Safety Profile and Effectiveness of Rivaroxaban for Patients With Venous Thromboembolism in Japan　- Results From Post-Marketing Surveillance (XASSENT).

BACKGROUND: The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period. CONCLUSIONS: XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

Outcomes of sorafenib treatment of advanced renal cell carcinoma according to IMDC risk criteria: analysis of Japanese real-world data from postmarketing all-patient surveillance of sorafenib.

Aim: To assess sorafenib survival outcomes in renal cell carcinoma patients using standard International Metastatic Renal Cell Carcinoma Data Consortium (IMDC) risk criteria. Patients & methods: The authors restratified a real-world cohort of 3255 advanced renal cell carcinoma patients, obtained from Japanese sorafenib postmarketing surveillance, to assess survival outcomes using IMDC criteria; intermediate risk was subdivided into intermediate 1 (Int-1) and imterdemiate 2 (Int-2; one and two risk factors, respectively). Results: Overall, 2225 (68%) IMDC-evaluable patients were reclassified as favorable (17%), intermediate (62%) and poor (21%) risk, with median progression-free survival of 10.4, 8.1 and 3.4 months, respectively. Int-1 (36%) and Int-2 (26%) subgroups had median progression-free survival of 10.1 and 6.0 months, respectively. Sorafenib had acceptable safety/tolerability. Conclusion: Sorafenib effectiveness was promising for IMDC intermediate risk, particularly Int-1, warranting further investigation.

Intravitreal aflibercept for diabetic macular edema in real-world clinical practice in Japan: 24-month outcomes.

PURPOSE: To report the safety and effectiveness of intravitreal aflibercept (IVT-AFL) for diabetic macular edema (DME) in the real-world clinical practice setting in Japan. METHODS: In this prospective, multicenter, observational, post-marketing surveillance, patients with DME newly receiving IVT-AFL were enrolled. During a 24-month follow-up, the primary outcome was the occurrence of safety events. Other pre-specified endpoints were effectiveness indicators, such as best-corrected visual acuity (BCVA), central retinal thickness, and injection frequency. RESULTS: In total, 646 patients administered at least one IVT-AFL injection were included in the safety analysis. During the follow-up period, adverse events occurred in 42 patients (6.50%), whereas adverse drug reactions occurred in 12 (1.86%). In the 12 patients who had adverse drug reactions, seven events occurred in seven patients within the first month of the most recent injection. In addition, 622 patients were included in the effectiveness analysis set. The number of injections over 24 months was 3.6 ± 3.0 (mean ± standard deviation [SD]). BCVA (logarithm of the minimum angle of resolution) was 0.437 ± 0.362 (mean ± SD) (n = 622) at baseline and 0.321 ± 0.348 (n = 177) after 24 months of treatment with IVT-AFL. Central retinal thickness was 440.8 ± 134.2 µm (mean ± SD) (n = 444) at baseline and 355.5 ± 126.4 µm (n = 140) at 24 months. CONCLUSION: Routine administration of IVT-AFL for DME was not associated with new safety concerns, and BCVA outcomes were maintained over 24 months in the real-world setting. Nonetheless, patients in this real-world setting received fewer injections than those in clinical trials, suggesting that a margin for improvement exists in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02425501.

Bleeding patterns of women with heavy menstrual bleeding or dysmenorrhoea using the levonorgestrel-releasing intrauterine system: results from a real-world observational study in Japan (J-MIRAI).

