There were no exclusion criteria and consecutive patients who met the eligibility criteria were registered. All patients were followed until March 2017. Co-primary endpoints were ischemic strokes including transient ischemic attack and hemorrhagic stroke including subarachnoid hemorrhage. The secondary endpoints were all-cause mortality, ischemic events (acute coronary syndrome, ischemic strokes, or systemic embolism), and major bleedings defined by ISTH and TIMI criteria. We estimated HRs of OACs and APT combination relative to OACs alone by Cox proportional hazard model adjusting for clinically relevant confounders. Results: Median age was 74 (range 20-101) years of 7826 registered patients. Sustained NVAF accounted for 49% and 73% of patients had history of CAD. Cumulative incidences of ischemic stroke and hemorrhagic stroke at 4 years were 3.8% and 0.91% in No-APT group while 5.3% and 1.2% in APT group, respectively (Figure). Adjusted HRs (95%CI) of APT group for ischemic stroke and hemorrhagic stroke were 1.03 (0.76-1.40) and 1.27 (0.67-2.4), respectively. Adjusted HRs (95%CI) for all-cause mortality, ischemic events, and major bleedings were 0.98 (0.79-1.23), 0.98 (0.74-1.32), and 1.25 (1.00-1.57), respectively. Conclusions: Adding APT in patients on AOC for NVAF did not decrease ischemic strokes and not increase hemorrhagic strokes. Because combination therapy might increase the risk of major bleedings, OAC alone should be prioritized.

Introduction: We investigated how the degree of reperfusion affects functional outcomes according to the puncture-to-reperfusion time and preoperative condition in patients with acute large vessel occlusion. Methods: A post-hoc analysis of the RESCUE-Japan Registry 2, a prospective multicenter registry enrolling patients with acute cerebral large vessel occlusion from 46 centers in Japan between October 1, 2014 and September 30, 2016, was conducted. Among the 2,420 patients in the RESCUE-Japan 2 registry, 1,073 patients who achieved successful reperfusion with endovascular therapy were analyzed. We compared the functional and safety outcomes between patients with modified thrombolysis in cerebral infarction grades 3 (mTICI-3) and 2b (mTICI-2b). Results: The proportion of patients with favorable outcomes (modified Rankin Scale scores of 0 to 2 at 90 days after onset) was higher among patients with mTICI-3 than among those with mTICI-2b (52% versus 38 %; adjusted OR, 1.96; 95% CI, 1.49-2.56). Compared to those in the patients with mTICI-2b within 30 minutes after puncture, favorable outcomes tended to be more common in patients who achieved mTICI-3 within 90 minutes after puncture (0-29 minutes: adjusted OR, 2.60; 95% CI, 1.24-5.46, 30-59 minutes adjusted OR, 1.65; 95% CI, 0.85-3.21, 60-89 minutes: adjusted OR, 1.61; 95% CI, 0.77-3.37; Figure). mTICI-3 reperfusion was associated with favorable outcomes in both anterior (adjusted OR, 1.81; 95% CI, 1.34-2.44) and posterior vessel occlusion (adjusted OR, 2.40; 95% CI, 1.06-5.44). There was no heterogeneity in the effect of mTICI-3 reperfusion on the outcomes with respect to age, NIHSS score, use of alteplase, late-presenting, distal vessel occlusion, or ASPECTS. Conclusions: mTICI-3 reperfusion, possibly even when reperfusion delays slightly, was superior to mTICI-2b. Achieving complete reperfusion, not only early reperfusion, is important to improve the outcomes regardless of preoperative condition.

Background: Statin therapy was reported to be associated with lower risk of recurrence of stroke and better functional outcomes in patients with acute ischemic stroke. However, the effect of statin therapy in patients with acute large vessel occlusion (LVO) was not well scrutinized. Thus, we evaluated the effect of statin administration after the onset of stroke on functional outcome based on the large registry study of acute LVO. Methods: RESCUE-Japan Registry-2 was a physician initiated registry study enrolled consecutive patients with acute LVO who were admitted within 24 hours of onset. We compared those with and without statin after onset in terms of modified Rankin Scale (mRS) at 90 days. We estimated the common odds ratio (OR) for a shift towards better mRS adjusting for confounders. Result: Among 2420patients registered, 2399 patients were eligible. Mean age was 75.9 years and men accounted for 55%. Statin were administered in 447 patients(19%) after admission. There are more atherothrombotic cerebral infarction (statin group: 34.2% vs non-statin group: 12.1%, p Conclusions: Statin administration after onset of acute LVO was significantly associated with better functional outcome and mortality within 90 days. Our findings should be attested by randomized clinical trials in patients with acute LVO in future

