Real-world evidence of raloxifene versus alendronate in preventing non-vertebral fractures in Japanese women with osteoporosis: retrospective analysis of a hospital claims database.

We conducted a retrospective cohort study using a de-identified hospital administrative claims database to assess the risk of non-vertebral fracture in Japanese women with osteoporosis treated with raloxifene compared with alendronate. The study included Japanese women ≥50 years of age with newly initiated alendronate or raloxifene treatment between July 2008 and March 2013 (index date was defined as the day of first prescription for alendronate or raloxifene), and had any claim with an osteoporosis definition during the study period. A total of 37,056 patients in the database initiated treatment, and there were 4802 and 1250 patients included in the alendronate and raloxifene analysis groups, respectively. The mean observation period in the alendronate group (529.2 days) was significantly longer than that for the raloxifene group (473.5 days, P < 0.001). Non-vertebral fractures accumulated linearly, at a similar rate, for both study drugs: incidence at 1 year was 2.83 and 2.64% for the alendronate and raloxifene groups, respectively. For the relative risk of non-vertebral fracture within 1 year, the adjusted hazard ratio was 0.933 for raloxifene versus alendronate, indicating that the relative risk of non-vertebral fracture was similar for the two drugs. The effectiveness of raloxifene in preventing non-vertebral fractures in Japanese women with osteoporosis was similar to that of alendronate. Therefore, raloxifene may be worthy of consideration as an alternative treatment.

Recurrent Stroke and Bleeding Events after Acute Cardioembolic Stroke-Analysis Using Japanese Healthcare Database from Acute-Care Institutions.

BACKGROUND: To understand the reality of patients who experienced a cardioembolic stroke (CES) is important because of the high incidence of recurrent stroke and the need to account for bleeding risk in relation to the need for anticoagulation treatment. We elucidated the current real-world medical care in patients who had a CES and identified the risk factors for recurrent stroke. METHODS AND RESULTS: The study comprised 9804 patients who were diagnosed with CES between April 2008 and September 2013 as identified in a healthcare database used by acute-care institutions in Japan. We analyzed the incidence and risk factors of stroke and bleeding events in CES patients. The incidence of stroke was 10.3% during the median observation period of 68 days, mainly consisting of recurrent CES (8.5%). The incidence of bleeding events and intracranial bleeding was 10.3% and 7.0%, respectively. The recurrence of ischemic stroke was significantly lower, and brain hemorrhage was significantly higher in the anticoagulation treatment group. The factors related to an increased risk of stroke were a history of cerebral infarction or transient ischemic attack, diabetes, and increase of CHA2DS2-VASc and CHADS2 scores. The risk factors for bleeding events were hypertension, renal dysfunction, and use of proton pump inhibitors (PPIs). CONCLUSIONS: The patients who experienced CES had a high rate of recurrent stroke or CES, mainly consisting of recurrent CES. Although anticoagulation may be beneficial for reducing recurrence of ischemic stroke, careful management is required given consideration of increased risk of brain hemorrhage during anticoagulation treatment, especially for patients with hypertension, renal dysfunction, and use of PPIs.

Duration and clinical outcome of dual antiplatelet therapy after percutaneous coronary intervention: a retrospective cohort study using a medical information database from Japanese hospitals.

In this real-world, retrospective cohort study of 9753 patients in Japan prescribed dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI), we investigated DAPT duration and determined factors associated with early DAPT discontinuation and with event rates in patients who discontinued DAPT. The study period was April 1, 2012-March 31, 2018; endpoints comprised composite efficacy [death, myocardial infarction (MI), and stroke] and bleeding (intracranial, gastrointestinal, and requiring transfusion) endpoints. Overall, 68.8% of patients were continuing DAPT at 3 months post-PCI. Patients without major efficacy or safety events within 3 months after index PCI were included in a landmark analysis set (LAS; n = 7056), and categorized as DAPT ≥ 3 months (continuation) versus < 3 months (discontinuation). In the two LAS analysis groups, there was no difference in the composite bleeding endpoint (P = 0.067), although the incidence of the composite efficacy endpoint was higher in the discontinuation group (P < 0.001). In multivariate regression analysis, age ≥ 75 years, minor bleeding after PCI, history of cerebral infarction, history of cerebral or gastrointestinal bleeding, atrial fibrillation, dialysis, and anticoagulant use after PCI were associated with early DAPT discontinuation. Acute coronary syndrome, history of MI, kidney disorder, and anticoagulant use after PCI were associated with the composite efficacy endpoint in the discontinuation group. In conclusion, early DAPT discontinuation is more likely in patients at high bleeding risk, but may influence the occurrence of ischemic events in these patients. Determination of DAPT duration should take into account potential ischemic risk, even in patients at high bleeding risk.