PURPOSE: To collect real-world safety and clinical outcome data on the levonorgestrel-releasing intrauterine system (LNG-IUS) for functional/organic heavy menstrual bleeding (HMB) and dysmenorrhoea in Japanese women (J-MIRAI). MATERIALS AND METHODS: In this prospective, multicentre, single-cohort, open-label, post-authorisation study, we assessed menstrual blood loss after LNG-IUS insertion by changes from baseline in pictorial blood loss assessment chart (PBAC) scores. Scores for the menorrhagia multi-attribute scale (MMAS) were collected for 12 months to assess quality of life. RESULTS: We included 47 patients with complete PBAC score and patient diary data. The median PBAC score before LNG-IUS insertion was 159.0, which decreased significantly to 6.0 at 12 months post-insertion; for patients with adenomyosis (n = 20), PBAC score decreased from 174.5 pre-insertion to 19.5 at 12 months. The number of patient-reported bleeding days was correlated with PBAC score ≥5. The proportion of women with prolonged bleeding decreased from 85.7% to 34.6% by the study's end. Some women reported no bleeding after the first 90-day reference period. The mean MMAS overall score significantly increased from 50.50 before insertion to 88.67 at 12 months. CONCLUSIONS: Japanese women with functional/organic HMB experienced substantial reductions in bleeding symptoms and improvements in quality of life after 12-month use of the LNG-IUS.

Real-world safety and effectiveness of radium-223 in Japanese patients with castration-resistant prostate cancer (CRPC) and bone metastasis: exploratory analysis, based on the results of post-marketing surveillance, according to prior chemotherapy status and in patients without concomitant use of second-generation androgen-receptor axis-targeted agents.

BACKGROUND: Based on results from Japanese post-marketing surveillance, exploratory analyses were performed to investigate real-world outcomes of radium-223 for metastatic CRPC (mCRPC) according to patient characteristics. METHODS: This non-interventional, prospective study enrolled mCRPC patients selected for radium-223 treatment in clinical practice. Six-month safety and effectiveness were evaluated in subgroups who had/had not received prior chemotherapy (prior-chemo/no prior-chemo groups), and a subgroup who had not received concomitant androgen-receptor axis-targeted agents (ARATs). RESULTS: In the overall population (n = 296), the prior-chemo group (n = 126) tended to have more bone metastases, more analgesic use, and higher prostate-specific antigen values than the no prior-chemo group (n = 170). Incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and ≥ grade 3 drug-related hematological TEAEs were 47% vs. 53%, 25% vs. 29%, and 4% vs. 7% in the no prior-chemo and prior-chemo groups, respectively. Incidences of TEAEs (61%), drug-related TEAEs (36%), and ≥ grade 3 drug-related hematological events (12%) were numerically higher in 33 patients who had received two lines of prior chemotherapy. Multivariate analysis showed that two lines of prior chemotherapy, and hemoglobin, platelet, and lactate dehydrogenase values were baseline factors significantly related to ≥ grade 2 platelet count decreased. Safety and effectiveness in patients without concomitant ARATs (n = 201) were similar to those in the overall population. CONCLUSION: In a real-life setting, radium-223 was well tolerated irrespective of prior chemotherapy, but relatively higher incidences of TEAEs and hematotoxicities were suggested in patients with two lines of prior chemotherapy, possibly reflecting more advanced disease. Radium-223 safety and effectiveness in patients without concomitant ARATs were favorable.

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.

Clinical Risk Factors of Thromboembolic and Major Bleeding Events for Patients with Atrial Fibrillation Treated with Rivaroxaban in Japan.

