Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation.

BACKGROUND: The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated. METHODS: From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months. RESULTS: Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54). CONCLUSIONS: Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

Bridging Therapy With Heparin Before Starting Rivaroxaban in Ischemic Stroke or Transient Ischemic Attack With Non-Valvular Atrial Fibrillation.

BACKGROUND: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01-3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant. CONCLUSIONS: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

Nutritional supplement drink reduces inflammation and postoperative depression in patients after off-pump coronary artery bypass surgery.

BACKGROUND: Coronary artery bypass grafting is a surgical treatment for ischemic heart disease. Although development in surgical technique and improvement of perioperative management reduced the postoperative complications, some patients still delayed in progress of postoperative rehabilitation. In this study, we aimed to investigate the effect of daily intake of an herbal medicine-containing drink for rehabilitation after surgery in patients with ischemic heart disease. AIM: To investigate the effect of taking an herbal medicine-containing, commercially available drink for postoperative rehabilitation in those patients. METHODS: Patients who underwent isolated off-pump coronary artery bypass (OPCAB) surgery were divided into two groups depend on the timing of the admission to the hospital: the Yunker (YKR) group, that consumed one bottle of a caffeine-free nutritional supplement drink on a daily basis and the control group (CTL) that underwent regular rehabilitation. RESULTS: A total of 229 patients (CTL = 130, YKR = 99) were enrolled. No significant differences were observed in the baseline characteristics between the two groups. The YKR group had a significantly increased number of daily steps postoperatively (P < 0.05) and had significantly lower postoperative serum tumor necrosis factor-alpha levels (P < 0.01), while no significant differences were observed in the levels of other inflammatory or stress-related cytokines (interleukin-6, adiponectin, superoxide dismutase, and urine 8-hydroxy-2'-deoxyguanosine) between the two groups. Also, the YKR group showed a significant improvement in the Hospital Anxiety and Depression Score (P < 0.05). Moreover, there were no differences in postoperative complications and the duration of postoperative hospital stay between the two groups. CONCLUSION: Our results demonstrated that the daily intake of an herbal medicine-containing drink after OPCAB surgery may have beneficial effects on cardiac rehabilitation by reducing inflammation markers and depression.

Impact of body mass index on real-world outcomes of rivaroxaban treatment in Japanese patients with non-valvular atrial fibrillation.

This sub-analysis of the XAPASS, a prospective, single-arm, observational study, aimed to evaluate relationships between body mass index (BMI) and safety (major bleeding and all-cause mortality) and effectiveness [stroke/non-central nervous system (non-CNS) systemic embolism (SE)/myocardial infarction (MI)] outcomes in Japanese patients with non-valvular atrial fibrillation (NVAF) receiving rivaroxaban. Patients were categorized according to BMI (kg/m2) as underweight (< 18.5), normal weight (18.5 to < 25), overweight (25 to < 30), or obese (≥ 30). In total, 9578 patients with NVAF completed the 1-year follow-up and were evaluated; of these, 7618 patients had baseline BMI data. Overall, 542 (5.7%), 4410 (46.0%), 2167 (22.6%), and 499 (5.2%) patients were underweight, normal weight, overweight, and obese, respectively. Multivariable Cox regression analysis demonstrated that none of the BMI categories were independent predictors of major bleeding whereas being underweight was independently associated with increased all-cause mortality [hazard ratio (HR) 3.56, 95% confidence interval (CI) 2.40-5.26, p < 0.001]. The incidence of stroke/non-CNS SE/MI was higher in patients who were underweight than in those of normal weight (HR 2.11, 95% CI 1.20-3.70, p = 0.009). However, in multivariable analyses, being underweight was not identified as an independent predictor of stroke/non-CNS SE/MI (HR 1.64, 95% CI 0.90-2.99, p = 0.104). In conclusion, the high incidence of thromboembolic events and all-cause mortality in patients who were underweight highlights that thorough evaluation of disease status and comorbidities may be required in this population.

Real-world outcomes of rivaroxaban treatment in elderly Japanese patients with nonvalvular atrial fibrillation.