Background Recently, direct oral anticoagulants have been introduced for venous thromboembolism ( VTE ), which might change the management strategies of VTE . However, there have been limited data on the current real‐world practice pattern for VTE in Asian countries. Methods and Results The JROAD‐DPC (Japanese Registry of All Cardiac and Vascular Diseases\xF6Diagnosis Procedure Combination) is a nationwide claim database from 1022 hospitals in Japan between April 2012 and March 2017. We identified 54 369 patients who were hospitalized with a diagnosis of VTE at admission based on the International Classification of Diseases, Tenth Revision ( ICD‐10 ) code. The mean age was 69.1±15.6 years, 59% were women, and mean body mass index was 23.5±5.0 kg/m 2 . The proportion of patients with deep vein thrombosis decreased over time from 72% in 2012 to 38% in 2017. After the release of direct oral anticoagulants, the proportion of patients receiving direct oral anticoagulants increased dramatically among patients with anticoagulation therapy at discharge with the use of edoxaban, rivaroxaban, and apixaban in 35%, 22%, and 27% of patients, respectively, in 2017. On the other hand, the proportion of patients receiving warfarin decreased from 94% in 2012 to 15% in 2017. The median length of a hospital stay decreased over time from 20 days in 2012 to 13 days in 2017 in patients with pulmonary embolism, and from 14 days in 2012 to 12 days in 2017 in patients with deep vein thrombosis. The median cost of hospitalization for pulmonary embolism moderately decreased over time, whereas that for deep vein thrombosis slightly decreased over time. Conclusions A nationwide claim‐based database provided the current practice pattern for VTE in Japan, which revealed dynamic changes after the release of direct oral anticoagulants. Clinical Trial Registration URL : www.umin.ac.jp . Unique identifier: UMIN 000037868.

Background and Purpose— Endovascular therapy is effective against acute cerebral large vessel occlusion (LVO). However, many patients do not receive such interventions because of the lack of timely identification of the type of stroke. If the types of stroke (any stroke, LVO, intracranial hemorrhage [ICH], and subarachnoid hemorrhage [SAH]) were to be predicted at the prehospital stage, better access to appropriate interventions would be possible. Japan Urgent Stroke Triage (JUST) score was clinical prediction rule to classify suspected patients of acute stroke into different types at the prehospital stage. Methods— We obtained information for signs and symptoms and medical history of consecutive suspected patients of acute stroke at prehospital stage from paramedics and final diagnosis from the receiving hospital. We constructed derivation cohort in the historical multicenter cohort study from June 2015 to March 2016 and validation cohort in the prospective multicenter cohort study from August 2016 to July 2017. The derivation and the validation cohorts included 1229 and 1007 patients, respectively. We constructed multivariate logistic regression models with 21 variables to develop clinical prediction rules, which distinguish between different types of stroke: any stroke, LVO, ICH, and SAH. Results— Among the 1229 patients (median age, 72 years; 55% men) in the derivation cohort, 533 stroke, 104 LVO, 169 ICH, and 57 SAH cases were observed. The developed rules showed that the areas under the receiver operating curves were 0.88 for any stroke, 0.92 for LVO, 0.84 for ICH, and 0.89 for SAH. The validation cohort of 1007 patients (median age, 75 years; 56% men) showed that the areas under the curves of any stroke, LVO, ICH, and SAH were 0.80, 0.85, 0.77, and 0.94, respectively. Conclusions— These clinical prediction rules can help paramedics classify the suspected patients of stroke into any stroke, LVO, ICH, and SAH groups with excellent accuracy.

Lactate clearance is useful to guide initial resuscitation of patients with septic shock. We conducted this study to evaluate whether dexmedetomidine increases lactate clearance in patients with septic shock. This was a randomized controlled trial that involved a post hoc subgroup analysis. Adult patients with septic shock under ventilation were randomized to receive sedation strategy with or without dexmedetomidine (60 in the dexmedetomidine and 51 in the nondexmedetomidine groups). The primary outcome was the lactate clearance at 6 h, defined as the percent decrease in lactate from randomization to 6 h after. The median Acute Physiology and Chronic Health Evaluation II score was 25 (interquartile range 19-31). The median serum lactate value at randomization was lower in the dexmedetomidine group than in the nondexmedetomidine group (4.0 mmol/L vs. 4.8 mmol/L; P = 0.053). The lactate clearance at 6 h was higher in the dexmedetomidine group, although this was not statistically significant (23.3 ± 29.8 vs. 11.1 ± 54.4, mean difference 12.2, 95% confidence interval (CI), -4.4 to 28.8). After adjusting for the lactate level at randomization, lactate clearance at 6 h was significantly higher in the dexmedetomidine group (adjusted mean difference 18.5, 95% CI, 2.2-34.9). There was no statistically significant difference in the 28-day mortality between the dexmedetomidine and the nondexmedetomidine groups (13 [22%] vs. 18 [35%] patients, P = 0.11). In conclusion, among mechanically ventilated patients with septic shock, sedation with dexmedetomidine resulted in increased lactate clearance compared with sedation without dexmedetomidine.

Background: The dual antiplatelet therapy (DAPT) score was developed to estimate ischemic and bleeding risks from the DAPT study. However, few studies validated its utility externally. We sought to validate the utility of the DAPT score in the Japanese population. Methods: In a pooled cohort of 3 studies conducted in Japan (the CREDO-Kyoto [Coronary Revascularization Demonstrating Outcome Study in Kyoto] Registry Cohort-2, RESET [Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial], and NEXT [NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial]), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention among patients with a DAPT score ≥2 (high DS) and a DAPT score Results: Among 12 223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3944 patients had high DS and 8279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%, P =0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%, P =0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%, P =0.03; 1.5% versus 0.8%, P =0.002; 0.7% versus 0.3%, P P P =0.03, respectively). Conclusions: In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.

