Antiplatelets for Cardiovascular Disease in Non-valvular AF with Rivaroxaban: A Subanalysis of the EXPAND Study.

AIM: In this subanalysis of the EXPAND study, we evaluated the risks and benefits of rivaroxaban plus antiplatelet therapy (APT) for patients with non-valvular atrial fibrillation (NVAF) complicated by stable coronary artery disease (CAD), ischemic stroke, or peripheral artery disease (PAD). METHODS: From the EXPAND study population (n=7,141), patients with NVAF complicated by stable CAD (n=886), ischemic stroke (n=1,231), or PAD (n=160) were included. Patients complicated by any of them were set as ALL (n=2,030). Patients were all treated with rivaroxaban (10 or 15 mg/day) with (+) or without (-) APT. Efficacy outcomes were symptomatic stroke＋systemic embolism (SE), symptomatic stroke＋SE＋myocardial infarction＋cardiovascular death, and all-cause death. Safety outcomes included major and any bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for differences between the APT(+) and APT(-) groups. RESULTS: There were no significant differences in the efficacy outcomes between the APT(+) and APT(-) groups in the ALL cohort or in the CAD and STROKE sub-cohorts. In the PAD subcohort, the HR [95% CI] for all-cause death in the APT(+) group increased (4.43 [1.05-18.71]; p=0.043). In the APT(+) group, the HR [95% CI] for any bleeding increased in the ALL cohort (1.28 [1.01-1.62]; p=0.044) and STROKE subcohort (1.42 [1.01-2.01]; p=0.047), and for major bleeding in the CAD subcohort (2.00 [1.01-3.93]; p=0.046). CONCLUSIONS: Rivaroxaban with APT did not reduce ischemic outcomes in patients with stable CAD or ischemic stroke; however, it did increase the risk of bleeding in patients with stable CAD or ischemic stroke.

Predictive Performance of Machine Learning-Based Models for Poststroke Clinical Outcomes in Comparison With Conventional Prognostic Scores: Multicenter, Hospital-Based Observational Study.

BACKGROUND: Although machine learning is a promising tool for making prognoses, the performance of machine learning in predicting outcomes after stroke remains to be examined. OBJECTIVE: This study aims to examine how much data-driven models with machine learning improve predictive performance for poststroke outcomes compared with conventional stroke prognostic scores and to elucidate how explanatory variables in machine learning-based models differ from the items of the stroke prognostic scores. METHODS: We used data from 10,513 patients who were registered in a multicenter prospective stroke registry in Japan between 2007 and 2017. The outcomes were poor functional outcome (modified Rankin Scale score >2) and death at 3 months after stroke. Machine learning-based models were developed using all variables with regularization methods, random forests, or boosted trees. We selected 3 stroke prognostic scores, namely, ASTRAL (Acute Stroke Registry and Analysis of Lausanne), PLAN (preadmission comorbidities, level of consciousness, age, neurologic deficit), and iScore (Ischemic Stroke Predictive Risk Score) for comparison. Item-based regression models were developed using the items of these 3 scores. The model performance was assessed in terms of discrimination and calibration. To compare the predictive performance of the data-driven model with that of the item-based model, we performed internal validation after random splits of identical populations into 80% of patients as a training set and 20% of patients as a test set; the models were developed in the training set and were validated in the test set. We evaluated the contribution of each variable to the models and compared the predictors used in the machine learning-based models with the items of the stroke prognostic scores. RESULTS: The mean age of the study patients was 73.0 (SD 12.5) years, and 59.1% (6209/10,513) of them were men. The area under the receiver operating characteristic curves and the area under the precision-recall curves for predicting poststroke outcomes were higher for machine learning-based models than for item-based models in identical populations after random splits. Machine learning-based models also performed better than item-based models in terms of the Brier score. Machine learning-based models used different explanatory variables, such as laboratory data, from the items of the conventional stroke prognostic scores. Including these data in the machine learning-based models as explanatory variables improved performance in predicting outcomes after stroke, especially poststroke death. CONCLUSIONS: Machine learning-based models performed better in predicting poststroke outcomes than regression models using the items of conventional stroke prognostic scores, although they required additional variables, such as laboratory data, to attain improved performance. Further studies are warranted to validate the usefulness of machine learning in clinical settings.

Effect of smoking status on clinical outcomes after reperfusion therapy for acute ischemic stroke.