Direct oral anticoagulants (DOACs), such as rivaroxaban, reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). However, it is still unclear whether the stroke reduction benefit outweighs the bleeding risk in elderly Japanese patients with NVAF. The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was a real-world, prospective observational, post-marketing surveillance study on the safety and effectiveness of rivaroxaban in Japanese clinical practice. This sub-analysis evaluated the clinical outcomes of elderly patients aged ≥ 75 years. At the 1-year follow-up, there were 4,685 (48.91%) and 4,893 (51.09%) patients aged ≥ 75 and < 75 years, respectively. Safety and effectiveness outcomes were compared between patients aged ≥ 75 years and those aged < 75 years, and among 3 elderly sub-populations (age ranges: 75-79, 80-84, and ≥ 85 years). Patients aged ≥ 75 years had higher rates of major bleeding [2.22 vs. 1.35 events per 100 patient-years, hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.17-2.28] and composite of stroke (ischemic or hemorrhagic)/non-central nervous system (non-CNS) systemic embolism (SE)/myocardial infarction (MI) (2.41 vs. 1.21 events per 100 patient-years, HR 1.97, 95% CI 1.40-2.77) compared to patients aged < 75 years. Intracranial hemorrhage rates were < 1 event per 100 patient-years in both groups (0.85 vs. 0.59 events per 100 patient-years, HR 1.43, 95% CI 0.85-2.40). Kaplan-Meier curves of major bleeding and stroke/non-CNS SE/MI showed that no significant differences of cumulative event rates were identified among the 3 elderly sub-populations. Stepwise Cox regression analyses revealed that creatinine clearance (CrCl) (<50 mL/min), hepatic impairment, and hypertension were specific predictors for major bleeding and no specific predictors were found for stroke/non-CNS SE/MI in patients aged ≥ 75 years. In conclusion, safety and effectiveness event rates were higher in patients aged ≥ 75 years compared with those aged < 75 years, yet, no distinct differences were observed among the 3 elderly sub-populations.

Real-World Outcomes of Rivaroxaban Treatment in Patients with Both Nonvalvular Atrial Fibrillation and a History of Ischemic Stroke/Transient Ischemic Attack.

INTRODUCTION: Prior stroke is a risk factor for stroke and bleeding during anticoagulation in patients with atrial fibrillation (AF). Although rivaroxaban is widely prescribed to reduce their risk of stroke in patients with nonvalvular AF (NVAF), the real-world evidence on rivaroxaban treatment is limited. We aimed to examine the outcomes of rivaroxaban treatment in NVAF patients with prior ischemic stroke/transient ischemic attack (TIA) by using the data of the Xarelto Post-Authorization Safety and Effectiveness Study in Japanese -Patients with AF, a prospective, single-arm, observational study. METHODS: The clinical outcomes of 9,578 patients who completed the 1-year follow-up were evaluated. Safety and effectiveness outcomes were compared between patients with and without prior ischemic stroke/TIA. RESULTS: Among the patients, 2,153 (22.5%) had prior ischemic stroke/TIA. They were significantly older and had lower body weight, lower creatinine clearance, higher CHADS2, CHA2DS2-VASc, and modified HAS-BLED scores as compared to those without prior ischemic stroke/TIA. Any bleeding (9.1 vs. 7.2 events per 100 patient-years), major bleeding (2.3 vs. 1.6 events per 100 patient-years), and stroke/non-central nervous system systemic embolism/myocardial infarction (3.4 vs. 1.3 events per 100 patient-years) were more frequent in patients with prior ischemic stroke/TIA. Stepwise regression analysis suggested that body weight of ≤50 kg and diabetes mellitus were predictive of major bleeding in patients with prior ischemic stroke/TIA. CONCLUSIONS: Safety and effectiveness event rates were higher in patients with prior ischemic stroke/TIA than those without. This might be explained by differences in several risk profiles including age, body weight, renal function, and risk scores such as CHADS2 between the groups. Clinicaltrials.gov: NCT01582737.

Development of Quality Indicators of Stroke Centers and Feasibility of Their Measurement Using a Nationwide Insurance Claims Database in Japan　­ J-ASPECT Study ­

BACKGROUND: We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. METHODS AND RESULTS: We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. CONCLUSIONS: We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Real-world outcomes of rivaroxaban treatment in patients with nonvalvular atrial fibrillation and worsening renal function.

BACKGROUND: Rivaroxaban is a direct oral anticoagulant administered to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was a prospective, observational, post-marketing surveillance study that examined the safety and effectiveness of rivaroxaban in routine clinical practice. This sub-analysis of the XAPASS investigated the outcomes of patients with worsening renal function (WRF). METHODS: The XAPASS included 11,308 patients with NVAF who began treatment with rivaroxaban. Of 9578 patients who completed 1-year follow-up, the 7509 patients, for whom the change in creatinine clearance could be assessed, were included in the present analysis. Patients with WRF were those with a decrease in creatinine clearance of ≥20% from enrollment to any time point; patients with stable renal function (SRF) were those without such a decrease. Outcomes in patients with WRF versus SRF were compared at 1 year. RESULTS: We identified 1229 patients with WRF and 6280 patients with SRF. Patients with WRF were older and had higher mean CHADS2 and modified HAS-BLED scores compared to patients with SRF. The incidence rates of any bleeding (hazard ratio: 1.12; 95% confidence interval: 0.88-1.41), major bleeding (1.20; 0.75-1.90), and the composite endpoint stroke/systemic embolism/myocardial infarction (1.06; 0.65-1.71) were similar between the two groups. CONCLUSIONS: No association between WRF and occurrence of any bleeding, major bleeding, and stroke/systemic embolism/myocardial infarction was observed in patients with AF on rivaroxaban treatment during 1-year follow-up in real-world clinical practice. Clinicaltrials.gov: NCT01582737.

Nationwide Actions Against Heart Failure Pandemic in Japan　- What Should We Do From Academia?