We conducted a study to estimate the seroprevalence of coronavirus disease 2019 (COVID-19) in Kobe, Japan with positive immunoglobulin G (IgG) rate of 3.3% (95% confidence interval [CI] 2.3%-4.6%) in April 2020. Because there were large concerns about the spread of COVID-19 among citizens thereafter, we conduct a follow-up cross-sectional study to estimate the seroprevalence, and we also added a validation study using a different assay.We conducted cross-sectional serologic testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody using 1000 samples from patients at outpatient settings who visited the clinic from May 26 to June 7, 2020, stratified by the decade of age and sex. We used both Kurabo and Abbott serology assays to identify IgG against SARS-CoV-2.There were 18 and 2 positive IgG among 1000 serum samples using Kurabo and Abbott serology assays, respectively (1.8%, 95% CI 1.1%-2.8%, and 0.2%, 95% CI 0.02%-0.7% respectively). By applying the latter figure to the census of Kobe City (population: 1,518,870), it is estimated that the number of people with positive IgG is 3038 (95% CI: 304-10,632) while a total of 285 patients were identified by polymerase chain reaction (PCR) testing at the end of the study period. Assuming Abbott assay as the reference, Kurabo assay had calculated sensitivity and specificity of 100% and 98.4% respectively. Age and sex adjusted prevalence of positivity was calculated to be 0.17%.We found a lower seroprevalence than 2 months before in Kobe city although the figures were still higher than those detected by PCR. Kurabo assay showed more false positives than true positives despite reasonable sensitivity and specificity, due to low prevalence in Kobe.

There was no previous report on the prognostic impact of new-onset or improved anemia after discharge from acute decompensated heart failure (ADHF).We analyzed 771 patients with ADHF and who were followed in multicenters in Japan was divided into 4 groups based on the hemoglobin values at discharge and 6-month index visit: 373 patients (48.4%) with persistent anemia, 87 patients (11.3%) with new-onset anemia, 91 patients (11.8%) with improved anemia, and 220 patients (28.5%) without anemia.The primary outcome measure was a composite of all-cause death or HF hospitalization after index visit. The cumulative 6-month incidences of the primary outcome measure were 25.2% for persistent anemia, 18.5% for new onset anemia, 9.0% for improved anemia, and 9.2% for no anemia (log-rank P

PURPOSE To determine the prevalence of errors in segmentation of the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) boundary in spectral-domain optical coherence tomography (SDOCT) images, and to identify factors associated with the errors. MATERIALS AND METHODS Peripapillary RNFL circle scans and macular 3-dimensional scans of consecutive cases imaged with SDOCT (RS-3000 Advance; Nidek, Gamagori, Japan) were retrospectively reviewed by a glaucoma specialist. Images with signal strength index (SSI)

Background and Purpose— Several studies suggested that statins during hospitalization were associated with better disability outcomes in patients with acute ischemic stroke, but only 1 small randomized trial is available. Methods— We conducted a multicenter, open-label, randomized controlled trial in patients with acute ischemic strokes in 11 hospitals in Japan. Patients with acute ischemic stroke and dyslipidemia randomly received statins within 24 hours after admission in the early group or on the seventh day in the delayed group, in a 1:1 ratio. Statins were administered for 12 weeks. The primary outcome was patient disability assessed by modified Rankin Scale at 90 days. Results— A total of 257 patients were randomized and analyzed (early 131, delayed 126). At 90 days, modified Rankin Scale score distribution did not differ between groups ( P =0.68), and the adjusted common odds ratio of the early statin group was 0.84 (95% confidence interval, 0.53–1.3; P =0.46) compared with the delayed statin group. There were 3 deaths at 90 days (2 in the early group, 1 in the delayed group) because of malignancy. Ischemic stroke recurred in 9 patients (6.9%) in the early group and 5 patients (4.0%) in the delayed group. The safety profile was similar between groups. Conclusions— Our randomized trial involving patients with acute ischemic stroke and dyslipidemia did not show any superiority of early statin therapy within 24 hours of admission compared with delayed statin therapy 7 days after admission to alleviate the degree of disability at 90 days after onset. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02549846.

Background: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive. Methods: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care–controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity. Results: The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91–1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83–1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P >0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82–1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group ( P =0.03), and the incidence of hemorrhagic stroke was not different between groups. Conclusions: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00110448.

