Timing of Initiation of Xanthine Oxidase Inhibitors Based on Serum Uric Acid Level Does Not Predict Renoprognosis in Patients with Preserved Kidney Function.

Background: Despite recent evidence of remaining possibility that early initiation of xanthine oxidase inhibitors (XOIs) is beneficial in renoprognosis for patients with stage 2 or less chronic kidney disease (CKD), no evidence is available regarding the difference in renoprognosis based on serum uric acid (sUA) levels at the initiation of XOIs among patients with preserved kidney function. Methods: New XOI initiators were divided into quartiles based on baseline sUA. Primary outcome was the composite incidence of a significant estimated glomerular filtration rate (eGFR) decline (≥40% decline in eGFR from baseline or development of eGFR <30 mL/1.73 m2/min) or all-cause death within 5 years. Results: After excluding inapplicable patients, 1170 XOI initiators were analyzed (mean ± standard deviation age: 68 ± 14.3 years; sUA: 10.6 ± 1.15 mg/dL). On overall median [interquartile range (IQR)] follow-up of 824 (342, 1576) days, incidence rate of the primary outcome was 287 per 1000 person-years for 5 years. Although the nonadjusted model showed a dose-response association between baseline sUA level and the outcome, the adjusted model showed no significant association. Adjusted hazard ratios (95% confidence interval) of the second, third, and fourth quartiles of baseline sUA with the composite outcome within 5 years compared to the first quartile were 1.00 (0.78, 1.29), 1.00 (0.80, 1.30), and 1.02 (0.80, 1.32), respectively. Conclusions: Early initiation of XOIs did not predict a significant benefit on renoprognosis even among the population with preserved kidney function. The validity of initiating XOIs with the aim of improving renoprognosis based on sUA is questionable.

Cardiovascular Safety of Atomoxetine and Methylphenidate in Patients With Attention-Deficit/Hyperactivity Disorder in Japan: A Self-Controlled Case Series Study.

OBJECTIVE: To investigate the association between atomoxetine or methylphenidate use and arrhythmia, heart failure (HF), stroke, and myocardial infarction (MI) in attention-deficit/hyperactivity disorder (ADHD) patients mainly focused on the people of working age. METHODS: In a self-controlled case series study using a Japanese claims database, we identified events of arrhythmia, HF, stroke, and MI among 15,472 atomoxetine new users and 12,059 methylphenidate new users. Adjusted incidence rate ratios (aIRRs) of outcome events were estimated using multivariable conditional Poisson regression. RESULTS: An increased risk of arrhythmia was observed during the first 7 days after the initial atomoxetine exposure (aIRR 6.22, 95% CI [1.90, 20.35]) and in the subsequent exposure (3.23, [1.58, 6.64]). No association was found between methylphenidate exposure and arrhythmia, nor between atomoxetine or methylphenidate exposure and HF. The limited number of stroke and MI cases prevented thorough analysis. CONCLUSIONS: Clinicians should consider monitoring for arrhythmia after patients initiating or re-initiating atomoxetine.

Are Dental Procedures Associated With Pyogenic Vertebral Osteomyelitis?