Predictive factors for achievement of mucosal healing by budesonide 2-mg foam in ulcerative colitis: a pooled analysis of data from two clinical trials.

BACKGROUND/AIMS: Mucosal healing (MH) of distal lesions in ulcerative colitis (UC) has recently been confirmed with budesonide 2-mg foam (BF) treatment in 2 clinical trials; however, few studies have investigated the predictive factors for complete MH. METHODS: We conducted a post hoc analysis using pooled data from phase II and III clinical trials evaluating the efficacy and safety of BF for UC. Additionally, we analyzed the relationships between complete MH and baseline factors and clinical symptoms from baseline to week 6. RESULTS: Among the 291 Japanese patients from the 2 pooled clinical studies, 119 patients in the BF twice a day group and 117 in the placebo group were included in the full analysis set. The proportion of patients with a rectal bleeding (RB) subscore of 0 was significantly higher in the BF group than in the placebo group after a 5-day treatment (P<0.05). After a 2-day treatment, significantly more patients in the BF group had a stool frequency (SF) subscore of 0 than patients in the placebo group (P<0.05). Multivariate analysis showed that complete MH at week 6 was influenced by baseline SF subscore and 5-aminosalicylic acid (5-ASA) enema or suppository use (P=0.0086 and P=0.0015, respectively). The relationship between complete MH at week 6 and RB subscore after week 2 was also confirmed. CONCLUSIONS: Normal SF at baseline, history of 5-ASA topical product use, and elimination of RB after week 2 are suggested predictors of complete MH at week 6 with twice-daily BF treatment.

Retrospective analysis of medical costs and resource utilization for severe hypoglycemic events in patients with type 2 diabetes in Japan.

AIMS/INTRODUCTION: The present study aimed to describe hospital utilization and examine actual medical costs for severe hypoglycemic events in patients with type 2 diabetes mellitus in Japan. MATERIALS AND METHODS: Medical resource utilization associated with severe hypoglycemia was evaluated using a receipt database of acute-care hospitals in Japan. Patients with type 2 diabetes treated with antihyperglycemic agents were included. Severe hypoglycemic events were identified and divided into two groups: with or without hospitalization. Total and attributable medical costs per event were calculated based on the actual medical treatment after severe hypoglycemic events. Attributable costs were estimated from the receipt codes directly associated with the treatment of severe hypoglycemia. RESULTS: In the hospitalized patients, the median length of hospital stay was 11 days, and the median total and attributable medical costs were ¥402,081 and ¥302,341, respectively. The majority of the hospitalized patients underwent a radiographic examination and general blood tests. Apart from the hospitalization costs, the costs associated with diagnosis accounted for 29.6% of the total medical costs. In the outpatients, 60.6% visited hospitals only once for the severe hypoglycemic event, whereas 11.4% visited hospitals daily for a week after the severe hypoglycemic event. The mean number of hospital visits of the outpatient after a severe hypoglycemic event was 2.7 ± 2.6 days. The median total and attributable medical costs were ¥265,432 and ¥4,628, respectively. CONCLUSIONS: Significant medical resources are used for the treatment of severe hypoglycemic events of patients with type 2 diabetes in Japan.

Incidence rate and patient characteristics of severe hypoglycemia in treated type 2 diabetes mellitus patients in Japan: Retrospective Diagnosis Procedure Combination database analysis.