BACKGROUND: It is important to understand the risk of thromboembolism and bleeding in patients with nonvalvular atrial fibrillation (NVAF) receiving direct oral anticoagulants; however, data on risk factors in Japanese patients are limited. METHODS: XAPASS (Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation) is a prospective observational study examining the safety and effectiveness of rivaroxaban in Japanese real-world clinical practice. We investigated risk factors for stroke/noncentral nervous system systemic embolism (non-CNS SE)/myocardial infarction (MI) and major bleeding using 1-year follow-up data. Associations between baseline characteristics and outcomes were examined by Cox regression analysis. RESULTS: During April 2012-June 2014, 11,308 patients newly started with rivaroxaban treatment were enrolled. Of 9578 patients with 1-year data fixed as of September 2017, 6220 patients who received appropriate dosages of rivaroxaban for their creatinine clearance were included in the present safety outcomes subanalysis, and 6198 were included in the effectiveness outcomes analysis. Stroke/non-CNS SE/MI was observed in 97 of 6198 patients (1.6%, 1.8 events/100 patient-years), and major bleeding occurred in 102 of 6220 patients (1.6%, 1.9 events/100 patient-years). Age greater than or equal to 75 years (hazard ratio [HR]: 2.27; [95% confidence interval (CI): 1.49, 3.47]), prior ischemic stroke/transient ischemic attack (2.08; [1.38, 3.13]), and antiplatelet use (3.23; [1.83, 5.70]) were associated with stroke/non-CNS SE/MI. Creatinine clearance less than 50 mL/min (HR: 1.86; [95% CI: 1.26, 2.75]), diabetes (1.55; [1.02, 2.35]), and antiplatelet use (3.04; [1.70, 5.45]) were associated with major bleeding. CONCLUSIONS: These results would help physicians to assess risks in Japanese patients with NVAF receiving rivaroxaban.

Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting.

BACKGROUND: Regorafenib improved the overall survival (OS) of patients with metastatic colorectal cancer (mCRC) who progress after standard therapies in two phase III trials. The present large-scale prospective observational study evaluated the safety and effectiveness of regorafenib administered to Japanese patients with mCRC in real-life setting. MATERIALS AND METHODS: Patients with mCRC were prospectively registered and initially received ≤160 mg oral regorafenib daily, at the investigator's discretion, for weeks 1-3 of each 4-week cycle. The study's primary aim was to assess safety, particularly unexpected clinically significant adverse drug reactions (ADRs). A Cox's proportional hazards model was used to evaluate the association between OS, hand-foot skin reaction (HFSR), and baseline characteristics. RESULTS: We evaluated 1,227 of 1,301 patients (enrolled from March 2013 to May 2015). ADRs occurred in 89.3% of patients (mostly within the first 4 weeks) and were a major reason for discontinuing treatment. The most frequent ADRs were HFSR, liver injury, and hypertension. The cumulative incidence of HFSR and liver injury was higher in patients who initially received 160 mg than in those who received ≤120 mg. The incidence of hypertension and fatigue was similar between groups. Median OS was 6.9 months (95% confidential interval, 6.4-7.4). OS was associated with early onset of HFSR and good performance status (PS) but not with the initial dose. CONCLUSION: The outcomes of this study were consistent with those of clinical trials. There were no new safety concerns. Regorafenib treatment would not be recommended for patients with higher PS. IMPLICATIONS FOR PRACTICE: Previous clinical trials demonstrated regorafenib improved overall survival in patients with metastatic colorectal cancer who progress after standard chemotherapies. Because the eligibility criteria of the trials were restricted compared with a real-world setting, the data from the trials may not fully represent the profiles of regorafenib in clinical practice. This large-scale observational study showed that the safety and effectiveness of regorafenib in clinical practice were generally consistent with previous trials. The majority of patients reported adverse drug reactions within the first 4 weeks, most commonly hand-foot skin reaction. Regorafenib treatment would not be recommended for patients with higher performance status.

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.

Outcomes associated with under-dosing of rivaroxaban for management of non-valvular atrial fibrillation in real-world Japanese clinical settings.