BACKGROUND: Dental procedures can lead to bacteremia and have been considered a potential risk factor for pyogenic vertebral osteomyelitis (PVO). However, data on the association between dental procedures and PVO are limited. QUESTIONS/PURPOSES: (1) After controlling for relevant confounding variables, are dental procedures associated with an increased risk of PVO? (2) Does antibiotic prophylaxis before dental procedures effectively decrease the risk of PVO? METHODS: A case-crossover study was conducted to investigate the association between dental procedures and PVO using a Japanese claims database. The advantage of this study design is that confounding factors that do not vary over time are automatically adjusted for, because cases act as their own controls. From April 2014 to September 2021, the database included 8414 patients who were hospitalized for PVO. Of these, 50% (4182 of 8414) were excluded because they had not undergone any dental procedures before the index date, a further 0.1% (10 of 8414) were excluded because they were younger than 18 years at the index date, and a further 7% (623 of 8414) were excluded because they did not have at least 20 weeks of continuous enrollment before the index date, leaving 43% (3599 of 8414) eligible for analysis here. The mean age was 77 ± 11 years, and 55% (1985 of 3599) were men. Sixty-five percent (2356 of 3599) of patients had a diagnosis of diabetes mellitus, and 42% (1519 of 3599) of patients had a diagnosis of osteoporosis. We compared the frequency of dental procedures between a 4-week hazard period before the admission date for PVO and two control periods, 9 to 12 weeks and 17 to 20 weeks before the admission date for PVO, within individuals. We calculated odds ratios and 95% confidence intervals using conditional logistic regression analysis. RESULTS: Comparing the hazard and matched control periods within individuals demonstrated that dental procedures were not associated with an increased risk of PVO (OR 0.81 [95% CI 0.72 to 0.92]; p < 0.001). Additional analysis stratified by antibiotic prophylaxis use showed that antibiotic prophylaxis was not associated with a lower OR of developing PVO after dental procedures (with antibiotic prophylaxis: OR 1.11 [95% CI 0.93 to 1.32]; p < 0.26, without antibiotic prophylaxis: OR 0.72 [95% CI 0.63 to 0.83]; p < 0.001). Our sensitivity analyses, in which the exposure assessment interval was extended from 4 to 8 or 12 weeks and exposure was stratified by whether the dental procedure was invasive, demonstrated results that were consistent with our main analysis. CONCLUSION: Dental procedures were not associated with an increased risk of subsequent PVO in this case-crossover study. The effectiveness of antibiotic prophylaxis was not demonstrated in the additional analysis that categorized exposure according to the use of antibiotic prophylaxis. Our results suggest that the association between dental procedures and PVO may have been overestimated. Maintaining good oral hygiene may be important in preventing the development of PVO. The indications for antibiotic prophylaxis before dental procedures should be reconsidered in view of the potential risk of adverse drug reactions to antibiotic prophylaxis and the emergence of drug-resistant pathogens. Larger randomized controlled trials are needed to confirm these findings and assess the role of antibiotic prophylaxis. LEVEL OF EVIDENCE: Level III, therapeutic study.

Glucocorticoid treatment and clinical outcomes in patients with polymyalgia rheumatica: A cohort study using routinely collected health data.

OBJECTIVE: We aimed to describe the following in patients with polymyalgia rheumatica (PMR): (1) real-world glucocorticoid (GC) therapy, (2) improvement in inflammatory parameters associated with disease activity (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]), and (3) incidence of GC-related adverse events (AEs). METHODS: A cohort study was conducted using a Japanese electronic medical records database. We included newly diagnosed PMR patients aged≥50years with baseline CRP levels≥10mg/L and/or ESR>30mm/h and an initial GC dose of≥5mg/day. The outcomes were GC dose, inflammatory parameters, and GC-related AEs. RESULTS: A total of 373 PMR patients (mean age, 77.3 years) were analyzed. The median initial GC dose was 15.0mg/day, which gradually decreased to 3.5mg/day by week 52. The median cumulative GC dose at week 52 was 2455.0mg. The median CRP level on day 0 was 64.3mg/L, which decreased during weeks 4-52 (1.4-3.2mg/L). At week 52, 39.0% of patients had a CRP level>3.0mg/L. The cumulative incidence of GC-related AEs at week 52 was 49.0% for osteoporosis, 30.2% for diabetes, 14.9% for hypertension, 12.2% for peptic ulcer, 11.3% for dyslipidemia, 2.9% for glaucoma, and 4.3% for serious infection. The incidence of osteoporosis and diabetes increased with the GC dose. CONCLUSION: The incidence of GC-related AEs was associated with the GC dose in PMR patients. Further research is required to identify treatment strategies that can effectively control PMR disease activity while minimizing GC use.

Clinical Characteristics and Outcomes of Patients With Venous Thromboembolism Receiving Edoxaban in the Real World.