Background Association of baseline hemoglobin levels with long‐term adverse events after percutaneous coronary interventions has not been yet thoroughly defined. We aimed to assess the clinical impact of baseline hemoglobin on long‐term ischemic and bleeding risk after percutaneous coronary intervention. Methods and Results Using the pooled individual patient‐level data from the 3 percutaneous coronary intervention studies, we categorized 19 288 patients into 4 groups: high‐normal hemoglobin (≥14.0 g/dL; n=7555), low‐normal hemoglobin (13.0–13.9 g/dL in men and 12.0–13.9 g/dL in women; n=5303), mild anemia (11.0–12.9 g/dL in men and 11.0–11.9 g/dL in women; n=4117), and moderate/severe anemia (GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries Trial) moderate/severe bleeding, with adjusted hazard ratios of 1.22 (95% CI, 1.04–1.44), 1.73 (95% CI, 1.47–2.04), and 2.31 (95% CI, 1.92–2.78), respectively. Moderate/severe anemia also correlated with significant excess risk relative to high‐normal hemoglobin for the ischemic composite end point of myocardial infarction/ischemic stroke (adjusted hazard ratio, 1.33; 95% CI, 1.11–1.60), whereas low‐normal hemoglobin and mild anemia did not. However, the excess risk of low‐normal hemoglobin, mild anemia, and moderate/severe anemia relative to high‐normal hemoglobin remained significant for ischemic stroke and for mortality. Conclusions Decreasing baseline hemoglobin correlated with incrementally higher long‐term risk for major bleeding, ischemic stroke, and mortality after percutaneous coronary intervention. Even within normal range, lower baseline hemoglobin level correlated with higher ischemic and bleeding risk.

Background: It has not been yet adequately addressed whether the addition of the nonstatin LDL-C (low-density lipoprotein cholesterol)-lowering agents on top of statins has the same magnitude of risk reduction in the cardiovascular events as compared with more-intensive statin therapy. Methods and Results: We performed a systematic review and meta-analysis of RCTs (randomized controlled trials) comparing more- versus less-intensive lipid-lowering therapy (LLT) on clinical outcomes in patients with atherosclerotic cardiovascular risk. We included 23 studies involving 133 037 patients (more-intensive LLT: 67 691 patients and less-intensive LLT: 65 346 patients). We evaluated 3 types of more- versus less-intensive LLT including more versus less statins (57 672 patients), combination therapy of ezetimibe versus statins alone (20 688 patients), or a PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor with statins versus statins alone (54 677 patients). The odds for major adverse cardiovascular events (MACE; equivalent to the composite of coronary heart death, nonfatal myocardial infarction, stroke, or coronary revascularization) were significantly lower in the more-intensive LLT group compared with the less-intensive LLT group in the entire study population (odds ratio, 0.84; 95% CI, 0.79–0.88; P P P P Conclusions: In this meta-analysis, more-intensive LLT as compared with less-intensive LLT was associated with significant odds reduction for MACE in the entire study population and in all the 3 categories of more-intensive LLT such as more-intensive statin therapy, ezetimibe, and PCSK9 inhibitors. However, overall odds reduction for MACE and odds reduction for MACE per 20 mg/dL LDL-C reduction were different across the 3 types of more-intensive LLT. Registration: URLs: https://www.crd.york.ac.uk/PROSPERO/ and http://www.umin.ac.jp/ctr . Unique identifiers: PROSPERO: CRD42018081196, and UMIN-CTR: R000036229.

Background Data are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database. Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm2, N=645; group 2: 0.8 cm2 ≥AVA >0.6 cm2, N=465; and group 3: AVA ≤0.6 cm2, N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5‐year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5‐year incidence of the primary outcome measure (a composite of aortic valve–related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P, See Editorial by Tribouilloy et al

Background and Purpose: Clinical outcomes after successful endovascular therapy in patients with acute ischemic stroke are associated with several factors including onset-to-reperfusion time (ORT). The objective of the current study was to assess whether ORT is associated with outcomes in elderly. Methods: Among 2420 patients enrolled in the RESCUE 2 study, a prospective stroke registry with acute cerebral large-vessel occlusion at 46 centers between October 2014 and January 2017, we enrolled 397 elderly patients more than 80 with successful reperfusion after thrombectomy (thrombolysis in cerebral infarction [TICI] score of 2b or 3) in the current analysis. The rates of good outcome (modified Rankin Scale [mRS] scores of 0-2 at 3 months) were compared among the three categories of ORT ( Results: The rates of good outcome were 41% (30/73), 34% (26/77), and 25% (62/247) in each category of ORT. Odds ratio and 95% confidence interval for good outcome were 0.68 and 0.49-0.94 per 1 category delay. Conclusion: ORT was associated with good outcome even in elderly patients.

Introduction: In endovascular treatment (EVT) for acute large vessel occlusion (LVO), multiple passes may promote arterial endothelial injury, potentially reducing clinical efficacy and safety. However, data comparing outcome between single and multiple passes are scarce. Methods: In the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism (RESCUE)-Japan Registry 2, 2420 patients with acute stroke due to LVO were registered between October 2014 and January 2017. Among them, 1064 patients treated with EVT were analyzed. We classified patients into two groups, a single-pass group and a multiple-pass group, archiving good recanalization (TICI2b-3) in single or multiple passes, and analyzed clinical features and outcomes. Multivariate analyses were performed to determine whether single-pass recanalization was independently associated with improved outcomes and to identify factors associated with needing only a single pass. Results: 592 patients were recanalized by single pass, and 472 patients by multiple passes. Compared with the multiple-pass group, fewer patients in the single-pass group suffered extracranial internal carotid artery occlusion (9.6% vs 14.4%, p=0.014), and more patients suffered M2 occlusion (18.6% vs 14.0%, p=0.045) Onset to recanalization time in the single-pass group was shorter than the multiple-pass group (378.3 minutes vs 397.2 minutes, p=0.00012) Cardiogenic embolic stroke was present in 78.7% and 66.5% of single- and multiple-pass groups (p Conclusion: Achievement of recanalization in a single pass was associated with good clinical outcome.

