Use of diagnostic likelihood ratio of outcome to evaluate misclassification bias in the planning of database studies.

BACKGROUND: The diagnostic likelihood ratio (DLR) and its utility are well-known in the field of medical diagnostic testing. However, its use has been limited in the context of an outcome validation study. We considered that wider recognition of the utility of DLR would enhance the practices surrounding database studies. This is particularly timely and important since the use of healthcare-related databases for pharmacoepidemiology research has greatly expanded in recent years. In this paper, we aimed to advance the use of DLR, focusing on the planning of a new database study. METHODS: Theoretical frameworks were developed for an outcome validation study and a comparative cohort database study; these two were combined to form the overall relationship. Graphical presentations based on these relationships were used to examine the implications of validation study results on the planning of a database study. Additionally, novel uses of graphical presentations were explored using some examples. RESULTS: Positive DLR was identified as a pivotal parameter that connects the expected positive-predictive value (PPV) with the disease prevalence in the planned database study, where the positive DLR is equal to sensitivity/(1-specificity). Moreover, positive DLR emerged as a pivotal parameter that links the expected risk ratio with the disease risk of the control group in the planned database study. In one example, graphical presentations based on these relationships provided a transparent and informative summary of multiple validation study results. In another example, the potential use of a graphical presentation was demonstrated in selecting a range of positive DLR values that best represented the relevant validation studies. CONCLUSIONS: Inclusion of the DLR in the results section of a validation study would benefit potential users of the study results. Furthermore, investigators planning a database study can utilize the DLR to their benefit. Wider recognition of the full utility of the DLR in the context of a validation study would contribute meaningfully to the promotion of good practice in planning, conducting, analyzing, and interpreting database studies.

Antidyslipidemic Drug Prescriptions and Lipid Control Status After Unfavorable Annual Health Checkup Results: A Retrospective Cohort Study Using a Health Insurance Database.

BACKGROUND: Japanese employers are obligated to offer employees annual health checkups and guidance programs for their health promotion and maintenance to prevent cardiovascular (CV) and lifestyle-related diseases. Under these programs, checkup recipients are notified of the checkup results, and in case of abnormal findings, employers are expected to provide employees with follow-up encouragement to change their behavior; for example, with medical consultations or lifestyle modifications. However, the effect of these programs on behavioral changes and their subsequent clinical outcomes has not been clearly assessed. OBJECTIVE: The aim of this study was to investigate changes in CV risk management behaviors after receiving unfavorable health checkup results on serum lipid levels among subjects without antidyslipidemic drug prescription and uncontrolled lipid levels and at elevated risk of CV events in a real-world setting. PATIENTS AND METHODS: This retrospective cohort study used a Japanese employment-based health insurance database managed by MinaCare Co., Ltd. This study analyzed the data from the annual health checkups of recipients aged 20-74 years with data on their low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), and triglyceride (TG) values from 2015 to 2017, who had uncontrolled lipid levels based on their checkup results at baseline in 2015, and without prescription records of antidyslipidemic drugs. Lipid status was considered uncontrolled if any of the following were detected: LDL-c ≥ 140 mg/dL, HDL-c < 40 mg/dL, or TG ≥ 150 mg/dL. Changes in antidyslipidemic drug prescription, as a primary CV risk management behavior measure, and in lipid control status in 2016 and 2017 were investigated. Potential factors associated with lipid control were also explored using logistic regression analysis. RESULTS: Among 154,421 subjects without antidyslipidemic drug prescription and with uncontrolled lipid levels in 2015, 93.6% remained without antidyslipidemic drug prescription in both 2016 and 2017. Of these subjects, 76.8% and 76.4% continued having uncontrolled lipid levels in 2016 and 2017, respectively. Fewer subjects without prescription achieved lipid control than those with prescription. Various factors were associated with lipid control, with high LDL-c as the greatest risk factor for uncontrolled lipid levels. CONCLUSIONS: These results suggest that most health checkup recipients may not have changed their behaviors; that is, they may have not sought medical treatment and continued having uncontrolled lipid levels in the years following the unfavorable health checkup results. To encourage subjects to initiate desirable behavioral changes, more practical support may be essential.

Relationship of Annual Health Checkups with the Subject's Subsequent Behavior of Cardiovascular Risk Management in a Real-World Setting in Japan: A Retrospective Cohort Study on Changes in Antihypertensive Drug Prescription and Blood Pressure from 2015 to 2017.