Smoking has detrimental effects on the cardiovascular system; however, some studies have reported better clinical outcomes after thrombolysis for ischemic stroke in smokers than in nonsmokers, a phenomenon known as the smoking paradox. Therefore, this study aimed to examine the smoking paradox in patients with ischemic stroke receiving reperfusion therapy. Data were collected from a multicenter hospital-based acute stroke registry in Fukuoka, Japan. The 1148 study patients were categorized into current and noncurrent smokers. The association between smoking and clinical outcomes, including neurological improvement (≥ 4-point decrease in the National Institutes of Health Stroke Scale during hospitalization or 0 points at discharge) and good functional outcomes (modified Rankin Scale score of 0-2) at 3 months, was evaluated using logistic regression analysis and propensity score-matched analysis. Among the participants, 231 (20.1%) were current smokers. The odds ratios (ORs) of favorable outcomes after adjusting for potential confounders were not significantly increased in current smokers (OR 0.85, 95% confidence interval [CI] 0.60-1.22 for neurological improvement; OR 0.95, 95% CI 0.65-1.38 for good functional outcome). No significant association was found in the propensity score-matched cohorts. Smoking cessation is strongly recommended since current smoking was not associated with better outcomes after reperfusion therapy.

Body temperature in the acute phase and clinical outcomes after acute ischemic stroke.

BACKGROUND: This study aimed to examine whether post-stroke early body temperature is associated with neurological damage in the acute phase and functional outcomes at three months. METHODS: We included 7,177 patients with acute ischemic stroke within 24 h of onset. Axillary temperature was measured daily in the morning for seven days. Mean body temperature was grouped into five quintiles (Q1: 35.1‒36.5°C, Q2: 36.5‒36.7°C, Q3: 36.7‒36.8°C, Q4: 36.8‒37.1°C, and Q5: 37.1‒39.1°C). Clinical outcomes included neurological improvement during hospitalization and poor functional outcome (modified Rankin scale score, 3-6) at three months. A logistic regression analysis was performed to evaluate the association between body temperature and clinical outcomes. RESULTS: The patient's mean (SD) age was 70.6 (12.3) years, and 35.7% of patients were women. Mean body temperature was significantly associated with less neurological improvement from Q2 (odds ratios [95% confidence interval], 0.77 [0.65-0.99] vs. Q1) to Q5 (0.33 [0.28-0.40], P for trend <0.001) even after adjusting for potential confounders, including baseline neurological severity, C-reactive protein levels, and post-stroke acute infections. The multivariable-adjusted risk of poor functional outcome linearly increased from Q2 (1.36 [1.03-1.79]) to Q5 (6.44 [5.19-8.96], P for trend <0.001). These associations were maintained even in the analyses excluding patients with acute infectious diseases. Multivariable-adjusted risk of poor functional outcome was higher in patients with early body temperature elevation on days 1-3 and with longer duration with body temperature >37.0°C. CONCLUSIONS: Post-stroke early high body temperature is independently associated with unfavorable outcomes following acute ischemic stroke.

Association between abdominal adiposity and clinical outcomes in patients with acute ischemic stroke.

BACKGROUND: It is unclear whether abdominal adiposity has an additional effect on post-stroke outcomes. This study aimed to determine whether waist circumference (WC) is independently associated with clinical outcomes after acute ischemic stroke. METHODS: We enrolled patients with acute ischemic stroke from a multicenter hospital-based stroke registry in Fukuoka, Japan. We measured WC on admission and categorized patients into four groups (Q1-Q4) according to the quartiles in females and males. The clinical outcomes were poor functional outcome (modified Rankin scale score 2-6) and death from any cause. Logistic regression analysis was performed to estimate the odds ratio and 95% confidence interval of the outcomes of interest after adjusting for potential confounding factors, including body mass index (BMI). RESULTS: A total of 11,989 patients (70.3±12.2 years, females: 36.1%) were included in the analysis. The risk of poor functional outcome significantly decreased for Q2-Q4 (vs. Q1) at discharge and Q2-Q3 (vs. Q1) at 3 months, even after adjusting for potential confounders, including BMI. In contrast, adjustment of BMI eliminated the significant association between WC and all-cause death at discharge and 3 months. The association between high WC and favorable functional outcome was not affected by fasting insulin levels or homeostatic model assessment for insulin resistance and was only found in patients without diabetes (P = 0.02 for heterogeneity). CONCLUSIONS: These findings suggest that abdominal adiposity has an additional impact on post-stroke functional outcome, independent of body weight and insulin action.