Background and Purpose: The DAWN trial showed the efficacy of endovascular thrombectomy between 6 to 24hours after time last known well (TLKW) in acute stroke patients with clinical-imaging mismatch. We examined the validity of patient selection using Alberta Stroke Program Early CT Score on diffusion weighted imaging (DWI-ASPECTS) in a real-world setting. Methods: In a Japanese nationwide registry study, 2420 patients with acute stroke due to large vessel occlusion within 24 hours from onset/TLKW were registered between October 2014 and January 2017. Among them, patients were included according to the inclusion criteria of the DAWN trial where ischemic core volume was replaced with DWI-ASPECTS: occlusion of the internal carotid artery or the middle cerebral artery M1 portion, 6 to 24 hours from onset/TLKW, DWI-ASPECTS ≥7 and initial NIHSS ≥10, and DWI-ASPECTS ≥6 and NIHSS ≥20 in patients younger than 80 years old. The favorable outcome was defined as a modified Rankin Scale of 0 to 2 at 90 days after onset. Results: Of 78 patients who were eligible to inclusion criteria, 54 (69%, mean 75±13 years old) underwent endovascular therapy (EVT) and 24 (31%, mean 76±14 years old) did not. Median initial NIHSS was 18 (IQR, 13-23) and 20 (IQR, 14-23), respectively (p = 0.67). Initial DWI-ASPECTS was significantly higher in the EVT group than in the non-EVT group (median [IQR], 8 [7-9] vs 7 [7-8], p = 0.009). The favorable outcome was achieved in 52% of the EVT group and 13% of the non-EVT group (adjusted odds ratio, 8.1; 95% CI, 2.0-33.3, p = 0.004). In terms of safety outcome, any intracranial hemorrhage within 72 hours was not different between the two groups (24% vs 33%, p = 0.56). The recurrence of stroke (5.6% vs 4.2%, p = 1.00) and mortality (4.2% vs 3.7%, p = 1.00) within 90 days were also not different. Conclusions: Patient selection using clinical-DWI mismatch can be useful to determine the indication of endovascular treatment in late presenting stroke with anterior large vessel occlusion.

Background: Several studies have shown that women have a poorer prognosis after stroke than men. However, there were scanty data on sex difference in the management and clinical outcomes of acute ischemic stroke due to large vessel occlusion. Methods: Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism (RESCUE)-Japan Registry 2 in Japan registered patients with acute ischemic stroke due to large vessel occlusion who were admitted within 24 hours of onset from 2014 to 2017. We estimated the likelihood to receive endovascular therapy between the sexes. Primary outcome was good functional outcome defined by modified Rankin Scale (mRS) of 0-2 at 90 days after onset. Secondary outcome was the mortality within 90 days after onset. Adjusted odds ratio (OR) was estimated by logistic regression model accounted for potential confounders. Safety endpoints were all bleeding included intracerebral hemorrhage, recurrence of stroke within 90 days. Results: Among 2399 patients registered, 1087 patients were female and 1312 were male. Mean age was 80 and 73 years in female and male patients, respectively. Cardioembolic stroke consisted of 77% and 71% of female and male patients, respectively. 47.9% of female patients received the endovascular therapy compared with 57.7% in the counterparts (adjusted OR 0.69, 95%CI 0.58-0.83). Good outcome was observed in 27.3% and 44.2% the female and male patients, respectively (p Conclusions: Female patients with acute cerebral large vessel occlusion has poor prognosis compared to male. Female patients were less likely to receive endovascular therapy than male but such lower utilization of endovascular therapy accounted for a part of poor prognosis in female patients. The causes of poor prognosis in female patients should be attested in addition to the improved access to endovascular therapy in female.

