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.

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.

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).

Cell-Free Synthesis of Plant Receptor Kinases.

The wheat germ cell-free protein synthesis system has been used as a eukaryotic protein production system since it was first reported in 1964. Although initially the productivity of this system was not very high, it has now become one of the most versatile protein production systems, thanks to the enhancements made by several groups. In this chapter, we report a protein production method for plant receptor kinases using the wheat cell-free system. We describe a method for the preparation of a cell-free extract from wheat germ, the split-primer PCR method for preparation of transcription templates, and the bilayer cell-free protein synthesis method.

Autophosphorylation Assays Using Plant Receptor Kinases Synthesized in Cell-Free Systems.

The wheat germ cell-free protein synthesis system has a significant advantage for high-throughput production of eukaryotic multidomain proteins in a folded state. In this chapter, we describe two kinds of methods for performing autophosphorylation assay of plant receptor kinases (PRKs) by using the wheat cell-free system. One is an in vitro kinase assay performed using biotin-streptavidin affinity purification technology, and the other is a luminescence-based high-throughput assay for autophosphorylation analysis. We anticipate that our cell-free-based methods might facilitate the characterization of plant PRKs.

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.

The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts.

OBJECTIVE: Nitric oxide (NO) is known to act as a mediator of tissue injury as well as being a potent endogenous vasodilator. The functional and metabolic effects of NO on ischemia-reperfusion injury are still controversial. The aim of this study was to clarify the relationship between the degree of NO synthase (NOS) inhibition and the effects on ischemia-reperfusion injury. METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. The recovery of left ventricular developed pressure (LVDP), creatine kinase (CK) release, and myocardial high energy phosphates were measured in hearts perfused with or without NOS inhibitors, L-N(G)-monomethyl arginine (L-NMMA) or N(G)nitro-L-arginine methylester (L-NAME). NOS inhibitors exerted different effects on the recovery of LVDP and CK release depending on the concentration. The low dose of L-NMMA improved the recovery of LVDP, decreased the CK release during reperfusion, and preserved the myocardial adenosine triphosphate content after reperfusion. In contrast, the high dose of L-NMMA had adverse effects. L-NMMA reduced NO release in coronary effluent in a dose-dependent fashion. Both effects of L-NMMA were abolished by excessive co-administration of L-arginine and the same doses of D-N(G)-monomethyl arginine (D-NMMA) showed no effect on ischemia-reperfusion injury. Therefore, both effects were due to NOS inhibition. In addition, L-NMMA suppressed the myocardial malondialdehyde accumulation, an indicator of oxidative stress, which might be attributed to the beneficial effects by partial NOS inhibition. On the other hand, the high dose L-NMMA significantly decreased coronary fl ow during aerobic perfusion and reperfusion. Therefore, it is conceivable that the vasoactive NOS inhibition contributes to the harmful effects, which might exceed the beneficial effects due to a decrease in oxidative stress. CONCLUSION: The present results showed that NO inhibitors had dual effects on mechanical function and energy metabolism depending on the concentration. Non-vasoactive inhibition of NOS had beneficial effects due to the suppression of oxidative injury. However, strong vasoactive inhibition of NOS exacerbated the ischemia-reperfusion injury.