AIMS/INTRODUCTION: To evaluate the incidence rate of and identify factors associated with severe hypoglycemic episodes in patients with treated type 2 diabetes mellitus. MATERIALS AND METHODS: Using Diagnosis Procedure Combination hospital-based medical database, we carried out a retrospective cohort study to assess the incidence rate of severe hypoglycemia in treated type 2 diabetes mellitus patients. We evaluated the associations between severe hypoglycemia and age, sex, complications, and current use of insulin or sulfonylurea (SU) in a nested case-control study. RESULTS: Of 166,806 eligible patients, 1,242 had episodes of severe hypoglycemia during the observational period. The incidence rate of the first hypoglycemic events was 3.70/1,000 patient years. Based on the nested case-control analysis, age was associated with hypoglycemic events with adjusted odds ratios (ORs) of 1.64 or 65-74-year-old patients and 3.79 for ≥75-year-old patients in comparison with 20-64-year-old patients. Comorbidities, such as cognitive impairment, cancer, macrovascular disease and diabetic complications (retinopathy, nephropathy and neuropathy), were associated with severe hypoglycemia, with adjusted ORs ranging from 1.25 to 3.80. Severe hypoglycemic events also increased in patients with current use of both SU and insulin, either SU or insulin, with adjusted ORs of 18.36, 6.31 or 14.07, respectively, compared with patients with other antihyperglycemic agents. In patients with an SU glimepiride, adjusted ORs increased dose-dependently from 3.65 (≤1 mg) to 13.34 (>2 mg). CONCLUSIONS: The incidence rate of severe hypoglycemia in this cohort was 3.70/1,000 patient years. Age, cognitive impairment, cancer, diabetic complications, current use of insulin + SU and SU dosage were identified as risk factors for severe hypoglycemia.

Predictors of venous thromboembolism recurrence and the bleeding events identified using a Japanese healthcare database.

BACKGROUND: Treatment to prevent the recurrence of venous thromboembolism (VTE) and prevent bleeding events should be given to patients with VTE in an appropriate balance in relation to relevant predictors. We elucidated the current medical care in a real world setting and quantified predictors using a Japanese healthcare database. METHODS: The study included 3578 patients who were diagnosed with VTE between April 2008 and September 2013 at a Japanese acute-care hospital and included in the hospital database. Twenty-four patients who had a VTE event during the 180-day period after enrollment were excluded. We analyzed the incidence of recurrent VTE, incidence of bleeding events, and predictors in VTE patients. Events were defined by disease, medication, imaging, and laboratory testing, among other factors. RESULTS: The rate of recurrence of VTE events was 7.2 per 100 patient-years. The incidence rate of bleeding events was 8.3 per 100 patient-years. The presence of malignant disease, antipsychotic drugs, and nonsteroidal anti-inflammatory drugs increased the risk for recurrent VTE. The predictors for bleeding events were malignant disease, central venous catheterization, cancer chemotherapy, stroke, and diabetes. CONCLUSIONS: These findings obtained from healthcare database suggest predictors either for recurrent VTE and bleeding that should be considered when selecting treatment to reduce the risk of recurrent VTE and mitigate bleeding.

Incidence of venous thromboembolism and bleeding events in patients with lower extremity orthopedic surgery: a retrospective analysis of a Japanese healthcare database.