Background and Purpose: Recent studies have demonstrated that endovascular reperfusion therapy improves clinical outcomes at 90 days after ischemic stroke. However, effects on long-term outcomes are not well known. The objective of the current study was to assess whether successful reperfusion was associated with a temporal change in modified Rankin Scale (mRS) score from 90 days to 1 year after endovascular therapy. Methods: We retrospectively analyzed a database of consecutive patients with acute ischemic stroke who received endovascular therapy between April 2006 and March 2016 at 4 centers. We compared the incidences of improvement and deterioration in patients with successful reperfusion (i.e., modified thrombolysis in cerebral infarction score of 2b or 3) with those in patients with unsuccessful reperfusion. We defined improvement and deterioration as a decrease and an increase of 1 or more points on the mRS score from 90 day to 1 year after endovascular therapy, respectively. Results: A total of 268 patients were included in the current study. The rate of patients with improvement tended to be higher in patients with successful reperfusion than in patients with unsuccessful reperfusion (20% [34/167 patients] vs. 12% [12/101], P = 0.07). The rate of patients with deterioration was lower in patients with successful reperfusion than in patients with unsuccessful reperfusion (25% [42/167] vs. 42% [42/101], P < 0.01). After adjustment for confounders, successful reperfusion was associated with improvement (adjusted odds ratio, 2.65; 95% confidence interval, 1.23-5.73; P < 0.05) and deterioration (adjusted odds ratio, 0.33; 95% confidence interval, 0.18-0.62; P < 0.01), independent of the 90-day mRS score. Conclusions: Successful reperfusion has further beneficial effects on long-term outcomes beyond 90 days from stroke.

Objective: The efficacy of endovascular therapy (EVT) for distal middle cerebral artery (MCA) occlusion remain debatable. We compared the EVT with conservative therapy (no EVT) in real-world patients with distal MCA occlusion. Methods: We analyzed the data from the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism Japan Registry 2, which enrolled the consecutive patients with acute ischemic stroke due to large vessel occlusions. We selected patients with isolated M2 or M3 occlusion, and those with functional independence (modified Rankin Scale [mRS] score = Results: A total of 427 patients [372 (87%) were M2 occlusion] were analyzed from 2420 patients originally enrolled in the registry. There were 190 patients in EVT and 237 in no EVT groups. The EVT group showed a higher baseline NIHSS score (median interquartile range [IQR], 15 [9-19] versus 8 [4-15]). The primary outcome occurred in 55.7% and 54.4% of the EVT and no EVT groups, respectively. There were no significant differences for a favorable outcome as a whole and the adjusted odds ratio (aOR) was 1.52 [95%CI, 0.97-2.42; p=0.06]. Subgroup analyses showed a favorable outcome for EVT group in the subgroup of M2 occlusion with aOR of 1.84 (95%CI, 1.13-3.00) and of NIHSS≥6 with aOR of 2.14 (95%CI, 1.29-3.55). Conclusions: In patients with distal MCA occlusion, EVT seems effective for patients with M2 segment occlusion or NIHSS≥6.

Background— Female sex was reported to be associated with lower risk for midterm restenosis and repeat revascularization after bare-metal stent implantation. However, the influence of sex on very long-term outcomes after bare-metal stent implantation has not been yet reported. Methods and Results— Among the 9877 patients in the multicenter Coronary Revascularization Demonstrating Outcome study in Kyoto (CREDO-Kyoto) registry cohort-1, bare-metal stent implantation was performed in 5313 patients (men, n=3742 and women, n=1571). Follow-up was completed in 4515 patients (85.0%) at 10 years (duration, 10.3±3.1 [0.0–14.1] years). The cumulative incidence of target-lesion revascularization (TLR) was 27% at 1 year and 34% at 10 years (0.8%/y beyond 1 year). Non–target-lesion revascularization (non-TLR) was the dominant coronary revascularization beyond 1 year (13% at 1 year and 31% at 10 years [2.0%/y beyond 1 year]). Cumulative incidence of stent thrombosis was low (1.2% at 1 year and 1.9% at 10 years). Women were older and had greater prevalence of cardiovascular risk factors than men. The cumulative 10-year incidences of and adjusted risk for TLR were significantly higher in men than in women (36% versus 30%, P P Conclusions— TLR and stent thrombosis continued to occur without attenuation up to 10 years after bare-metal stent implantation. Men in comparison with women were associated with higher adjusted 10-year risks for all-cause death, myocardial infarction, stroke, coronary artery bypass grafting, TLR, and non-TLR.

Introduction: The effectiveness of endovascular thrombectomy for acute cerebral large vessel occlusion (LVO) was proved, but many patients did not received such interventions because capable operators were not placed at all hospitals. If the type of stroke [large vessel occlusion, subarachnoid hemorrhage (SAH), intracranial hemorrhage (ICH), other cerebral infarction (CI)] was predicted at prehospital, better access to appropriate interventions were capable. We, thus, developed the clinical prediction rules to classify the type of stroke who were suspected to suffer acute stroke at prehospital, and validated them. Methods: We analyzed consecutive 1,229 patients who were suspected to suffer acute stroke from June, 2015 to March 2016. We obtained the history and physical signs at prehospital from paramedics and final diagnosis from hospital transferred. We constructed multivariate logistic regression models for 1) LVO, 2) SAH, 3) ICH, 4) CI, and developed the clinical prediction rules for each type. We prospectively validated the rules with another consecutive patients from August 2016 to July 2017 using mobile application. Results: In the derivation cohort, 104 LVO, 57 SAH, 169 ICH, and 183 CI were observed. The area under the receiver operating curve (AUC) of the rules were 0.90 for LVO, 0.90 for SAH, 0.85 for ICH, and 0.65 for CI. The validation cohort of 932 patients showed the sensitivity and specificity of the rules were 0.53 and 0.95 for LVO, 0.73 and 0.96 for SAH, 0.52 and 0.85 for ICH, 0.63 and 0.70 for CI. The AUCs of LVO, SAH, ICH, and CI were 0.85, 0.96, 0.77, and 0.67, respectively. Conclusions: The clinical prediction rule calculated by paramedics at prehospital can easily classify the patients who suspected to have stroke into LVO, SAH, ICH, and CI with excellent performance. By applying the rules, more patients would receive appropriate interventions without unnecessary delay.