The approved dose of oral anticoagulant rivaroxaban for patients with non-valvular atrial fibrillation (NVAF) in Japan is 15 mg once daily (od) in patients whose creatinine clearance is ≥ 50 mL/min, but recent real-world studies have demonstrated that these patients often received less than the recommended dose due to bleeding concerns. The effect of under-dosing on safety and effectiveness outcomes remains unclear. We used 1-year follow-up data from the XAPASS, a real-world Japanese prospective, single-arm, observational study. Of the 11,308 patients, 6521 patients who completed a 1-year follow-up and had a creatinine clearance ≥ 50 mL/min were included in this sub-analysis. Primary endpoints were any bleeding and a composite of stroke/non-central nervous system systemic embolism (non-CNS SE)/myocardial infarction (MI). Among the 6521 patients, 4185 (64.2%; mean CHADS2 score: 1.8) received the 15 mg od (recommended dose), whereas 2336 (35.8%; mean CHADS2 score: 2.3) received 10 mg od (under-dose). After adjusting for patient characteristics by propensity scoring and inverse probability of treatment weighting, incidence rates of major bleeding were comparable between under-dosed patients and patients who received the recommended dose (1.34 vs. 1.63 events/100 patient-years, p = 0.197), although the incidence rates of stroke/non-CNS SE/MI were higher in under-dosed patients than in those who received the recommended dose (2.15 vs. 1.48 events/100 patient-years, p = 0.009). In Japanese clinical practice, some NVAF patients receive rivaroxaban doses inconsistent with the recommendation. Considering the total clinical benefit, the recommended dose may be preferable in terms of balance of safety and effectiveness.Clinicaltrials.gov NCT01582737.

A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance.

OBJECTIVE: Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance. METHODS: All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians. RESULTS: Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand-foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7-8.1), and the overall survival rate at 1 year was 75.4% (73.5-77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis. CONCLUSIONS: Sorafenib for the treatment of advanced renal cell carcinoma under the labeled dose was feasible in daily medical practice, for its acceptable toxicity profile and favorable clinical benefit that were consistent with those in clinical trials.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting.

Background: Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Methods: Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Results: Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. Conclusion: The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. Clinical trial registration: https://clinicaltrials.gov, identifier NCT01933958.

Long-term surveillance provides real-world evidences of safety and effectiveness in intravitreal aflibercept treatment for age-related macular degeneration.

This prospective, multicentre, postmarketing surveillance were conducted to report on the long-term safety and effectiveness of intravitreal aflibercept (IVT-AFL) treatment in clinical practice of Japanese patients with neovascular age-related macular degeneration (nAMD) who newly initiated IVT-AFL treatment. The primary outcomes were the incidence of adverse events (AEs) and of adverse drug reactions (ADRs) over 36 months. Number of injections, timing of ADR occurrence, and some effectiveness index were also summarised. A total of 3,872 patients received 7.2 ± 5.8 (mean ± standard deviation) injections, and AEs occurred in 5.73% of patients. ADRs were reported in 2.76% of patients, with ocular and nonocular ADRs in 2.07% and 0.72% of patients, respectively. Most vitreo-retinal events developed within 6 months of initial IVT-AFL treatment, and most instances of increased intraocular pressure and cerebral infarction developed after 6 months of follow-up. Mean best-corrected visual acuity and central retinal thickness were numerically better throughout the follow-up period compared with baseline. These results indicated acceptable tolerability and effectiveness of IVT-AFL treatment in patients with nAMD in clinical practice in Japan. Information regarding the risk and the timing of ADRs is valuable for safe and effective long-term treatment of patients with nAMD.Trial registration number: NCT01756248.

Real-World Data on Intravitreal Aflibercept for Macular Edema Secondary to Central Retinal Vein Occlusion: 24-Month Outcomes.