Temporal Generalizability of Machine Learning Models for Predicting Postoperative Delirium Using Electronic Health Record Data: Model Development and Validation Study.

BACKGROUND: Although machine learning models demonstrate significant potential in predicting postoperative delirium, the advantages of their implementation in real-world settings remain unclear and require a comparison with conventional models in practical applications. OBJECTIVE: The objective of this study was to validate the temporal generalizability of decision tree ensemble and sparse linear regression models for predicting delirium after surgery compared with that of the traditional logistic regression model. METHODS: The health record data of patients hospitalized at an advanced emergency and critical care medical center in Kumamoto, Japan, were collected electronically. We developed a decision tree ensemble model using extreme gradient boosting (XGBoost) and a sparse linear regression model using least absolute shrinkage and selection operator (LASSO) regression. To evaluate the predictive performance of the model, we used the area under the receiver operating characteristic curve (AUROC) and the Matthews correlation coefficient (MCC) to measure discrimination and the slope and intercept of the regression between predicted and observed probabilities to measure calibration. The Brier score was evaluated as an overall performance metric. We included 11,863 consecutive patients who underwent surgery with general anesthesia between December 2017 and February 2022. The patients were divided into a derivation cohort before the COVID-19 pandemic and a validation cohort during the COVID-19 pandemic. Postoperative delirium was diagnosed according to the confusion assessment method. RESULTS: A total of 6497 patients (68.5, SD 14.4 years, women n=2627, 40.4%) were included in the derivation cohort, and 5366 patients (67.8, SD 14.6 years, women n=2105, 39.2%) were included in the validation cohort. Regarding discrimination, the XGBoost model (AUROC 0.87-0.90 and MCC 0.34-0.44) did not significantly outperform the LASSO model (AUROC 0.86-0.89 and MCC 0.34-0.41). The logistic regression model (AUROC 0.84-0.88, MCC 0.33-0.40, slope 1.01-1.19, intercept -0.16 to 0.06, and Brier score 0.06-0.07), with 8 predictors (age, intensive care unit, neurosurgery, emergency admission, anesthesia time, BMI, blood loss during surgery, and use of an ambulance) achieved good predictive performance. CONCLUSIONS: The XGBoost model did not significantly outperform the LASSO model in predicting postoperative delirium. Furthermore, a parsimonious logistic model with a few important predictors achieved comparable performance to machine learning models in predicting postoperative delirium.

Effectiveness and safety of reduced-dose rivaroxaban for elderly patients with non-valvular atrial fibrillation: A subanalysis of the EXPAND study.

BACKGROUND: Establishing the appropriate rivaroxaban dose in older patients with non-valvular atrial fibrillation (NVAF) is important because of the high risk of adverse events. In this EXPAND study subanalysis, we examined the safety and efficacy of standard-dose (15 mg/day) and non-recommended reduced-dose (10 mg/day) rivaroxaban in patients aged ≥65 years with NVAF and preserved renal function. METHODS: The entire analysis population (ALL cohort [n = 3982]; ≥65 years) was divided into early elderly (ELD) (65-74 years [n = 1444]) and late ELD (≥75 years [n = 2386]) sub-cohorts. Each sub-cohort was divided into reduced-dose and standard-dose groups. Kaplan-Meier survival curves with adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were used to assess efficacy (thromboembolic events) and safety (hemorrhagic events) outcomes. RESULTS: The aHR for major bleeding did not differ between the dosages in any of the cohorts (aHRs: 0.86-0.93). There were no significant differences in the occurrence of stroke + systemic embolism (SE) or stroke + SE + myocardial infarction (MI) + cardiovascular (CV) death among the cohorts. The aHR for MI/unstable angina + interventional/CV surgery + CV death was higher with 10-mg/day rivaroxaban than 15-mg/day rivaroxaban in the ALL cohort (aHR: 1.56 [95% CI 1.02-2.37], p = 0.039) and the late ELD sub-cohort (aHR: 1.86 [95% CI 1.01-3.42], p = 0.045). CONCLUSIONS: Reduced-dose rivaroxaban may increase the risk of coronary artery events. The use of rivaroxaban 15 mg/day in patients with NVAF aged ≥75 years with preserved renal function was supported.

Association between decreases in serum uric acid levels and unfavorable outcomes after ischemic stroke: A multicenter hospital-based observational study.