Heart failure pandemic is rapidly approaching in Japan, requiring nationwide actions. In particular, the Japanese Circulation Society and related societies launched the Stroke and Cardiovascular Disease Control Act, which was passed by the National Diet, as the first ever legislative policy measure against stroke and cardiovascular disease. In association with this, actions against heart failure pandemic from the scientific field are also important. Because heart failure pandemic is a critical problem not only in Japan but also in many developed countries, we believe the nationwide approach, as summarized here, will greatly contribute to the development of cardiovascular medicine, particularly the management and treatment of heart failure worldwide.

Design and baseline characteristics of the Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS).

Background: The phase III Japanese Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) showed that the rivaroxaban group had a lower event rate of intracranial bleeding than the warfarin group and that rivaroxaban was noninferior to warfarin for the principal safety outcome. However, safety and effectiveness data from unselected patients with AF in everyday clinical practice in Japan are lacking. Methods: The Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) is a real-world, prospective, single-arm, observational study mandated by the Japanese authority as postmarketing surveillance. XAPASS involves patients with nonvalvular AF prescribed rivaroxaban. The principal safety outcome is a composite of major and nonmajor bleeding events, and the primary effectiveness outcome is the incidence of ischemic stroke, hemorrhagic stroke, noncentral nervous system systemic embolism, and myocardial infarction. Results: In total, 11 308 patients were enrolled from April 2012 to June 2014. Their age was 73.1 ± 9.9 years, and their CHADS 2 score was 2.2 ± 1.3. Female patients, patients aged ≥75 years, patients with a body weight of ≤50 kg, and patients with a creatinine clearance of <50 mL/min constituted 38.1%, 48.7%, 19.5%, and 23.9% of all patients, respectively. Almost half (53.2%) of patients were prescribed other anticoagulants before starting rivaroxaban. Conclusions: Data from this study will supplement those from the J-ROCKET AF and provide practical information for the optimal use of rivaroxaban for stroke prevention in Japanese patients with AF (Clinicaltrials.gov: NCT01582737).

Anticoagulation intensity of rivaroxaban for stroke patients at a special low dosage in Japan.

OBJECTIVES: In Japan, low-dose rivaroxaban [15 mg QD/10 mg QD for creatinine clearance of 30-49 mL/min] was approved for clinical use in NVAF patients partly because of its unique pharmacokinetics in Japanese subjects. The aim of the study was to determine the anticoagulation intensity of rivaroxaban and its determinant factors in Japanese stroke patients. METHODS: Consecutive stroke patients with NVAF admitted between July 2012 and December 2013 were studied. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and estimated plasma concentration of rivaroxaban (Criv) based on an anti-factor Xa chromogenic assay were measured just before and 4 and 9 h after administration at the steady state level of rivaroxaban. Determinant factors for Criv were explored using a linear mixed-model approach. RESULTS: Of 110 patients (37 women, 75±9 years old), 59 took 15 mg QD of rivaroxaban and 51 took 10 mg QD. Criv at 4 h was 186 ng/mL for patients taking 15 mg QD and 147 ng/mL for those taking 10 mg QD. Both PT and aPTT were positively correlated with Criv. Criv was 72% lower at 4 h in 15 patients receiving crushed tablets than in the other patients, and tablet crushing was significantly associated with lower Criv (adjusted estimate -0.43, 95% CI -0.60 to -0.26) after multivariate-adjustment. CONCLUSION: The anticoagulation effects of rivaroxaban in the acute stroke setting for Japanese NVAF patients were relatively low as compared with those in the ROCKET-AF and J-ROCKET AF trials. Tablet crushing, common in dysphagic patients, decreased Criv.

Factors influencing cooperation among healthcare providers in a community-based stroke care system in Japan.

Community-based stroke care in Japan is currently provided in acute hospitals, convalescent rehabilitation units, general practices, sanatorium-type wards, nursing care facilities, and in-home/commuting care services. We conducted a nationwide survey to identify factors influencing cooperation among the various providers of community-based stroke care. We sent questionnaires to 11,178 facilities and assessed the independent variables of excellent and fair cooperation among the care providers. Of the providers that responded, 66% were engaged in medical practice or long-term care for stroke patients. The following independent variables were inversely associated with excellent or fair cooperation in the community: area with the higher population density among 3 groups divided by tertile threshold (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.41-0.69), facilities covered by long-term care insurance (OR, 0.27; 95% CI, 0.22-0.34), and insufficient communication with local government (OR, 0.19; 95% CI, 0.14-0.24). Positive independent variables of excellent or fair cooperation were the sharing of patient information in the community (OR, 2.53; 95% CI, 1.78-3.66), use of a scale for assessing activities of daily living (OR, 1.93; 95% CI, 1.42-2.63), appropriate utilization of care support managers (OR, 1.91; 95% CI, 1.43-2.55), and adequate comprehension of the long-term care insurance system (OR, 1.54; 95% CI, 1.24-1.92). Our findings suggest that improved communication between healthcare providers and local government, along with appropriate attention to the problems facing providers covered by long-term care insurance, may improve community-based stroke care in Japan.