BACKGROUND: The effectiveness and safety of edoxaban for venous thromboembolism (VTE) in unselected real-world patients have not been fully evaluated.Methods and Results: In the Japanese nationwide administrative database, we identified 6,262 VTE patients in whom edoxaban was initiated; these patients were divided into 3 groups based on their index doses: 15 mg/day (n=235), 30 mg/day (n=4,532), and 60 mg/day (n=1,495). We evaluated patient characteristics, recurrent VTEs, and a composite endpoint of intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding. Patient characteristics among the 15-, 30-, and 60-mg edoxaban groups varied widely regarding several aspects, including age (mean 81.0, 76.2, and 65.0 years, respectively) and body weight (mean 49.5, 51.8, and 70.3 kg, respectively). At 180 days, the cumulative incidence of recurrent VTEs in the 15-, 30-, and 60-mg edoxaban groups was 4.4%, 2.6%, and 1.8%, respectively, whereas that of ICH or GI bleeding was 7.3%, 5.4%, and 3.3%, respectively. Subgroup analyses showed that the cumulative incidence of ICH or GI bleeding in patients in the 15-mg edoxaban group was 3.6% for patients aged ≥80 years, 8.4% for those with a body weight <60 kg, and 31.3% for those with renal dysfunction. CONCLUSIONS: Only a minority of patients with VTEs received a super low dose (15 mg) of edoxaban, and these patients may be at higher risk of bleeding as well as VTE recurrence.

Frequency and determinants of serum calcium monitoring during eldecalcitol therapy in patients with osteoporosis.

INTRODUCTION: Eldecalcitol (ELD) is an active vitamin D3 analog (AVD) commonly used to treat osteoporosis in Japan. Although routine monitoring of serum calcium levels during ELD therapy is recommended, little is known about the actual frequency and determinants of monitoring. MATERIALS AND METHODS: This was a descriptive cohort study using a Japanese electronic medical records database. We identified osteoporosis patients who initiated treatment with ELD or other AVDs (alfacalcidol and calcitriol) between April 1, 2011 and September 10, 2021. The index date for cohort entry was the first prescription date of ELD or other AVDs. The frequency of serum calcium monitoring was evaluated every 6 months. Determinants of serum calcium monitoring were identified using multivariable logistic regression models. We also calculated the incidence of hypercalcemia and the frequency of serum calcium monitoring within 6 months before hypercalcemia. RESULTS: We identified 12,671 ELD users and 7867 other AVD users. Within 6 months after cohort entry, 45.9% of ELD users and 58.7% of other AVD users underwent serum calcium monitoring. Female sex, no use of systemic corticosteroids, moderate-to-good renal function, treatment in smaller hospitals, and treatment in orthopedic surgery departments were associated with a lower likelihood of receiving serum calcium monitoring during ELD therapy. The incidence of hypercalcemia among ELD users was 6.36 per 100 person-years, with 20.6% of cases not receiving serum calcium monitoring before hypercalcemia. CONCLUSION: Our findings suggest that serum calcium monitoring is not given adequate attention during ELD therapy in routine clinical practice.

Association between dental procedures and periprosthetic joint infection: A case-crossover study.

BACKGROUND: Although the risk of dental procedures as a cause of bacteremia has been recognized, evidence regarding the association between dental procedures and late periprosthetic joint infection (LPJI) is scarce. We sought to determine whether dental procedures are associated with an increased risk of LPJI. METHODS: The study was conducted under a case-crossover design using a large claims database in Japan. We identified adult patients who had undergone dental procedures and were hospitalized for LPJI between April 2014 and September 2021. Exposure to dental procedures was assessed during a case period of 1-4 weeks, with two control periods of 9-12 weeks and 17-20 weeks, preceding LPJI hospital admission. Conditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of LPJI associated with dental procedures in the case period compared with the two control periods. RESULTS: In total, 241 patients with LPJI were included in the case-crossover study. At least one dental procedure was performed in 46 patients (19.1%) in the hazard period and in 75 patients (31.1%) in the control periods. The OR for LPJI with dental procedures was 0.96 (95% CI, 0.61-1.53; p = 0.88). Findings were robust in several sensitivity analyses, including stratification by whether the dental procedure included antibiotic prophylaxis. CONCLUSIONS: This study suggests that dental procedures are not associated with increased risk of LPJI, and will raise questions about the recommendation for antibiotic prophylaxis before dental procedures.

Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated With Antibiotic Use: A Case-Crossover Study.

BACKGROUND: Evidence is lacking on the association between antibiotic use and risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Asians. OBJECTIVE: We assessed the risk of SJS/TEN associated with different antibiotic classes in Japanese. METHODS: We conducted a case-crossover study using a claims database. Firth conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of SJS/TEN associated with antibiotic use in a 56-day hazard period versus 3 control periods. We created 18 cohorts for each antibiotic class and calculated 56-day cumulative incidence per 100,000 new users. The association between antibiotic class and SJS/TEN was also evaluated in each case using the ALgorithm of Drug causality for Epidermal Necrolysis (ALDEN). RESULTS: Our case-crossover study included 170 SJS/TEN cases. Increased ORs were observed for lincomycins (OR, 33.00 [95% CI, 3.74-4332.05]), trimethoprim-sulfamethoxazole (21.20 [6.73-105.98]), penicillins (14.39 [6.95-34.21]), glycopeptides (14.37 [3.17-136.10]), cephalosporins (7.06 [4.25-12.21]), aminoglycosides (6.55 [1.97-26.84]), quinolones (5.98 [3.34-11.20]), fosfomycin (5.40 [1.20-30.97]), carbapenems (5.09 [1.85-15.64]), tetracyclines (4.95 [1.78-15.27]), and macrolides (3.78 [2.13-6.83]). Cumulative incidence of SJS/TEN was 67.4 for trimethoprim-sulfamethoxazole, 86.2 for glycopeptides, and below 10.0 for the others. Despite the high incidence, only 2 cases had a probable causal relationship with glycopeptides. CONCLUSION: Some antibiotic classes, including lincomycins, glycopeptides, aminoglycosides, fosfomycin, and carbapenems, were newly suggested to be associated with risk of SJS/TEN; considered together with the high incidence for trimethoprim-sulfamethoxazole and glycopeptides, these findings warrant caution in clinical practice.

Adherence to and persistence with lacosamide, perampanel, lamotrigine, and levetiracetam in adult patients with focal epilepsy in Japan: A descriptive cohort study using a claims database.

Objective: We evaluated adherence to and 1-year persistence of two third-generation anti-seizure medications (ASMs), lacosamide and perampanel, in adult patients with focal epilepsy, compared with lamotrigine and levetiracetam. Methods: A cohort study was conducted using a Japanese health insurance claims database (JMDC Inc.). We identified patients with adult-onset focal epilepsy who initiated any of the four ASMs between August 31, 2016, and October 31, 2019. Patients were further classified into ASM-naïve patients initiating any of the four ASMs as first-line treatment, and ASM-experienced patients initiating any of the four ASMs as second- or later-line treatment. Outcomes included adherence (proportion of days covered [PDC], defined as the total number of days covered by ASMs divided by the total number of days in the follow-up period) and 1-year persistence for the four ASMs. Results: We identified 141 lacosamide, 75 perampanel, 80 lamotrigine, and 530 levetiracetam initiators. Among these, the proportion of ASM-naïve patients was highest in the levetiracetam group (60.8%), followed by the lamotrigine (25.0%), lacosamide (20.6%), and perampanel groups (1.3%). Mean PDC (standard deviation) was similar across the four groups, at 0.95 (0.08) for lacosamide, 0.93 (0.12) for perampanel, 0.92 (0.10) for lamotrigine and 0.94 (0.11) for levetiracetam. The proportion of patients persisting with treatment for 1 year was highest in the lacosamide group (73.0%), followed by the levetiracetam (58.3%), lamotrigine (57.5%), and perampanel groups (54.7%). In ASM-naïve patients, adherence and 1-year persistence were almost identical in the lacosamide, lamotrigine, and levetiracetam groups. Results for ASM-experienced patients did not significantly differ from those of all patients. Significance: With regard to adherence and 1-year persistence, lacosamide may be equal to or better than lamotrigine and levetiracetam, especially in patients with experienced ASM, while perampanel may be comparable to lamotrigine and levetiracetam in patients with experienced ASM.