BACKGROUND: The association between clinical outcomes in ischemic stroke patients and decreases in serum uric acid levels, which often occur during the acute phase, remains unknown. Herein, we aimed to investigate the association using a large-scale, multicenter stroke registry. METHODS: We analyzed 4,621 acute ischemic stroke patients enrolled in the Fukuoka Stroke Registry between June 2007 and September 2019 whose uric acid levels were measured at least twice during hospitalization (including on admission). The study outcomes were poor functional outcome (modified Rankin Scale score ≥3) and functional dependence (modified Rankin Scale score 3-5) at 3 months after stroke onset. Changes in uric acid levels after admission were evaluated using a decrease rate that was classified into 4 sex-specific grades ranging from G1 (no change/increase after admission) to G4 (most decreased). Multivariable logistic regression analyses were used to assess the associations between decreases in uric acid levels and the outcomes. RESULTS: The frequencies of the poor functional outcome and functional dependence were lowest in G1 and highest in G4. The odds ratios (95% confidence intervals) of G4 were significantly higher for poor functional outcome (2.66 [2.05-3.44]) and functional dependence (2.61 [2.00-3.42]) when compared with G1 after adjusting for confounding factors. We observed no heterogeneity in results for subgroups categorized according to age, sex, stroke subtype, neurological severity, chronic kidney disease, or uric acid level on admission. CONCLUSIONS: Decreases in serum uric acid levels were independently associated with unfavorable outcomes after acute ischemic stroke.

Non-linear association between body weight and functional outcome after acute ischemic stroke.

This study aimed to determine whether body weight is associated with functional outcome after acute ischemic stroke. We measured the body mass index (BMI) and assessed clinical outcomes in patients with acute ischemic stroke. The BMI was categorized into underweight (< 18.5 kg/m2), normal weight (18.5-22.9 kg/m2), overweight (23.0-24.9 kg/m2), and obesity (≥ 25.0 kg/m2). The association between BMI and a poor functional outcome (modified Rankin Scale [mRS] score: 3-6) was evaluated. We included 11,749 patients with acute ischemic stroke (70.3 ± 12.2 years, 36.1% women). The risk of a 3-month poor functional outcome was higher for underweight, lower for overweight, and did not change for obesity in reference to a normal weight even after adjusting for covariates by logistic regression analysis. Restricted cubic splines and SHapley Additive exPlanation values in eXtreme Gradient Boosting model also showed non-linear relationships. Associations between BMI and a poor functional outcome were maintained even after excluding death (mRS score: 3-5) or including mild disability (mRS score: 2-6) as the outcome. The associations were strong in older patients, non-diabetic patients, and patients with mild stroke. Body weight has a non-linear relationship with the risk of a poor functional outcome after acute ischemic stroke.

Decreased Estimated Glomerular Filtration Rate and Proteinuria and Long-Term Outcomes After Ischemic Stroke: A Longitudinal Observational Cohort Study.

BACKGROUND: It remains unclear how chronic kidney disease and its underlying pathological conditions, kidney dysfunction, and kidney damage, are associated with cardiovascular outcomes. This study aimed to determine whether kidney dysfunction (ie, decreased estimated glomerular filtration rate), kidney damage (ie, proteinuria), or both are associated with the long-term outcomes after ischemic stroke. METHODS: A total of 12 576 patients (mean age, 73.0±12.6 years; 41.3% women) with ischemic stroke who were registered in a hospital-based multicenter registry, Fukuoka Stroke Registry, between June 2007 and September 2019, were prospectively followed up after stroke onset. Kidney function was assessed by estimated glomerular filtration rate and categorized into G1: ≥60 mL/(min·1.73 m2), G2: 45-59 mL/(min·1.73 m2), and G3: <45 mL/(min·1.73 m2). Kidney damage was evaluated by proteinuria using a urine dipstick test and classified into P1: -, P2: ±/1+, and P3: ≥2+. Hazard ratios and 95% CI for events of interest were estimated by a Cox proportional hazards model. Long-term outcomes included recurrence of stroke and all-cause death. RESULTS: During the median follow-up of 4.3 years (interquartile range, 2.1-7.3 years), 2481 patients had recurrent stroke (48.0/1000 patient-years) and 4032 patients died (67.3/1000 patient-years). Chronic kidney disease was independently associated with increased risks of stroke recurrence and all-cause death even after adjustment for multiple confounding factors, including traditional cardiovascular risk factors. Both estimated glomerular filtration rate and proteinuria were independently associated with increased risks of stroke recurrence (multivariable-adjusted hazard ratio [95% CI], G3: 1.22 [1.09-1.37] versus G1, P3: 1.25 [1.07-1.46] versus P1) and death (G3: 1.45 [1.33-1.57] versus G1, P3: 1.62 [1.45-1.81] versus P1). In subgroup analyses, effect modifications were found in the association of proteinuria with death by age and stroke subtype. CONCLUSIONS: Kidney dysfunction and kidney damage were independently, but differently, associated with increased risks of recurrent stroke and all-cause death.