Objective Adverse drug events (ADEs) are a significant concern in daily practice; however, the profile of high-risk drugs remains unclear. Our objective was to categorize high-risk medication classes according to frequency and severity of ADEs. Methods The JADE study is a prospective cohort study of 3459 hospitalized adult patients. We investigated the ADEs and medications prescribed to the patients. The rate of ADEs for each medication class was calculated by dividing the number of ADEs by the number of patients who received each medication class on admission. Results Overall, 14,435 medications were ordered on admission for patients (median 4; interquartile range, 2-6). Electrolytes and fluids were most frequently prescribed (1876 patients, 54%). Sedatives, antibiotics, peptic ulcer drugs, and analgesics were also commonly prescribed. The frequency was similar in both elderly and younger patients. Among 1010 identified ADEs, antibiotics were most frequently associated with ADEs (31 ADEs per 100 prescribed patients on admission). In patients 65 years and older, corticosteroids, anticonvulsants, laxatives, nonsteroidal anti-inflammatory drugs, and antipsychotics were the 5 most frequent medication classes causing ADEs following antibiotics. In patients younger than 65 years, antibiotics were also the most frequent cause of ADEs, followed by laxatives, lipid-lowering agents, anticonvulsants, and corticosteroids. Among cardiovascular agent-associated ADEs, 46% were fatal or life threatening in elderly patients, whereas antihypertensives were most often associated with fatal or life-threatening ADEs (25%) in younger patients. Conclusions The medication classes frequently associated with ADEs did not necessarily induce severe ADEs.

Background Characteristics and prognosis of hemodialysis patients with severe aortic stenosis have not yet been well defined. Methods and Results The CURRENT AS (contemporary outcomes after surgery and medical treatment in patients with severe aortic stenosis) registry, a Japanese multicenter registry, enrolled 3815 consecutive patients with severe aortic stenosis. There were 405 hemodialysis patients (initial aortic valve replacement [ AVR ] group: N=135 [33.3%], and conservative group: N=270) and 3410 nonhemodialysis patients (initial AVR group: N=1062 [31.1%], and conservative group: N=2348). The median follow‐up duration after the index echocardiography was 1361 days, with 90% follow‐up rate at 2 years. The cumulative 5‐year incidence of all‐cause death was significantly higher in hemodialysis patients than in nonhemodialysis patients in both the entire cohort (71% versus 40%, P AVR group (63.2% versus 17.9%, P AVR group as compared with the conservative group was associated with significantly lower cumulative 5‐year incidences of all‐cause death (60.6% versus 75.5%, P P AVR procedure, was markedly higher in the hemodialysis patients than in the nonhemodialysis patients (21.2% and 2.3%, P Conclusions Among hemodialysis patients with severe aortic stenosis, the initial AVR strategy as compared with the conservative strategy was associated with significantly lower long‐term mortality risk, particularly the risk for sudden death, although the effect size for the survival benefit of the initial AVR strategy was smaller than that in the nonhemodialysis patients.

Background There are limited data regarding the risk stratification based on peak aortic jet velocity (Vmax) in patients with severe aortic stenosis ( AS ). Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the study population consisted of 1075 conservatively managed patients with Vmax ≥4.0 m/s and left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on Vmax (group 1, 4.0 ≤ Vmax AS ‐related events (aortic valve–related death or heart failure hospitalization) was incrementally higher with increasing Vmax (entire population; 38.0%, 49.4%, and 62.8%, P P =0.008; and asymptomatic patients; 29.4%, 38.9%, and 47.7%, P =0.005). After adjusting for confounders, the excess risk of group 2 and group 3 relative to group 1 for AS ‐related events remained significant (hazard ratio, 1.39; 95% CI , 1.07–1.81; P =0.02, and hazard ratio, 1.53; 95% CI , 1.17–2.00; P =0.002, respectively). The effect size of group 3 relative to group 1 for AS ‐related events in asymptomatic patients (N=479) was similar to that in symptomatic patients (N=596; hazard ratio, 1.59; 95% CI , 1.01–2.52; P =0.047, and hazard ratio, 1.67; 95% CI , 1.16–2.40, P =0.008, respectively), and there was no significant overall interaction between the symptomatic status and the effect of the Vmax categories on AS ‐related events (interaction, P =0.88). Conclusions In conservatively managed severe AS patients with preserved left ventricular ejection fraction, increasing Vmax was associated with incrementally higher risk for AS ‐related events. However, the cumulative 5‐year incidence of the AS ‐related events remained very high even in asymptomatic patients with less greater Vmax.