BACKGROUND: In Japan, workers receive a health checkup annually, and based on the results, a follow-up health guidance or intervention is provided when deemed necessary. However, it remains unclear whether the current real-world health checkup and guidance programs in Japan successfully lead to behavioral changes or improvement of clinical outcomes in individuals who require cardiovascular (CV) risk management. OBJECTIVE: This study aimed to explore the association between health checkup and the subsequent behavior change in CV risk management in subjects with uncontrolled blood pressure (BP) without antihypertensive drug prescription, who can have increased risk of CV events. PATIENTS AND METHODS: This was a retrospective cohort study that used health-checkup and claims data from a Japanese healthcare database managed by MinaCare Co., Ltd. Of those aged 20-74 years with available data on systolic and diastolic BP from 2015 to 2017, data from individuals with uncontrolled BP who were not prescribed antihypertensive drugs within 6 months before their baseline health checkup in 2015 were extracted and analyzed. The primary outcome measures were changes in antihypertensive drug prescription and BP control status based on health-checkup results from the baseline year (2015) to 2017. CV risk-management behavior was also assessed using body mass index (BMI) and smoking status, as these are the major modifiable CV risk factors. RESULTS: Among 39,242 subjects with uncontrolled BP without antihypertensive drug prescription at baseline, 88.9% remained without prescription in 2016. Of the subjects without prescription, 62.9% continued to have uncontrolled BP. Both statuses of the major modifiable CV risk factors remained unchanged in 2016: 92.1% of obese subjects (BMI ≥ 25 kg/m2) at baseline remained obese, and 93.8% of smokers at baseline aged ≥ 40 years continued to smoke. Logistic regression analysis revealed that age 60-69 years (vs. 40-49 years), hypertension (HT) stage II (vs. stage I), HT stage III (vs. stage I), and BMI ≥ 25.0 kg/m2 (vs. < 25.0 kg/m2) were factors associated with uncontrolled BP in 2016 (subsequent year), regardless of antihypertensive drug prescription. CONCLUSIONS: Untreated HT for years increases the risk of CV events. These results suggest that current health-checkup and guidance programs are inadequately effective for behavioral change. Further practices for committing to lifestyle modifications and seeking medical advice based on their health-checkup results need to be undertaken to improve health behavior.

Validation of novel identification algorithms for major adverse cardiovascular events in a Japanese claims database.

Predicting clinical outcomes can be difficult, particularly for life-threatening events with a low incidence that require numerous clinical cases. Our aim was to develop and validate novel algorithms to identify major adverse cardiovascular events (MACEs) from claims databases. We developed algorithms based on the data available in the claims database International Classification of Diseases, Tenth Revision (ICD-10), drug prescriptions, and medical procedures. We also employed data from the claims database of Jichi Medical University Hospital, Japan, for the period between October 2012 and September 2014. In total, we randomly extracted 100 potential acute myocardial infarction cases and 200 potential stroke cases (ischemic and hemorrhagic stroke were analyzed separately) based on ICD-10 diagnosis. An independent committee reviewed the corresponding clinical data to provide definitive diagnoses for the extracted cases. We then assessed the algorithms' accuracy using positive predictive values (PPVs) and apparent sensitivities. The PPVs of acute myocardial infarction, ischemic stroke, and hemorrhagic stroke were low only by diagnosis (81.6% [95% CI 72.5-88.7]; 31.0% [95% CI 22.8-40.3]; and 45.5% [95% CI 34.1-57.2], respectively); however, the PPVs were elevated after adding the prescription and procedure data (87.0% [95% CI 78.3-93.1]; 44.4% [95% CI 32.7-56.6]; and 46.1% [95% CI 34.5-57.9], respectively). When we added event-specific prescription and procedure data to the algorithms, the PPVs for each event increased to 70%-98%, with apparent sensitivities exceeding 50%. Algorithms that rely on ICD-10 diagnosis in combination with data on specific drugs and medical procedures appear to be valid for identifying MACEs in Japanese claims databases.

A Retrospective, Cross-Sectional Study on the Prevalence of Hyperuricemia Using a Japanese Healthcare Database.

OBJECTIVES: This study aims to evaluate the prevalence of hyperuricemia (HU) considering both serum uric acid (SUA) levels and medication status of urate-lowering drugs (ULDs), and the association between HU and its comorbidities using a Japanese healthcare database. MATERIALS AND METHODS: The study population consisted of 60,828 subjects who had at least one serum uric acid measurement between the fiscal years (FYs) 2010 and 2014 in a Japanese employment-based health insurance database (MinaCare Co., Ltd., Tokyo, Japan), which includes mutually linked medical/pharmaceutical claims data and health check-up data. Hyperuricemia was defined as a SUA level >7.0 mg/dL of the health check-up data and/or a prescription for a ULD. The association between HU and comorbidities were analyzed by comparing the prevalence of HU of each subgroup defined by presence or absence of comorbidity. RESULTS: The prevalence of HU in FY 2014 was 26.8% [95% confidence interval (CI): 26.2 to 27.3%] in male subjects and 0.9% (95% CI: 0.7 to 1.0%) in female subjects. According to the analyses by sex and age, a trend of increasing prevalence with age was observed in both males and females. The prevalence of HU remained stable both in males and females from FYs 2010 to 2014. The positive association between HU and well-known comorbidities were confirmed with the exception of diabetes mellitus and smoking status in male subjects. CONCLUSION: Our results provided a more accurate prevalence of HU in Japanese population. It is important to increase the awareness on HU in the society to reduce the burden of HU-related diseases.