BACKGROUND: Orthopedic surgeries of lower extremities such as total knee arthroplasty (TKA), total hip arthroplasty (THA), and hip fracture surgery (HFS) are widely considered to carry a high risk of developing deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE). Growing attention to epidemiological studies using a healthcare database led us to quantify the risks using a Japanese database to reveal recent medical care for such events. METHODS: The study comprised 36,947 patients who had undergone orthopedic surgeries of the lower extremities and whose medical information from April 2008 to September 2013 was available. The source population of the database was derived from 100 acute-care hospitals with Diagnosis Procedure Combination. The events were defined by diagnosis, medication, imaging, and laboratory tests. RESULTS: A breakdown of patients who underwent orthopedic surgeries by type of surgery showed 13.6% for TKA, 10.4% for THA, 56.8% for HFS, 1.5% for rupture of Achilles tendon, and 18.0% for simple fracture of lower extremities. The incidence for DVT, PTE, and bleeding events by type of surgery was 1.3, 0.2, and 1.0% for TKA; 0.9, 0.2, and 1.1% for THA; and 0.4, 0.1, and 1.8% for HFS, respectively. The population for risk factor analysis consisted of patients with similar background factors who underwent TKA, THA, or HFS. The statistically significant risk factors for PTE analyzed by the backward elimination procedure in a multivariate model were female sex, history of venous thromboembolism (VTE), thrombophilia, and varicose veins of lower extremity. CONCLUSIONS: The incidence of DVT, PTE, and bleeding events and the risk factors for DVT and PTE in patients by type of orthopedic surgeries of lower extremities found in our study are considered to be rational as they reflect evidence from real-world cases. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000012667.

Usefulness of a healthcare database for epidemiological research in atrial fibrillation.

BACKGROUND: Big data are gaining attention as a valuable resource for providing insights into a range of issues and questions in healthcare. We evaluated the capacity of a Japanese healthcare database to conduct epidemiological research in non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: We examined data collected between April 2008 and September 2013 in a Japanese healthcare database. Prior to the risk factor analysis, we validated the criteria for defining the occurrence of a stroke, systemic embolic event (SEE), and intracranial bleeding event during the study period. The validity was considered appropriate based on the resulting high positive predictive values. The data of 18,998 NVAF patients demonstrated that the incidence rates of stroke, SEE, and any bleeding events were 2.2, 0.08, and 2.4 per 100 patient-years, respectively. In patients who had not been treated with an anticoagulant, incidence of stroke significantly increased in higher CHADS2 or CHA2DS2-VASc score, 1.7 and 1.5 fold by 1 point increase, respectively. The use of a proton pump inhibitor (PPI) was also identified as an independent risk factor for stroke. In patients who had been treated with an anticoagulant, the independent risk factors for any bleeding events were hypertension, renal dysfunction, hepatic failure, medical history of stroke, older age (≥65 years), use of nonsteroidal anti-inflammatory drug, and PPIs. CONCLUSION: The data obtained in this study were comparable with results obtained in prospective cohort studies conducted in Japan.

Analysis of non-genetic risk factors for adverse skin reactions to radiotherapy among 284 breast cancer patients.

OBJECTIVES: We analyzed non-genetic risk factors for adverse skin reactions to irradiation at 4 collaborating Japanese institutions, to design future investigation into genetic risk factors for adverse skin reactions to irradiation in a multicenter setting. METHODS: From April 2001, 284 breast cancer patients, who underwent radiotherapy with breast-conserving surgery, were enrolled from 4 collaborating institutions in Japan. We graded skin reactions according to international scoring systems. Clinical factors were tested against adverse effects. RESULTS: Grade 1+ skin reactions were observed in 261 (92%) of the patients in less than 3 months, 118 (42%) at 3 months, and 29 (10%) at 6 months in the late phase. Univariate analysis of treatment risk factors (such as the use of a multi-leaf colimeter, wedge-filter, or immobilization device) for skin reactions revealed a significant association (p< 0.0001). After a variable selection procedure with logistic regression, the institution, operative procedure, and magnitude of photon energy remained significantly associated with acute skin reactions. Only the institution was an explanatory variable for skin reactions at 3 and 6 months in the final logistic model. CONCLUSION: After stratification, substantial remaining variations in the occurrence of skin reactions of a given level suggested that individual genetic factors contribute markedly to individual radiosensitivity. Analysis of genetic factors associated with adverse effects would be possible by stratifying patients according to institution. Selection of eligible institutions, where appropriate treatment modalities could be performed, would also be possible when planning such a study.

The Direct Cost of Parkinson Disease at Juntendo Medical University Hospital, Japan.