We thank Dr Ahmed and colleagues for their comment on our article recently published in Circulation .1 They are very interested in the sex difference in the effect of low-dose aspirin on the primary prevention of cardiovascular events. As they mentioned, earlier studies indicated that low-dose aspirin may be helpful for reducing the risk of stroke in women,2 whereas it may be advantageous for the risk of myocardial infarction in men.2 However, we did not show significant differences between the sexes in the preventive effect of low-dose aspirin in Japanese patients with diabetes mellitus who have no history of cardiovascular diseases. Their major concern was that the effect of aspirin might differ between premenopausal and postmenopausal women. In our study, we could …

Background— In patients with ST-segment–elevation acute myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention, long-term risks for cardiac and noncardiac death beyond acute phase of STEMI have not been thoroughly evaluated yet. Methods and Results— We identified 3942 STEMI patients who had primary percutaneous coronary intervention within 24 hours after onset between January 2005 and December 2007 in the CREDO-Kyoto AMI registry (Coronary Revascularization Demonstrating Outcome study in Kyoto Acute Myocardial Infarction) and evaluated their short-term (within 6-month) and long-term (beyond 6-month) incidences and causes of deaths. The cumulative 5-year incidence of all-cause death in the current study population was 20.4% (cardiac death, 12.2% and noncardiac death, 9.4%, respectively). The vast majority of deaths were cardiac in origin within 6-month (cardiac death, 8.0% and noncardiac death, 0.9%), whereas noncardiac death accounted for nearly two thirds of all-cause death beyond 6-month (cardiac death, 4.6% and noncardiac death, 8.5%). In the stratified analysis according to age, the proportion of noncardiac death was similar regardless of age although the absolute mortality rate was higher with increasing age. By the multivariable Cox regression models, the independent risk factors of all-cause death were advanced age, cardiogenic shock, renal dysfunction, large infarct size, and anterior wall infarction within 6 months after STEMI, and advanced age, previous heart failure, renal dysfunction, and liver cirrhosis beyond 6 months after STEMI, respectively. Conclusions— In STEMI patients who underwent primary percutaneous coronary intervention, the long-term risk for cardiac death was relatively low compared with that for noncardiac death, which accounted for nearly two thirds of all-cause death beyond 6 months.

Background— Noncardiac surgery after percutaneous coronary intervention (PCI) has been reported to be carrying high risk for both ischemic and bleeding complications. However, there has been no report comparing the incidence and outcomes of surgical procedures after coronary artery bypass grafting (CABG) with those after PCI. Methods and Results— Among 14 383 patients undergoing first coronary revascularization (PCI, n=12 207; CABG, n=2176) enrolled in the Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG Registry Cohort-2, surgical procedures were performed more frequently after CABG (n=560) than after PCI (n=2398; cumulative 3-year incidence: 27% versus 22%; unadjusted P P =0.9; adjusted hazard ratio, 0.97; 95% confidence interval, 0.47–1.89; P =0.9). The risk for the primary bleeding outcome measure (moderate or severe bleeding by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries classification) was lower in the CABG groups than in the PCI group (cumulative incidence: 1.3% versus 2.6%; unadjusted P =0.07; adjusted hazard ratio, 0.36; 95% confidence interval, 0.12–0.87; P =0.02). There were no interactions between the timing of surgery and the types of coronary revascularization (CABG/PCI) for both ischemic and bleeding outcomes. Conclusions— Surgical procedures were performed significantly more frequently after CABG than after PCI, particularly

Background— Long-term clinical outcomes of everolimus-eluting stent (EES) compared with sirolimus-eluting stent (SES) have not been evaluated fully yet, especially whether EES implantation could positively affect late adverse events reported after SES implantation occurring >1 year. Methods and Results— In this all-comer prospective multicenter randomized open-label trial, 3196 patients were assigned randomly to implant either EES (n=1596) or SES (n=1600). At 3 years, EES was noninferior to SES on the primary safety end point (all-cause death or myocardial infarction; 10.1% versus 11.5%; noninferiority P P =0.19). Cumulative incidence of definite stent thrombosis was low and was not significantly different between the 2 groups (0.5% versus 0.6%; P =0.81). There was no significant difference in the efficacy end point of target-lesion revascularization between the EES and SES groups (6.6% versus 7.9%; P =0.16). However, the cumulative incidence of target-lesion failure (cardiac death/target-vessel myocardial infarction/ischemia-driven target-lesion revascularization) was significantly lower in the EES group than in the SES group (8.8% versus 11.4%; P =0.01). By a landmark analysis at 1 year, the cumulative incidence of very late stent thrombosis and late target-lesion revascularization was not significantly different between the 2 groups (0.2% versus 0.2%; P =0.99 and 2.2% versus 2.9%; P =0.21, respectively). Conclusions— The efficacy and safety outcomes for this trial after EES implantation remained comparable with those after SES implantation through 3-year follow-up. However, improvement of clinical outcome after EES implantation compared with SES implantation was suggested by the significantly lower cumulative incidences of target-lesion failure, which has been the most widely used primary end point in the stent-versus-stent trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01035450.