Intake of Docosahexaenoic Acid-Enriched Milk Beverage Prevents Age-Related Cognitive Decline and Decreases Serum Bone Resorption Marker Levels.

The pathogenic mechanism of dementia is still unknown, and the fundamental treatment remains to be established. Thus, there is growing interest in preventing dementia through diet. One of the functional ingredients attracting attention is docosahexaenoic acid. We conducted a 12-month, randomized, double-blind, placebo-controlled clinical trial in healthy elderly Japanese individuals with a Mini-Mental State Examination score of 28 or higher at baseline using a docosahexaenoic acid-enriched milk beverage containing 297 mg docosahexaenoic acid and 137 mg eicosapentaenoic acid. Consumption of a docosahexaenoic acid-enriched milk beverage increased the fatty acid levels of docosahexaenoic acid and eicosapentaenoic acid in erythrocyte membranes, which was the primary outcome of this study. Moreover, intake of this beverage prevented age-related cognitive decline and decreased serum bone resorption marker levels. Our data demonstrate that, even at a low dose, long-term daily intake of docosahexaenoic acid prevents dementia and may show beneficial effect on bone health.

Comparison of hospital length of stay of acute ischemic stroke patients with non-valvular atrial fibrillation started on rivaroxaban or warfarin treatment during hospitalization.

OBJECTIVE: To compare the hospital length of stay (LOS) between rivaroxaban and warfarin in hospitalized acute stroke patients with non-valvular atrial fibrillation (NVAF) in Japan. METHODS: This was a retrospective, observational study using a Japanese hospital claims database. Data of NVAF patients who were started on oral anticoagulant (OAC) treatment during hospitalization were extracted and LOS-OAC (period from the initiation of index OAC therapy to the end of hospitalization or censoring date) and medical costs were compared between rivaroxaban and warfarin treatments. To compare LOS-OAC, a time-to-event analysis was performed using the Kaplan-Meier method. The analysis period was from April 2012 to December 2015. RESULTS: This study included 773 rivaroxaban users and 1077 warfarin users. After the propensity score matching, 546 patients for each treatment constituted the matched cohorts. Although the rivaroxaban users had a similar LOS-OAC to warfarin users (median, 18 vs. 19 days, p = .657) in the matched cohorts, 3 days shorter LOS-OAC was observed in the rivaroxaban users (median, 17 vs. 20 days, p = .043) after IPTW adjustment. Subgroup analysis by the severity of stroke after IPTW adjustment demonstrated that rivaroxaban users had a shorter LOS-OAC than warfarin users among patients with mild (median, 10 vs. 14 days) and moderate stroke severity (22 vs. 27 days), but not among those with severe stroke severity (26 vs. 25 days). LIMITATIONS: It is not possible to say that the only confounder was stroke severity and therefore other possible known and unknown confounders could not be ruled out. CONCLUSIONS: The rivaroxaban users had a 3-day shorter LOS-OAC after IPTW-adjustment. Using rivaroxaban was associated with 4-5 days shorter LOS-OAC than using warfarin in patients with mild or moderate stroke, though treatment selection did not have a large impact in patients with severe stroke.

A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.

AIMS: Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. METHODS: ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. RESULTS: Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/L); no patients developed hyperkalemia. CONCLUSION: When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

Predictive factors for bleeding during treatment with rivaroxaban and warfarin in Japanese patients with atrial fibrillation - Subgroup analysis of J-ROCKET AF.

BACKGROUND: Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. METHODS: The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. RESULTS: The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. CONCLUSIONS: Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively.

Rivaroxaban versus warfarin in Japanese patients with non-valvular atrial fibrillation in relation to hypertension: a subgroup analysis of the J-ROCKET AF trial.

The majority of the patients enrolled in the rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial had hypertension. In this subgroup analysis, we investigated differences in the safety and efficacy of rivaroxaban and warfarin in subjects with and without hypertension. The baseline blood pressure (BP) measurements of patients with hypertension in the rivaroxaban and warfarin groups were 130/77 mm Hg and 131/77 mm Hg, respectively, whereas those of patients without hypertension were 123/74 mm Hg and 124/73 mm Hg, respectively. The incidence rates of the principal safety outcomes in the rivaroxaban and warfarin groups were 18.39% per year and 16.81% per year, respectively, among patients with baseline hypertension (hazard ratio (HR): 1.10; 95% confidence interval (CI): 0.84-1.45) and 16.71% per year and 15.00% per year, respectively, among patients without hypertension at baseline (HR: 1.14; 95% CI: 0.66-1.97), indicating no significant interaction (P=0.933). The incidence rates of the primary efficacy endpoints in the rivaroxaban group and the warfarin group were 0.54% per year and 2.24% per year, respectively, in patients without baseline hypertension (HR: 0.25; 95% CI: 0.03-2.25), and 1.45% per year and 2.71% per year, respectively, in patients with baseline hypertension (HR: 0.54; 95% CI: 0.25-1.16), indicating no significant interaction (P=0.509). In conclusion, the safety and efficacy profile of rivaroxaban was similar to that of warfarin, independent of baseline hypertensive status.

Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation in relation to the CHADS2 score: a subgroup analysis of the J-ROCKET AF trial.