Comparison of Prasugrel and Clopidogrel in Thrombotic Stroke Patients with Risk Factors for Ischemic Stroke Recurrence: An Integrated Analysis of PRASTRO-I, PRASTRO-II, and PRASTRO-III.

INTRODUCTION: Patients with stroke are at a high risk of recurrence, and although they receive antiplatelet therapies such as clopidogrel for secondary prevention of non-cardioembolic stroke, the recurrence rate remains high. Three phase 3 trials (PRASTRO-I/II/III) were conducted to determine the efficacy of prasugrel in preventing recurrent stroke. Here, we performed an integrated analysis of these studies to confirm the generalizability of the PRASTRO-III findings and to supplement the small sample size of the study. METHODS: Patients from PRASTRO-I, PRASTRO-II, and PRASTRO-III with ischemic stroke (large-artery atherosclerosis or small-artery occlusion) and at least one of the following were included: hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease, or ischemic stroke history. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes in the intention-to-treat population. Bleeding events (life-threatening bleeding, major bleeding, and clinically relevant bleeding) were evaluated as the primary safety endpoint. Cumulative incidences and 95% confidence intervals (CIs) were calculated for the study outcomes using the Kaplan-Meier method. Hazard ratios (HRs) and 95% CIs were calculated using the Cox regression model. RESULTS: The data of 2,184, 274, and 230 patients from PRASTRO-I, PRASTRO-II, and PRASTRO-III, respectively, were analyzed (N = 2,688; prasugrel, N = 1,337; clopidogrel, N = 1,351). Stroke at enrollment was classified as large-artery atherosclerosis in 49.3% of patients and small-artery occlusion in 50.7% of patients. The primary efficacy endpoint composite incidence (prasugrel vs. clopidogrel) was 3.4% versus 4.3% (HR: 0.771, 95% CI: 0.522-1.138). The incidence of each component of the primary efficacy endpoint for prasugrel versus clopidogrel was 3.1% (n = 41) versus 4.1% (n = 55) for ischemic stroke, 0.3% (n = 4) versus 0.2% (n = 3) for MI, and no events of death from other vascular causes. For the primary safety endpoint, bleeding events were reported in 6.0% of patients in the prasugrel group versus 5.5% of patients in the clopidogrel group (HR: 1.074, 95% CI: 0.783-1.473). CONCLUSIONS: This integrated analysis supports the findings of PRASTRO-III. Prasugrel is a promising treatment that results in a numerical reduction in the composite incidence of ischemic stroke, MI, and death from other vascular causes in patients with ischemic stroke who are at a high risk of stroke recurrence. No major safety issues were observed for prasugrel.

Sex Differences in Long-Term Functional Decline after Ischemic Stroke: A Longitudinal Observational Study from the Fukuoka Stroke Registry.

INTRODUCTION: Data on sex differences in poststroke functional status for a period longer than 1 year based on large cohorts are sparse. This study aimed to determine whether there are sex differences in long-term functional decline after ischemic stroke. METHODS: We tracked functional status for 5 years among 3-month survivors of acute ischemic stroke and compared outcomes between women and men using a large-scale hospital-based stroke registry in Fukuoka, Japan. Functional status was assessed using the modified Rankin Scale (mRS). Functional dependency was defined as an mRS score of 3, 4, or 5. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals of outcomes after adjusting for possible confounders. RESULTS: A total of 8,446 patients (71.9 ± 12.5 years, 3,377 (40.0%) female patients) were enrolled in this study. Female sex was associated with a higher risk of functional dependency at 5 years poststroke even when adjusting for age, 3-month mRS score, and other confounding factors (multivariable-adjusted OR vs. men, 1.56 [95% confidence interval, 1.26-1.93]). This significant association of female sex with higher dependency at 5 years was also found among patients who were independent at 3 months poststroke. Subgroup analysis showed that increased risk of functional dependency in female patients was more marked in patients aged ≥75 years than in those aged <75 years (p for heterogeneity = 0.02). Conversely, female sex was associated with a lower risk of death. No sex difference was observed in stroke recurrence during 5 years poststroke. DISCUSSION/CONCLUSION: This longitudinal observational study suggests that female sex was independently associated with an increased risk of functional decline in the chronic phase of stroke, especially in older patients. There was no sex difference in 5-year stroke recurrence, and thus, other factors might be involved in more significant deterioration of functional status in female survivors of ischemic stroke. Further studies are needed to elucidate underlying causes of sex differences in long-term functional decline after stroke.