Predictors of the Need for Surgery in Cervical Ossification of the Posterior Longitudinal Ligament: A Retrospective Cohort Longitudinal Study Using a Claims-based Database.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim of this study was to determine predictors associated with the needfor cervical ossification of the posterior longitudinal ligament (cOPLL) surgery amongindividuals with cOPLL. SUMMARY OF BACKGROUND DATA: cOPLL is a spinal disorder caused by ectopic ossification of the posterior longitudinal ligament. However, factors associated with a higher rate of surgery to treat the neurological symptoms of cOPLL are poorly understood. MATERIALS AND METHODS: This retrospective population-based cohort study using a commercial administrative claims database from JMDC Inc. (Tokyo, Japan) enrolled patients newly diagnosed with cOPLL from April 2005 to October 2020 and followed to April 2021. A total of 1506 cOPLL patients aged 18 years or older with no history of cervical spine surgery and with a record of metabolic profiles obtained at general health checkups were included. Cox proportional hazards regression models identified patient characteristics and comorbidities associated with cOPLL surgery. RESULTS: Of 1506 patients with cOPLL with a median of 1.8 years of follow-up after initial cOPLL diagnosis, 439 (29.2%) received cOPLL surgery. The 1-year cumulative incidence (95% CI) was 26.0% (23.7-28.2). In multivariable Cox proportional regression analysis, male (hazard ratio: 1.68; 95% CI: 1.26-2.24; P < 0.001) and obesity (body mass index: ≥25) (hazard ratio: 1.45; 95% CI: 1.10-1.89; P = 0.007) were associated with an increased risk of cOPLL surgery. CONCLUSIONS: In this large claims-based study of adults newly diagnosed with cOPLL, males and obesity were associated with a higher risk of cOPLL surgery. These findings may help clinicians to predict the future course of cOPLL in patients, although further research is needed to elucidate the biological role of these progression-associated factors.

Risk of parkinsonism and related movement disorders with gabapentinoids or tramadol: A case-crossover study.

INTRODUCTION: A safety signal concerning parkinsonism and related movement disorders with gabapentinoids (gabapentin and pregabalin) or tramadol was detected by reviewing individual case reports and data mining in spontaneous report databases. Well-designed pharmacoepidemiological studies are needed to assess the signal. OBJECTIVE: This study aimed to investigate the association of exposure to gabapentinoids or tramadol with the risk of parkinsonism and related movement disorders. METHODS: We conducted a case-crossover study using a Japanese electronic medical records database. Patients with newly diagnosed parkinsonism or related movement disorders between January 1, 2007, and April 14, 2019, were identified. The diagnosis date of outcomes was defined as the index date. We assessed the exposure of each patient to gabapentinoids or tramadol during a 90-day hazard period ending 1 day before the index date and in three 90-day reference periods. Multivariable conditional logistic regression models were employed to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). To confirm the robustness of the primary findings, we also performed sensitivity analyses using a case-case-time-control design, a different time window for hazard and reference periods, a different definition of outcome, and different number of reference periods. RESULTS: A total of 28,972 eligible cases were included in the primary analysis. Exposure to gabapentinoids (aOR, 2.12; 95% CI, 1.73-2.61) and tramadol (aOR, 2.04; 95% CI, 1.57-2.64) was associated with increased risk. Results were consistent across sensitivity analyses. CONCLUSION: Our findings serve as a caution to physicians who prescribe gabapentinoids or tramadol in routine clinical practice.