Objective Many studies on the cost of Parkinson disease (PD) have been published; however, there are limited studies pertaining to this issue in Asia. This study looks to assess the direct medical costs of patients with PD at a university hospital in Japan by calculating the average monthly direct medical costs of PD patients from July to December 2008. Methods We enrolled 724 consecutive patients (411 women and 313 men) with PD who were registered in Japan's "Specified Disease Treatment Research Program" and obtained data on the total direct medical costs of all patients. Results Values are reported as the mean (standard deviation). The major finding of the direct medical cost analysis was that the outpatient clinic cost per subject (n=715) was USD 485.74 (376.31) per month. A multivariate analysis revealed that a younger age, the presence of wearing-off, hallucination, and longer disease duration increased the direct medical cost significantly. Disease severity had no influence on the direct medical costs. A longer disease duration was significantly correlated with higher hospitalization costs. Conclusion The direct medical cost of PD in Japan was found to be similar to that in Western countries. Costs due to productivity loss exceeded the direct costs, and they may be reduced through the better integration of PD patients in the work environment.

Increased risk of acute pancreatitis in patients with type 2 diabetes: an observational study using a Japanese hospital database.

BACKGROUND: Increased risks of acute pancreatitis in patients with type 2 diabetes mellitus have been reported recently in several countries. We aimed to estimate the risks of acute pancreatitis in Japanese patients with diabetes mellitus. METHODS/FINDINGS: We examined a large-scale hospital administrative database consisting of one million patients in 16 secondary medical care hospitals, from 2003 to 2010. The incidence rates of acute pancreatitis were estimated with cohort design; the odds ratios associated with diabetes mellitus and other comorbid risk factors were estimated with separate case-control analyses. In cohort analysis, the incidence of acute pancreatitis was higher in 14,707 diabetic patients than in 186,032 non-diabetic patients (4.75 vs. 1.65 per 1,000 patient-years) and increased in male patients and as age advanced. The adjusted odds ratio of acute pancreatitis in patients with diabetes mellitus was 1.86 (P<0.001) compared with non-diabetic patients in case-control analysis from 1,372 cases and 5,469 matched controls, which is consistent with the ones reported in previous studies. Alcoholism and gallstones were associated with a large increase in the risk of acute pancreatitis (adjusted odds ratio 13.40 and 14.29, respectively, P<0.001), although dyslipidemia was associated with significant risk reduction (adjusted odds ratio 0.62, P<0.001). CONCLUSIONS: This observational study ascertained the elevated incidence rates and risk of acute pancreatitis in Japanese patients with diabetes. The risk estimates in Japanese patients with diabetes were in agreement with the ones reported in previous studies, and the elevated risk of acute pancreatitis in patients with diabetes would be generalized in different locations/populations.

Influence of multiple genetic polymorphisms on genitourinary morbidity after carbon ion radiotherapy for prostate cancer.

PURPOSE: To investigate the genetic risk of late urinary morbidity after carbon ion radiotherapy in prostate cancer patients. METHODS AND MATERIALS: A total of 197 prostate cancer patients who had undergone carbon ion radiotherapy were evaluated for urinary morbidity. The distribution of patients with dysuria was as follows: Grade 0, 165; Grade 1, 28; and Grade 2, 4 patients. The patients were divided (2:1) consecutively into the training and test sets and then categorized into control (Grade 0) and case (Grade 1 or greater) groups. First, 450 single nucleotide polymorphisms (SNPs) in 118 candidate genes were genotyped in the training set. The associations between the SNP genotypes and urinary morbidity were assessed using Fisher's exact test. Then, various combinations of the markers were tested for their ability to maximize the area under the receiver operating characteristics (AUC-ROC) curve analysis results. Finally, the test set was validated for the selected markers. RESULTS: When the SNP markers in the SART1, ID3, EPDR1, PAH, and XRCC6 genes in the training set were subjected to AUC-ROC curve analysis, the AUC-ROC curve reached a maximum of 0.86. The AUC-ROC curve of these markers in the test set was 0.77. The SNPs in these five genes were defined as "risk genotypes." Approximately 90% of patients in the case group (Grade 1 or greater) had three or more risk genotypes. CONCLUSIONS: Our results have shown that patients with late urinary morbidity after carbon ion radiotherapy can be stratified according to the total number of risk genotypes they harbor.