Modification of the effects of age on clinical outcomes through management of lifestyle-related factors in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: This study examined the association between age and clinical outcomes after ischemic stroke, and whether the effect of age on post-stroke outcomes can be modified by various factors. METHODS: We included 12,171 patients with acute ischemic stroke, who were functionally independent before stroke onset, in a multicenter hospital-based study conducted in Fukuoka, Japan. Patients were categorized into six groups according to age: ≤ 45, 46-55, 56-65, 66-75, 76-85, and > 85 years. Logistic regression analysis was performed to estimate an odds ratio for poor functional outcome (modified Rankin scale score of 3-6 at 3 months) for each age group. Interaction effects of age and various factors were analyzed using a multivariable model. RESULTS: The mean age of the patients was 70.3 ± 12.2 years, and 63.9% were men. Neurological deficits at onset were more severe in the older age groups. The odds ratio of poor functional outcome linearly increased (P for trend <0.001), even after adjusting for potential confounders. Sex, body mass index, hypertension, and diabetes mellitus significantly modified the effect of age on the outcome (P < 0.05). The unfavorable effect of older age was greater in female patients and those with low body weight, whereas the protective effect of younger age was smaller in patients with hypertension or diabetes mellitus. CONCLUSIONS: Functional outcome worsened with age in patients with acute ischemic stroke, especially in females and those with low body weight, hypertension, or hyperglycemia.

Efficacy and Safety of Prasugrel vs Clopidogrel in Thrombotic Stroke Patients With Risk Factors for Ischemic Stroke Recurrence: A Double-blind, Phase III Study (PRASTRO-III).

AIM: To examine the efficacy and safety of prasugrel vs clopidogrel in thrombotic stroke patients at risk of ischemic stroke. METHODS: This multicenter, active-controlled, randomized, double-blind, double-dummy, parallel group study enrolled thrombotic stroke patients aged ≥ 50 years at risk of ischemic stroke. Patients received prasugrel (3.75 mg/day) or clopidogrel (75 or 50 mg/day) for 24-48 weeks; other antiplatelet drugs were prohibited. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes from the start to 1 day after treatment completion or discontinuation. Secondary efficacy endpoints included the incidences of ischemic stroke, MI, death from other vascular causes, ischemic stroke and transient ischemic attack, and stroke. Safety endpoints included bleeding events and adverse events (AEs). RESULTS: In the prasugrel (N=118) and clopidogrel (N=112; all received 75 mg) groups, the primary efficacy endpoint composite incidence (95% confidence interval) was 6.8% (3.0%-12.9%) and 7.1% (3.1%-13.6%), respectively. The risk ratio (prasugrel/clopidogrel) was 0.949 (0.369-2.443). Secondary efficacy endpoints followed a similar trend. The combined incidences of life-threatening, major, and clinically relevant bleeding were 5.0% and 3.5% in the prasugrel and clopidogrel groups, respectively. The incidences of all bleeding events and AEs were 19.2% and 24.6% and 76.7% and 82.5% in the prasugrel and clopidogrel groups, respectively. No serious AEs were causally related to prasugrel. CONCLUSIONS: We observed a risk reduction of 5% with prasugrel vs clopidogrel, indicating comparable efficacy. There were no major safety issues for prasugrel.

Hyporesponsiveness to erythropoiesis-stimulating agent in non-dialysis-dependent CKD patients: The BRIGHTEN study.

Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor renal and cardiovascular outcome. To assess the method for evaluating hyporesponsiveness to ESA in patients with ND-CKD, a multicenter, prospective, observational study of 1,980 adult patients with ND-CKD with renal anemia was conducted. Darbepoetin alfa (DA) and iron supplement administrations were provided according to the recommendation of the attached document and the guidelines of JSDT (Japanese Society of Dialysis and Transplantation). The primary outcomes were progression of renal dysfunction and major adverse cardiovascular events. ESA responsiveness was assessed using pre-defined candidate formulae. During the mean follow-up period of 96 weeks, renal and cardiovascular disease (CVD) events occurred in 683 (39.6%) and 174 (10.1%) of 1,724 patients, respectively. Among pre-set candidate formulae, the one expressed by dividing the dose of DA by Hb level at the 12-week DA treatment was statistically significant in predicting renal (hazard ratio [HR], 1.449; 95% confidence interval [CI], 1.231-1.705; P<0.0001) and CVD events (HR, 1.719; 95% CI, 1.239-2.386; P = 0.0010). The optimum cut-off values for both events were close to 5.2. In conclusion, hyporesponsiveness to ESA in ND-CKD cases, which is associated with a risk for renal and CVD events, may be evaluated practicably as the dose of DA divided by the Hb level at the 12-week DA treatment, and the cut-off value of this index is 5.2. A search for the causes of poor response and measures for them should be recommended in such patients. Trial registration: ClinicalTrials. gov Identifier: NCT02136563; UMIN Clinical Trial Registry Identifier: UMIN000013464.

Causes of ischemic stroke in young adults versus non-young adults: A multicenter hospital-based observational study.

BACKGROUND: Very few comparative studies have focused on the differences in the causes of ischemic stroke between young adults and non-young adults. This study was performed to determine what causes of ischemic stroke are more important in young adults than in non-young adults using a large-scale multicenter hospital-based stroke registry in Fukuoka, Japan. METHODS AND RESULTS: We investigated data on 15,860 consecutive patients aged ≥18 years with acute ischemic stroke (mean age: 73.5 ± 12.4 years, 58.2% men) who were hospitalized between 2007 and 2019. In total, 779 patients were categorized as young adults (≤50 years of age). Although vascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia, were less frequent in young adults than in non-young adults, the prevalence of diabetes mellitus and dyslipidemia in young adults aged >40 years were comparable to those of non-young adults. Lifestyle-related risk factors such as smoking, drinking, and obesity were more frequent in young adults than in non-young adults. As young adults became older, the proportions of cardioembolism and stroke of other determined etiologies decreased, but those of large-artery atherosclerosis and small-vessel occlusion increased. Some embolic sources (high-risk sources: arterial myxoma, dilated cardiomyopathy, and intracardiac thrombus; medium-risk sources: atrial septal defect, nonbacterial thrombotic endocarditis, patent foramen ovale, and left ventricular hypokinesis) and uncommon causes (vascular diseases: reversible cerebral vasoconstriction syndrome, moyamoya disease, other vascular causes, arterial dissection, and cerebral venous thrombosis; hematologic diseases: antiphospholipid syndrome and protein S deficiency) were more prevalent in young adults than in non-young adults, and these trends decreased with age. CONCLUSIONS: Certain embolic sources and uncommon causes may be etiologically important causes of ischemic stroke in young adults. However, the contribution of conventional vascular risk factors and lifestyle-related risk factors is not negligible with advancing age, even in young adults.

Day-by-Day Blood Pressure Variability in the Subacute Stage of Ischemic Stroke and Long-Term Recurrence.

BACKGROUND AND PURPOSE: This study aimed to determine whether variability of day-by-day blood pressure (BP) during the subacute stage of acute ischemic stroke is predictive of long-term stroke recurrence. METHODS: We analyzed 7665 patients (mean±SD age: 72.9±13.1 years; women: 42.4%) hospitalized for first-ever ischemic stroke in 7 stroke centers in Fukuoka, Japan, from June 2007 to November 2018. BP was measured daily during the subacute stage (4-10 days after onset). Its mean and coefficient of variation (CV) values were calculated and divided into 4 groups according to the quartiles of these BP parameters. Patients were prospectively followed up for recurrent stroke or all-cause death. The cumulative event rate was calculated with the Kaplan-Meier method. We estimated the hazard ratios and 95% confidence intervals of the events of interest after adjusting for potential confounders and mean BP values using Cox proportional hazards models. The Fine-Gray model was also used to account for the competing risk of death. RESULTS: With a mean (±SD) follow-up duration of 3.9±3.2 years, the rates of recurrent stroke and all-cause death were 3.9 and 9.9 per 100 patient-years, respectively. The cumulative event rates of recurrent stroke and all-cause death increased with increasing CVs of systolic BP and diastolic BP. The systolic BP CV was significantly associated with an increased risk of recurrent stroke after adjusting for multiple confounders and mean BP (hazard ratio [95% CI] for fourth quartile versus first quartile, 1.26 [1.05-1.50]); the risk of recurrent stroke also increased with an increasing systolic BP CV for nonfatal strokes (1.26 [1.05-1.51]) and when death was regarded as a competing risk (1.21 [1.02-1.45]). Similar associations were observed for the diastolic BP CV. CONCLUSIONS: Day-by-day variability of BP during the subacute stage of acute ischemic stroke was associated with an increased long-term risk of recurrent stroke.