Purpose: To report on the safety and effectiveness of intravitreal aflibercept (IVT-AFL) for macular edema secondary to central retinal vein occlusion (CRVO) in clinical practice in Japan. Patients and Methods: This prospective, noninterventional, multicenter post-authorization safety study enrolled patients who were treated with IVT-AFL for macular edema secondary to CRVO and followed up for 24 months. The primary outcome was the occurrence of safety events. Other pre-specified outcomes were indicators of effectiveness, including best corrected visual acuity (BCVA), central retinal thickness (CRT), and frequency of injections. Results: The safety analysis included 377 patients who received at least one IVT-AFL. Adverse events (AEs) occurred in 22 patients (5.84%) and adverse drug reactions occurred in 5 (1.33%) over 24 months. Of the 22 patients with AEs, 72.7% experienced their first AEs by the third injection. The effectiveness analysis set comprised 360 patients for whom data on each outcome could be collected. The number of injections over 24 months was 3.4 ± 2.4 (mean ± standard deviation [SD]). BCVA (logarithm of the minimum angle of resolution) was 0.709 ± 0.535 (mean ± SD) (n = 357) at baseline and 0.543 ± 0.559 (n = 97) after 24 months of treatment with IVT-AFL. CRT was 552.6 ± 211.3 µm (mean ± SD) (n = 214) at baseline and 331.5 ± 144.0 µm (n = 54) at 24 months. Conclusion: There were no new safety issues concerning routine administration of IVT-AFL for macular edema secondary to CRVO. BCVA recovered during 24 months of IVT-AFL treatment in the real-world setting. However, there was a trend toward less improvement compared with the results of randomized controlled trials, likely due in part to undertreatment.

Effectiveness and safety of sorafenib for renal cell, hepatocellular and thyroid carcinoma: pooled analysis in patients with renal impairment.

PURPOSE: Sorafenib is an oral multikinase inhibitor with regulatory approval in advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and refractory differentiated thyroid carcinoma (DTC). Vascular endothelial growth factor receptor (VEGFR) inhibitors like sorafenib may cause proteinuria. This study aimed to analyze the effectiveness and safety of sorafenib in RCC, HCC and DTC patients with chronic kidney disease (CKD). METHODS: This retrospective study analyzed integrated data from prospective post-marketing surveillance studies for advanced RCC, HCC and DTC. Background factors considered to affect patients' prognosis were balanced by propensity score matching using eGFR cut-off values of 60 mL/min/1.73 m2. RESULTS: In the combined matched population (N = 2430), sorafenib was equally effective in patients with lower and higher eGFR values. Sorafenib had an overall response rate (ORR: complete + partial responses) of 18.9% and a disease control rate (DCR: complete + partial responses + stable disease) of 67.0%. There were no significant differences between lower and higher eGFR groups for response rates. Renal function was maintained throughout the 12-month study period in the combined population and in each indication. Adverse events (AEs) and serious AEs were reported in 91.6% and 58.2% of propensity score-matched patients, and with no significant differences between lower and higher eGFR groups. CONCLUSION: The effectiveness and safety of sorafenib were similar in patients with eGFR < 60 and ≥ 60 mL/min/1.73 m2 during the 12-month observation period, and without impairing renal function.

Real-world outcomes of the levonorgestrel-releasing intrauterine system for heavy menstrual bleeding or dysmenorrhea in Japanese patients: A prospective observational study (J-MIRAI).

OBJECTIVES: We collected real-world data on the safety and clinical outcomes of the levonorgestrel-releasing intrauterine system (LNG-IUS) for heavy menstrual bleeding and dysmenorrhea. STUDY DESIGN: This was a prospective, multicenter, single-cohort, open-label, post-authorization 12-month follow-up study of Japanese patients initiating the LNG-IUS for heavy menstrual bleeding and/or dysmenorrhea. The primary endpoint was the safety profile based on adverse events and adverse drug reactions (ADRs), including expulsions and abnormal bleeding, within 12 months of LNG-IUS insertion. Secondary endpoints included changes from baseline in menstrual blood loss based on bleeding days and dysmenorrhea graded on a visual analog scale (VAS). RESULTS: Of the 595 patients included, many had underlying conditions such as adenomyosis (39.5%), uterine leiomyoma (30.8%), or endometriosis (12.9%). The incidences of ADRs and serious ADRs were 59.7% and 0.3%, respectively. Frequently reported ADRs were metrorrhagia (48.9%), procedural pain (14.1%), and ovarian cyst (6.2%). The cumulative incidence of expulsions at 12 months was 8.7%. Risk factors for expulsion were obesity (body mass index ≥25 kg/m2), adenomyosis, and uterine cavity length ≥8 cm. The median [interquartile range] VAS score for dysmenorrhea improved from 46.5 [13.0-68.0] at insertion to 1.0 [0.0-13.0] at 12 months, and improvements were also observed in chronic pelvic pain and painful defecation. CONCLUSIONS: The LNG-IUS safely and effectively reduced dysmenorrhea, chronic pelvic pain, and painful defecation. Risk factors for expulsion suggest that patients with underlying organic disease should be monitored carefully when using the LNG-IUS. IMPLICATIONS: The LNG-IUS is an effective treatment for secondary dysmenorrhea with organic disease, and for the reduction of chronic pelvic pain; however, physicians should be aware of the increased risk of expulsion in patients with organic conditions.

