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.

Initial responsiveness to darbepoetin alfa and its contributing factors in non-dialysis chronic kidney disease patients in Japan.

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN. METHODS: Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed. RESULTS: The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15-900 µg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein-creatinine ratio were independently associated with better initial response to DA (P = < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively). CONCLUSIONS: Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.

Clinical risk factors of stroke and major bleeding in patients with non-valvular atrial fibrillation under rivaroxaban: the EXPAND Study sub-analysis.

For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The risk factors for embolism and major bleeding under DOAC may be different from current reports. We analyzed the data set of the EXPAND Study to determine the risk factors for events among Japanese NVAF patients in the era of direct oral anticoagulant. Using the data of EXPAND Study, the validity for predictability of the CHADS2, CHA2DS2-VASc, and HAS-BLED scores was identified using the receiver operating characteristic curve analysis. Multivariate analysis was performed with the Cox proportional hazard model to determine the independent risk factors for stroke/systemic embolism and major bleeding among NVAF patients receiving rivaroxaban. Explanatory variables were selected based on the univariate analysis. A total of 7141 patients (mean age 71.6 ± 9.4 years, women 32.3%, and rivaroxaban 15 mg per day 56.5%) were included. Incidence rates of stroke/systemic embolism and major bleeding were 1.0%/year and 1.2%/year, respectively. The multivariate analysis revealed that only history of stroke was associated with stroke/systemic embolism (hazard ratio 3.4, 95% confidence interval 2.5-4.7, p < 0.0001). By contrast, age (1.7, 1.1-2.6, p = 0.0263), creatinine clearance (CrCl) 30-49 mL/min (1.6, 1.2-2.2, p = 0.0011), liver dysfunction (1.7, 1.1-2.8, p = 0.0320), history/disposition of bleeding (1.8, 1.0-3.0, p = 0.0348), and concomitant use of antiplatelet agents (1.6, 1.2-2.3, p = 0.0030) were associated with major bleeding. This sub-analysis showed that some components of the HAS-BLED score were independently associated with major bleeding in Japanese NVAF patients receiving anticoagulation therapy by rivaroxaban. Additionally, CrCl value of 30-49 mL/min was an independent predictor of major bleeding in patients receiving rivaroxaban.

The EXPAND study: Efficacy and safety of rivaroxaban in Japanese patients with non-valvular atrial fibrillation.

AIMS: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ±â€¯9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS2), as shown for warfarin in the XANTUS international prospective post-marketing study. CONCLUSIONS: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding.

Study Design and Baseline Characteristics of the EXPAND Study: Evaluation of Effectiveness and Safety of Xa Inhibitor, Rivaroxaban for the Prevention of Stroke and Systemic Embolism in a Nationwide Cohort of Japanese Patients Diagnosed as Non-Valvular Atrial Fibrillation.

The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective, non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%, and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent) AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension, congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and 20.2%, respectively. The proportions of patients with a CHADS2 score ≤ 1 and a CHA2DS2-VASc score ≤ 1 were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with non-valvular AF.

[Neurological decompression illness in a Japanese breath-held diver: a case report].

We report a Japanese breath-hold diver (Ama) who presented neurological disorders after diving. He repeated diving into 25-30 meters depth in the sea for 6 hours. After diving, he felt dizziness and unsteady gait. Neurological examination showed left quadrant hemianopia, bilateral limb ataxia and ataxic gait. Head CT revealed gas bubbles in the left parietal lobe. In CT scan on 3 days after onset, gas bubbles disappeared and low density areas were observed in the bilateral parietal lobes. Brain imaging (DWI, T(2)WI and FLAIR) demonstrated high intensity in the parieto-occipital lobes. Neither pulmonary barotrauma nor intracardiac shunt was detected. He was diagnosed as having neurological decompression illness and therefore underwent hyperbaric oxygen therapy. The pathogenesis of this case was considered to be microbubbles induced by decompression. The present case suggests that repetitive rapid surfacing from the deep sea causes neurological decompression illness even in the breath-hold diver.

Cerebral venous thrombosis associated with iron deficiency anemia.

A 55-year-old man presented with generalized seizures and postictal left hemiparesis. Computed tomography scanning of his head showed a low density area in the right frontal lobe. Cerebral angiography demonstrated a partial defect in the superior sagittal sinus and cortical veins, indicating the presence of cerebral venous thrombosis. He had bleeding from a peptic ulcer and the laboratory data revealed iron deficiency anemia concomitant with an elevation of D-dimer and thrombin-antithrombin III complex (TAT). After the anemia resolved with the treatment of the peptic ulcer and iron supplementation, the TAT and D-dimer levels were normalized, and the occluded veins were recanalized. In a cerebral venous thrombosis associated with iron deficiency anemia, treatment for the anemia may improve hypercoagulable state without antithrombotic therapy, although the long-term monitoring of TAT and D-dimer levels is required.