Regional Disparity of Reperfusion Therapy for Acute Ischemic Stroke in Japan: A Retrospective Analysis of Nationwide Claims Data from 2010 to 2015.

Background We aimed to determine whether a regional disparity exists in usage of reperfusion therapy (intravenous recombinant tissue plasminogen activator [IV rt-PA] and endovascular thrombectomy [EVT]) and post-reperfusion 30-day mortality in patients with acute ischemic stroke, and which regional factors are associated with their usage. Methods and Results We retrospectively investigated 69 948 patients (mean age±SD, 74.9±12.0 years; women, 41.4%) with acute ischemic stroke treated with reperfusion therapy between April 2010 and March 2016 in Japan using nationwide claims data. Regional disparity was evaluated using Gini coefficients for age- and sex-adjusted usage of reperfusion therapy and 30-day post-reperfusion in-hospital death ratio in 47 administrative regions. The association between regional factors and reperfusion therapy usage was evaluated with fixed-effects regression models. During the study period, Gini coefficients showed low inequality (0.11-0.15) for use of IV rt-PA monotherapy and IV rt-PA and/or EVT and extreme inequality (0.49) for EVT usage in 2010, which became moderate inequality (0.25) by 2015. The densities of stroke centers and endovascular specialists, as well as market concentration, were associated with increased usage of reperfusion therapy whereas the proportion of rural residents and delayed ambulance transport were negatively associated with usage. Inequality in the standardized death ratio after EVT was extreme (0.86) in 2010 but became moderate (0.29) by 2015; inequality was low to moderate (0.17-0.23) for IV rt-PA monotherapy and IV rt-PA and/or EVT. Conclusions Scrutinizing existing data sources revealed regional disparity in reperfusion therapy for acute ischemic stroke and its associated regional factors in Japan.

ß-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke.

Background and Purpose: Little is known about how ß-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether ß-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin resistance influences this association in a prospective study of patients with acute stroke. Methods: A total of 3590 nondiabetic patients with acute ischemic stroke (mean age, 71 years) were followed up for 3 months. ß-Cell function was assessed using the homeostasis model assessment for ß-cell function (HOMA-ß). Study outcomes were poor functional outcome (modified Rankin Scale score, 3­6) and stroke recurrence at 3 months after stroke onset and neurological deterioration (≥2-point increase in the National Institutes of Health Stroke Scale score) at discharge. Logistic regression analysis was used to evaluate the association between quintile levels of serum HOMA-ß and clinical outcomes. Results: The age- and sex-adjusted odds ratios for poor functional outcome and neurological deterioration increased significantly with decreasing HOMA-ß levels (P for trend, <0.001 and 0.001, respectively). These associations became more prominent after adjustment for HOMA-insulin resistance and were substantially unchanged even after further adjustment for other confounders, namely, body mass index, dyslipidemia, hypertension, estimated glomerular filtration rate, stroke subtype, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy (odds ratio [95% CI] for the first versus fifth quintile of HOMA-ß, 3.30 [2.15­5.08] for poor functional outcome and 10.69 [4.99­22.90] for neurological deterioration). Such associations were not observed for stroke recurrence. In stratified analysis for the combination of HOMA-ß and HOMA-insulin resistance levels, lower HOMA-ß and higher HOMA-insulin resistance levels were independently associated with increased risks of poor functional outcome and neurological deterioration. Conclusions: Our findings suggest that ß-cell dysfunction is significantly associated with poor short-term clinical outcome independently of insulin resistance in nondiabetic patients with acute ischemic stroke.