Changes in Prescription of Psychotropic Drugs After Introduction of Polypharmacy Reduction Policy in Japan Based on a Large-Scale Claims Database.

BACKGROUND AND OBJECTIVES: In Japan, polypharmacy reduction policy, which reduces the reimbursement of medical cost, was introduced to address unnecessary psychotropic polypharmacy. The rule was applied to the prescriptions of three or more anxiolytics or three or more hypnotics in the policy introduced in 2012. The prescriptions of four or more antidepressants or four or more antipsychotics were added to the rule in the policy revised in 2014. Furthermore, the prescriptions of three or more drugs of anxiolytics, hypnotics, antidepressants, or antipsychotics were subject to the reduction criteria of the policy revision in 2016. Benzodiazepine receptor agonists (BZs) are classified both into anxiolytics and hypnotics, and the reduction rule was not applied to the category of BZs before April 2018. This study aimed to examine the effect of the policy on the prescriptions of four drug categories as well as BZs from the point of view of the number of drugs and doses. METHODS: This was a retrospective observational study using a large-scale Japanese health insurance claims database. Patients who were prescribed at least one psychotropic drug (anxiolytic, hypnotic, antidepressant, or antipsychotic) during the study period (from April 2011 to March 2017) were selected. Segmented regression analysis was used to analyze the proportions of patients with three or more or four or more drugs as well as patients above clinically recommended doses, and the means of the average daily doses by drug category. RESULTS: A total of 312,167 patients were identified as a study population. The proportions of patients with three or more drugs in anxiolytics, hypnotics, antidepressants, and antipsychotics significantly decreased after the introduction or revisions of the policy, but not BZs. The proportions of patients with three or more drugs in March 2017 were 0.9%, 2.0%, 1.2%, 2.4%, and 8.9% in anxiolytics, hypnotics, antidepressants, antipsychotics, and BZs, respectively. The effect of the policy in reducing the proportions of patients above clinically recommended doses was identified in antipsychotics after the revision in 2016, but not identified in the sum of anxiolytics and hypnotics as well as BZs after the revision in 2014, and antidepressants after the revision in 2016. The proportions of monotherapy were increased from April 2011 to March 2017 only for antidepressants (76.9% → 80.8%) and antipsychotics (79.8% → 82.1%), and not changed or decreased for anxiolytics (85.2% → 85.7%), hypnotics (78.6% → 77.6%), sum of anxiolytics and hypnotics (68.1% → 65.7%), BZs (68.0% → 67.3%), and sum of psychotropic drugs (52.1% → 49.9%). CONCLUSIONS: The polypharmacy reduction policy reduced the proportions of patients with three or more drugs in four drug categories, but not BZs. Only limited effects were seen for reducing the proportions of patients above clinically recommended doses. The policy was revised in April 2018 again. Further investigation is needed to examine the effect of the revision in 2018.

Database Analysis of Eplerenone Use in Japanese Hypertensive Patients in Clinical Practice.

Eplerenone, a mineralocorticoid receptor antagonist (MRA), is available in Japan, but details of its use in clinical settings have not been thoroughly investigated. Thus, this study was aimed at examining the characteristics of eplerenone-prescribed hypertensive patients in Japan, describing the combination patterns of antihypertensive medications, and comparing eplerenone's mean doses with respect to concomitant diseases. Data of 160,992 hypertensive patients who used the same drugs for six months or more were collected from an insurance database from January 1, 2009, to December 31, 2013. The number of MRA-receiving patients among the extracted population was 3,274 (2%). Compared to patients on eplerenone or spironolactone, patients on neither drug had fewer comorbidities. Eplerenone was administered in combination with calcium channel blockers and angiotensin II receptor blockers in 23.1% and as monotherapy in 6.6% of cases. The most frequent initial daily dose of eplerenone was 50 mg/day followed by 25 mg/day irrespective of the presence of a comorbidity. MRA use was as low as 2%, but its use was more frequent in patients with comorbidities compared to that of other antihypertensives. Despite studies showing eplerenone's efficacy and safety in high-risk hypertensive patients with albuminuria, the drug is not widely used.

Investigation of the properties of the "switching decision rule" described in the Japanese guideline for human bioequivalence studies.