Impact of three major risk factors on clinical outcomes in patients with nonvalvular atrial fibrillation receiving rivaroxaban: Sub-analysis from the XAPASS study.

Background: To evaluate the impact of three risk factors (age [≥75 years], renal impairment [creatinine clearance <50 ml/min], and low body weight [≤50 kg]) on the risk of any bleeding events, all-cause mortality, and stroke, non-central nervous system (non-CNS) systemic embolism (SE), and myocardial infarction (MI) in patients with nonvalvular atrial fibrillation (NVAF) treated with rivaroxaban in a real-world clinical setting. Methods: The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) is a prospective, single-arm, observational study. Enrolled patients were divided into four subgroups by the number of risk factors. Results: Overall, 9823 patients were included: 4299 with low risk, 2816 with moderate risk, 1574 with high risk, and 1134 with very high risk. The hazard ratios (95% confidence interval) (reference: low risk) for the moderate-, high-, and very-high-risk groups were 1.62 (1.19, 2.21) (p = 0.002), 2.15 (1.47, 3.15) (p < 0.001), and 2.49 (1.60, 3.87) (p <0.001) for major bleeding, and 1.98 (1.47, 2.66), 2.29 (1.59, 3.29), and 2.74 (1.81, 4.16) (p <0.001 for all) for stroke/non-CNS SE/MI, respectively. Conclusions: Age ≥75 years and renal impairment, but not low body weight, were determinants for major bleeding. The accrual of three risk factors was associated with increased risk for major bleeding and stroke/non-CNS SE/MI in patients with NVAF receiving rivaroxaban; there was no increase in the cumulative risk for these with an increasing number of risk factors.

[Exploratory Analysis Results from Post-marketing Surveillance Study of Radium-223 in Japanese Patients with Castration-resistant Prostate Cancer and Bone Metastases: Subgroup Analysis by Age].

OBJECTIVE: To perform an exploratory analysis on the safety and effectiveness of radium-223 (Ra-223) by patient baseline age, using the results of a post-marketing surveillance study of Ra-223 in castration-resistant prostate cancer patients with bone metastasis in Japan. METHOD: The safety analysis population of 296 patients was stratified into two groups based on age (<75 and ≥ 75 years-old [yo]), and their characteristics, drugrelated treatment-emergent adverse events (TEAEs), and clinical laboratory values were evaluated. Additionally, these endpoints were evaluated in patients aged ≥ 80 yo. RESULTS: There were 148 patients in each of the <75-yo and ≥ 75-yo age groups, and 69 patients in the ≥ 80-yo age group. The characteristics of patients in the <75-yo group were suggestive of more aggressive disease at diagnosis of prostate cancer and a greater proportion of patients had prior chemotherapy compared with patients in the ≥ 75-yo age group. The incidences of overall drugrelated TEAEs and drug-related hematological TEAEs were slightly higher in the <75-yo age group; however, there was little difference in the incidences of drug-related TEAEs leading to drug discontinuation (1.4-4.1%) between patient groups. Changes in total alkaline phosphatase and prostate-specific antigen values were similar in all groups. CONCLUSIONS: Ra-223 therapy seemed tolerable regardless of age in real-world practice in Japan. Especially, there were no new safety concerns of Ra-223 in elderly patients.