Incidence of Surgical Site Infection Following Lateral Lumbar Interbody Fusion Compared With Posterior/Transforaminal Lumbar Interbody Fusion: A Propensity Score-Weighted Study.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The objective of this study was to compare the incidence of surgical site infection (SSI) after lateral lumbar interbody fusion (LLIF) and posterior/transforaminal lumbar interbody fusion ( P /TLIF). SUMMARY OF BACKGROUND DATA: Previous studies have shown that LLIF can improve neurological symptoms to a comparable degree to P /TLIF. However, data on the risk of SSI after LLIF is lacking compared with P /TLIF. MATERIALS AND METHODS: The study was conducted under a retrospective cohort design in patients undergoing LLIF or P /TLIF for lumbar degenerative diseases between 2013 and 2020 using a hospital administrative database. We used propensity score overlap weighting to adjust for confounding factors including age, sex, body mass index, comorbidities, number of fusion levels, hospital size, and surgery year. We estimated weighted odds ratios (ORs) and 95% CIs for SSI within 30 days postoperatively. RESULTS: We compared the risk of SSI between 2874 patients who underwent LLIF and 24,245 patients who received P/TLIF Patients who had received LLIF were at significantly less risk of experiencing an SSI compared with those receiving P/TLIF (0.7% vs. 1.2%; weighted OR: 0.57; 95% CI: 0.36 -0.92; P=0.02). As a secondary outcome, patients who had received LLIF had less risk of transfusion (7.8% vs. 11.8%; weighted OR: 0.63; 95% CI:0.54 -0.73; P <0.001). CONCLUSIONS: In this large retrospective cohort study of adults undergoing lumbar interbody fusion, LLIF was associated with a significantly lower risk of SSI than P /TLIF. The small, but significantly, decreased risk of SSI associated with LLIF may inform decisions regarding the technical approach for lumbar interbody fusion.

Reoperation Rates of Microendoscopic Discectomy Compared With Conventional Open Lumbar Discectomy: A Large-database Study.