In a human bioequivalence (BE) study, the conclusion of BE is usually based on the ratio of geometric means of pharmacokinetic parameters between a test and a reference products. The "Guideline for Bioequivalence Studies of Generic Products" (2012) issued by the Japanese health authority and other similar guidelines across the world require a 90% confidence interval (CI) of the ratio to fall entirely within the range of 0.8 to 1.25 for the conclusion of BE. If prerequisite conditions are satisfied, the Japanese guideline provides for a secondary BE criterion that requires the point estimate of the ratio to fall within the range of 0.9 to 1.11. We investigated the statistical properties of the "switching decision rule" wherein the secondary criterion is applied only when the CI criterion fails. The behavior of the switching decision rule differed from either of its component criteria and displayed an apparent type I error rate inflation when the prerequisite conditions were not considered. The degree of inflation became greater as the true variability increased in comparison to the assumed variability used in the sample size calculation. To our knowledge, this is the first report in which the overall behavior of the combination of the two component criteria was investigated. The implications of the in vitro tests on human BE and the accuracy of the intra-subject variability have impacts on appropriate planning and interpretation of BE studies utilizing the switching decision rule.

A retrospective, cross-sectional study of real-world values of cardiovascular risk factors using a healthcare database in Japan.

BACKGROUND: Data collected by the Japanese Ministry of Health, Labour and Welfare (MHLW), namely data from the Specific Health Checkups and Specific Health Guidance (MHLW-SH) and the National Health and Nutrition Survey (MHLW-H&N) allow assessment of blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) in Japan. Recently, a large database of employment-based health insurance has been developed by MinaCare Co. Ltd. METHODS: A retrospective, cross-sectional study using the Japanese healthcare checkup database developed by MinaCare Co. Ltd. was designed to investigate the distribution of real-world values of BP, LDL-C, and HbA1c in Japan. Data in the MinaCare database were also compared with those in the two national data sources to assess the extent to which the health status in Japan is reflected in each data source. RESULTS: Of the healthcare checkup results of 232515 subjects in the 2011 MinaCare database, 49.9% were male and 50.1% were female. The age of the subjects ranged from < 20 to > 70 years. The proportion of subjects with systolic BP (SBP) ≥ 140 mmHg, LDL-C ≥ 140 mg/dL, and HbA1c ≥ 6.1% generally increased with increasing age. If one focused on the upper-end age group representing the majority of the MinaCare study population (i.e. age range, 55-59 years), the proportions of subjects with SBP ≥ 140 mmHg, LDL-C ≥ 140 mg/dL, and HbA1c ≥ 6.1% were 19.0%/12.2% (males/females), 27.2%/42.7%, and 13.5%/5.4%, respectively. The MinaCare database was mostly comparable with the two national data sources; however, some notable differences in BP and lipid parameters were found between MHLW-H&N and the other two data sources. CONCLUSIONS: Analysis of the MinaCare database indicated that a substantial proportion of subjects did not achieve the target BP, LDL-C, and HbA1c levels to reduce the risk of future cardiovascular and cerebrovascular disease events. The results were generally consistent with those of the national data sources. Considering its characteristics of low selection bias, large sample size, wide age distribution, and high flexibility in analysis of subject-level data, the MinaCare database is highly valuable for studying the health status of the population covered by employment-based health insurance.

A 10-month, open-label evaluation of desvenlafaxine in Japanese outpatients with major depressive disorder.

The objective of this study was to evaluate the long-term safety of desvenlafaxine for continuation treatment of major depressive disorder (MDD) in Japanese patients. This was a phase 3, multicenter, 10-month, open-label study with flexible dosing of desvenlafaxine (25, 50, 100 mg/day). Japanese patients with MDD who had completed an 8-week, double-blind, placebo-controlled study in which patients received 25 or 50 mg/day desvenlafaxine or placebo were enrolled. In this study, patients received desvenlafaxine 25 mg/day from days 1 to 14, with subsequent upward titration, to a maximum of 100 mg/day, determined by clinical response. Of 304 patients, 75 (24.7%) discontinued during the on-therapy period; patient request was the most common reason (11.5%). Treatment-emergent adverse events were reported by 240 patients (78.9%) during the on-therapy period; the most common adverse events were nasopharyngitis (37.2%), somnolence (11.5%), headache (10.5%), and nausea (10.2%). For the ITT-LOCF population, the mean change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score was -4.76 (95% confidence interval: -5.47 to -4.05); continued numerical improvements in the HAM-D17 total scores and other depression outcome measures were observed irrespective of treatment in the previous study. Long-term use of desvenlafaxine was safe and well tolerated, with a clinical benefit/risk profile similar to that in other populations.