BACKGROUND: Results from a trial of rivaroxaban versus warfarin in 1280 Japanese patients with atrial fibrillation (J-ROCKET AF) revealed that rivaroxaban was noninferior to warfarin with respect to the principal safety outcome. In this subanalysis, we investigated the safety and efficacy of rivaroxaban and warfarin in relation to patients' CHADS2 scores. RESULTS: The mean CHADS2 score was 3.25, and the most frequent scores were 3 and 4. No statistically significant interactions were observed between principal safety outcome event rates and CHADS2 scores with respect to treatment groups (P value for interaction = .700). Irrespective of stratification into moderate- and high-risk groups based on CHADS2 scores of 2 and 3 or more, respectively, no differences in principal safety outcome event rates were observed between rivaroxaban- and warfarin-treated patients (moderate-risk group: hazard ratio [HR], 1.06; 95% confidence interval [CI], .58-1.95; high-risk group: HR, 1.11; 95% CI, .86-1.45; P value for interaction = .488). The primary efficacy end point rate in the rivaroxaban-treated group was numerically lower than in the warfarin-treated group, regardless of risk group stratification (moderate-risk group: HR, .46; 95% CI, .09-2.37; high-risk group: HR, .49; 95% CI, .22-1.11; P value for interaction = .935). CONCLUSION: This subanalysis indicated that the safety and efficacy of rivaroxaban compared with warfarin were similar, regardless of CHADS2 score.

Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF.

BACKGROUND: The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in patients with atrial fibrillation (AF). Our aim was to determine the net clinical benefit (NCB) from the results of the J-ROCKET AF trial, in which rivaroxaban was compared with warfarin in Japanese patients with AF. METHODS: Two strategies were adopted to quantify the NCB. First, the NCB was calculated as the number of ischemic strokes avoided with anticoagulation minus the number of excess intracranial hemorrhage (ICH) with a weight of 1.5. Second, the composite end point of major bleeding events and secondary efficacy end points (stroke, noncentral nervous system systemic embolism, myocardial infarction and death) to ascertain the NCB were established. Subgroup analysis by CHADS2 score or creatinine clearance was also performed. RESULTS: The adjusted NCB, which was given a weight of 1.5 for ICH, was nominally significant in favor of rivaroxaban therapy (difference in incidence rate -2.13; 95% confidence interval [CI]: -.26 to -3.99). Furthermore, the event rate of the composite end point tended to be lower in patients treated with rivaroxaban than in those treated with warfarin (rivaroxaban: 4.97% per year, warfarin: 6.11% per year; difference in incidence rate: -1.14; 95% CI: -3.40 to 1.12). The event rate of the composite end point tended to be consistently low in patients treated with rivaroxaban in the subanalysis by CHADS2 score and renal function. CONCLUSION: Analysis of the NCB supports that rivaroxaban therapy provides clinical benefit for Japanese patients with AF.

Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation for the secondary prevention of stroke: a subgroup analysis of J-ROCKET AF.

BACKGROUND: The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin. METHODS: In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group). RESULTS: Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively). CONCLUSIONS: The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group.

Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation: subanalysis of J-ROCKET AF for patients with moderate renal impairment.

BACKGROUND: In the 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) study, rivaroxaban 15 mg once daily was given to patients with creatinine clearance (CrCl) ≥ 50 ml/min (preserved renal function), and was reduced to 10mg once daily in patients with CrCl 30-49 ml/min (moderate renal impairment). The aim of this subanalysis was to assess the safety and efficacy of the adjusted dose of rivaroxaban compared with warfarin in a cohort with moderate renal impairment. METHODS AND RESULTS: Compared with patients with preserved renal function, those with moderate renal impairment (22.2% of all randomized patients) had higher rates of bleeding and stroke events irrespective of study treatment. Among those with moderate renal impairment, the principal safety endpoint occurred at 27.76%/year with rivaroxaban vs. 22.85%/year with warfarin (hazard ratio [HR], 1.22; 95% confidence interval [CI]: 0.78-1.91) and the rate of the primary efficacy endpoint was 2.77%/year vs. 3.34%/year (HR, 0.82; 95% CI: 0.25-2.69), respectively. There were no significant interactions between renal function and study treatment in the principal safety and the primary efficacy endpoints (P=0.628, 0.279 for both interactions, respectively). CONCLUSIONS: The safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and preserved renal function.

[Development of auditory-visual spatial integration using saccadic response time as the index].

We measured saccadic response time (SRT) to investigate developmental changes related to spatially aligned or misaligned auditory and visual stimuli responses. We exposed 4-, 5-, and 11-month-old infants to ipsilateral or contralateral auditory-visual stimuli and monitored their eye movements using an electro-oculographic (EOG) system. The SRT analyses revealed four main results. First, saccades were triggered by visual stimuli but not always triggered by auditory stimuli. Second, SRTs became shorter as the children grew older. Third, SRTs for the ipsilateral and visual-only conditions were the same in all infants. Fourth, SRTs for the contralateral condition were longer than for the ipsilateral and visual-only conditions in 11-month-old infants but were the same for all three conditions in 4- and 5-month-old infants. These findings suggest that infants acquire the function of auditory-visual spatial integration underlying saccadic eye movement between the ages of 5 and 11 months. The dependency of SRTs on the spatial configuration of auditory and visual stimuli can be explained by cortical control of the superior colliculus. Our finding of no differences in SRTs between the ipsilateral and visual-only conditions suggests that there are multiple pathways for controlling the superior colliculus and that these pathways have different developmental time courses.