BACKGROUND: Microendoscopic discectomy for lumbar disc herniation has been shown to be as effective as traditional microdiscectomy or open discectomy in terms of clinical outcomes such as pain relief, and it is less invasive. Nevertheless, the reoperation rate for microendoscopic discectomy compared with microdiscectomy or open discectomy remains unclear, possibly due to difficulties in conducting follow-up of sufficient duration and in obtaining information about reoperation in other facilities. QUESTIONS/PURPOSES: (1) What is the rate of reoperation after microendoscopic discectomy for primary lumbar disc herniation on a large scale at a median of 4 years postoperatively? (2) Is there any difference in revision rate at a median of 4 years and within 90 days postoperatively based on surgical method? METHODS: We conducted a retrospective, comparative study of adult patients who underwent microendoscopic discectomy or microdiscectomy or open discectomy for lumbar disc herniation from April 2008 to October 2017 and who were followed until October 2020 using a commercially available administrative claims database from JMDC Inc. This claims-based database provided information on individual patients collected across multiple hospitals, which improved the accuracy of postoperative reoperation rates. We included 3961 patients who received microendoscopic discectomy or microdiscectomy or open discectomy between April 2008 and October 2017 in the JMDC claims database. After applying exclusion criteria, 50% (1968 of 3961) of patients were eligible for this study. Propensity score-weighted analyses were conducted in 646 patients in the microendoscopic discectomy group and in 1322 in the microdiscectomy or open discectomy group, with a median (IQR) of 4 years (3 to 6) of follow-up in both groups. Mean patient age was 42 ± 12 years in the microendoscopic discectomy group and 43 ± 12 years in the microdiscectomy or open discectomy group. Males accounted for 78% (505 of 646) of patients in the microendoscopic discectomy group and 79% (1050 of 1322) of patients in microdiscectomy or open discectomy group. The proportion of patients with diabetes mellitus in the microendoscopic discectomy group (10% [64 of 646]) was less than in the microdiscectomy or open discectomy group (15% [195 of 1322]). The primary outcome was Kaplan-Meier survivorship free from any type of additional lumbar spine surgery at a median of 4 years after the index surgery. The secondary outcome was survival probability using the Kaplan-Meier method with endpoints of any type of reoperation within 90 days after the index surgery. To determine which procedure had the higher revision rate, we conducted propensity score overlap weighting analysis, which controlled for potential confounding variables such as age, sex, comorbidities, and type of hospital as well as Cox proportional hazard models to estimate HRs and 95% confidence intervals (CIs). RESULTS: The 5-year cumulative reoperation rate was 12% (95% CI 9% to 15%) in the microendoscopic discectomy group and 7% (95% CI 6% to 9%) in the microdiscectomy or open discectomy group. After controlling for potentially confounding variables like age, sex, and diabetes mellitus, the microendoscopic discectomy group had a higher reoperation risk than the microdiscectomy or open discectomy group (weighted HR 1.57 [95% CI 1.14 to 2.16]; p = 0.004). Within 90 days of the index surgery, after controlling for potentially confounding variables like age, sex, and diabetes mellitus, we found no difference between the microendoscopic discectomy group and microdiscectomy or open discectomy group in terms of risk of reoperation (weighted HR 1.38 [95% CI 0.68 to 2.79]; p = 0.38). CONCLUSION: Given the higher reoperation risk with microendoscopic discectomy compared with microdiscectomy or open discectomy at a median of 4 years of follow-up, surgeons should select microdiscectomy or open discectomy, despite the current popularity of microendoscopic discectomy. The revision risk of microendoscopic discectomy compared with microdiscectomy or open discectomy in the long term remains unclear. Future large, prospective, multicenter cohort studies with long-term follow-up are needed to confirm the association between microendoscopic discectomy and risk of reoperation. LEVEL OF EVIDENCE: Level Ⅲ, therapeutic study.

Clinical epidemiology and pharmacoepidemiology studies with real-world databases.

Hospital-based registry data, including patients' information collected by academic societies or government based research groups, were previously used for clinical research in Japan. Now, real-world data routinely obtained in healthcare settings are being used in clinical epidemiology and pharmacoepidemiology. Real-world data include a database of claims originating from health insurance associations for reimbursement of medical fees, diagnosis procedure combinations databases for acute inpatient care in hospitals, a drug prescription database, and electronic medical records, including patients' medical information obtained by doctors, derived from electronic records of hospitals. In the past ten years, much evidence of clinical epidemiology and pharmacoepidemiology studies using real-world data has been accumulated. The purpose of this review was to introduce clinical epidemiology and pharmacoepidemiology approaches and studies using real-world data in Japan.

Comparative effectiveness and safety of edoxaban, rivaroxaban, and apixaban in patients with venous thromboembolism: A cohort study.

BACKGROUND: Although several studies have compared the effectiveness and safety of rivaroxaban and apixaban in patients with venous thromboembolism (VTE), direct comparison of these drugs with edoxaban is lacking. OBJECTIVE: We compared the effectiveness and safety of edoxaban, rivaroxaban, and apixaban in patients with VTE. PATIENTS/METHODS: In this retrospective cohort study using a Japanese hospital administrative database, we identified three mutually exclusive groups of patients with VTE beginning treatment with edoxaban, rivaroxaban, or apixaban. Primary effectiveness outcome was recurrent VTE, and principal safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding. Subjects were followed for up to 180 days. Baseline characteristics among groups were balanced using propensity score matching weights. RESULTS: Three thousand three hundred sixty-nine edoxaban, 1592 rivaroxaban, and 1998 apixaban initiators were identified. There were no significant differences among the three drugs in the prevention of recurrent VTE (adjusted incidence rate ratio [aIRR], 0.77; 95% confidence interval [CI], 0.45-1.30 for edoxaban vs. rivaroxaban; aIRR, 0.92; 95% CI, 0.54-1.56 for edoxaban vs. apixaban; and aIRR, 1.20; 95% CI, 0.69-2.10 for rivaroxaban vs. apixaban), or in the risk of intracranial hemorrhage or gastrointestinal bleeding (aIRR, 1.57, 95% CI, 0.85-2.90 for edoxaban vs. rivaroxaban; aIRR, 1.30, 95% CI, 0.76-2.23 for edoxaban vs. apixaban; and aIRR, 0.83, 95% CI, 0.42-1.64 for rivaroxaban vs. apixaban). CONCLUSIONS: In routine care, edoxaban, rivaroxaban, and apixaban appear to have similar effectiveness and safety in the treatment of VTE.

Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case-control and cohort studies.

BACKGROUND: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. METHODS: We conducted a matched case-control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. RESULTS: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of "probable" or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated "unlikely" in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were "very unlikely". CONCLUSIONS: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.

Utility of a Specific Health Checkup Database Containing Lifestyle Behaviors and Lifestyle Diseases for Employee Health Insurance in Japan.

BACKGROUND: The Japanese Ministry of Health, Labour and Welfare introduced Specific Health Checkups (SHC) to identify individuals at risk of metabolic syndrome (MS). This study aimed to describe the SHC database developed by the Japan Medical Data Center Co., Ltd. (JMDC) as a means of exploring lifestyle behaviors and lifestyle diseases among working generations. METHODS: We conducted a retrospective, cross-sectional study of employees and their families using the JMDC-SHC database to describe the prevalence of lifestyle behaviors (smoking, exercise, dietary habits, drinking habits, and sleeping) and lifestyle diseases (MS, hypertension, dyslipidemia, and diabetes mellitus). Results were compared with data from the 2015 National Health and Nutrition Survey (NHNS) in Japan as a benchmark. RESULTS: All 646,869 enrollees in the JMDC-SHC database were included, of whom 66.5% were men. Age ranged from 40-74 years. Compared with the results of the NHNS, the JMDC-SHC subjects were younger and had fewer MS components and a lower prevalence of diabetes and hypertension. Subjects in their 40s were most likely to have unhealthy lifestyle behaviors in all age groups (eg, smoking: 41.0% in men and 10.2% in women). The SHC group had more favorable behaviors overall, but underweight was more prevalent in the SHC females. CONCLUSIONS: The JMDC-SHC population showed different lifestyle and lifestyle disease profiles to the NHNS population, probably due to its different age, gender, and employment distributions. Development of healthcare policies and plans for working generations would benefit from the selection of an age- and employment-appropriate database.

Development of an electronic medical record-based algorithm to identify patients with Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), severe drug reactions, are often misdiagnosed due to their rarity and lack of information on differential diagnosis. The objective of the study was to develop an electronic medical record (EMR)-based algorithm to identify patients with SJS/TEN for future application in database studies. From the EMRs of a university hospital, two dermatologists identified all 13 patients with SJS/TEN seen at the Department of Dermatology as the case group. Another 1472 patients who visited the Department of Dermatology were identified using the ICD-10 codes for diseases requiring differentiation from SJS/TEN. One hundred of these patients were then randomly sampled as controls. Based on clinical guidelines for SJS/TEN and the experience of the dermatologists, we tested 128 algorithms based on the use of ICD-10 codes, clinical courses for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) of each algorithm were calculated, and the optimal algorithm was defined as that with high PPV and maximal sensitivity and specificity. One algorithm, consisting of a combination of clinical course for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus, but not ICD-10 codes, showed a sensitivity of 76.9%, specificity of 99.0%, PPV of 40.5%, NPV of 99.8%, and DOR of 330.00. We developed a potentially optimized algorithm for identifying SJS/TEN based on clinical practice records. The almost perfect specificity of this algorithm will prevent bias in estimating relative risks of SJS/TEN in database studies. Considering the small sample size, this algorithm should be further tested in different settings.