Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET® in Japan: a new-user cohort study.

BACKGROUND: In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function. METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group). RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period. CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.

Real-world prescription of anti-COVID-19 drugs in hospitalized patients with COVID-19 in Japan.

OBJECTIVE: Prescription trends and patterns of anti-COVID-19 drugs in hospitalized patients were examined based on real world data to understand the use of anti-COVID-19 drugs in clinical practice in Japan. DESIGN: The longitudinal and cross-sectional study was conducted utilizing data from January 1, 2019 to December 31, 2021 of the MID-NET® medical information database, which stored the electronic medical records, administrative claim data, and diagnosis procedure combination data of patients in Japan. PARTICIPANTS: Hospitalized patients with a COVID-19-related diagnosis who received at least one anti-COVID-19 drug between April 1, 2020 and December 31, 2021. EXPOSURES: The following 14 drugs were included in this study: remdesivir, baricitinib, combination product of casirivimab and imdevimab, favipiravir, dexamethasone, ivermectin, azithromycin, nafamostat mesylate, camostat mesylate, ciclesonide, tocilizumab, sarilumab, combination product of lopinavir and ritonavir, and hydroxychloroquine. RESULTS: We identified 5,717 patients hospitalized with COVID-19 and prescribed at least one anti-COVID-19 drug. The entire cohort generally included patients over 41-50 years and more males. The most common prescription pattern was dexamethasone monotherapy (22.9%), followed by the concomitant use of remdesivir and dexamethasone (15.0%), azithromycin monotherapy (15.0%), remdesivir monotherapy (10.2%), and nafamostat mesylate monotherapy (8.5%). However, an often prescribed anti-COVID-19 drug differed depending on the period. CONCLUSIONS AND RELEVANCE: This study revealed the real-world situation of anti-COVID-19 drug prescriptions in hospitalized COVID-19 patients in Japan. A prescribed drug would depend on the latest scientific evidence, such as efficacy, safety, and approval status, at the time of prescription. Understanding the prescription of anti-COVID-19 drugs will be important for providing the most up-to-date treatments to patients and evaluating the benefit and/or risk of anti-COVID-19 drugs based on the utilization of an electronic medical record database.

Dealing with missing data in laboratory test results used as a baseline covariate: results of multi-hospital cohort studies utilizing a database system contributing to MID-NET® in Japan.

BACKGROUND: To evaluate missing data methods applied to laboratory test results used for confounding adjustment, utilizing data from 10 MID-NET®-collaborative hospitals. METHODS: Using two scenarios, five methods dealing with missing laboratory test results were applied, including three missing data methods (single regression imputation (SRI), multiple imputation (MI), and inverse probability weighted (IPW) method). We compared the point estimates of adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) between the five methods. Hospital variability in missing data was considered using the hospital-specific approach and overall approach. Confounding adjustment methods were propensity score (PS) weighting, PS matching, and regression adjustment. RESULTS: In Scenario 1, the risk of diabetes due to second-generation antipsychotics was compared with that due to first-generation antipsychotics. The aHR adjusted by PS weighting using SRI, MI, and IPW by the hospital-specific-approach was 0.61 [95%CI, 0.39-0.96], 0.63 [95%CI, 0.42-0.93], and 0.76 [95%CI, 0.46-1.25], respectively. In Scenario 2, the risk of liver injuries due to rosuvastatin was compared with that due to atorvastatin. Although PS matching largely contributed to differences in aHRs between methods, PS weighting provided no substantial difference in point estimates of aHRs between SRI and MI, similar to Scenario 1. The results of SRI and MI in both scenarios showed no considerable changes, even upon changing the approaches considering hospital variations. CONCLUSIONS: SRI and MI provide similar point estimates of aHR. Two approaches considering hospital variations did not markedly affect the results. Adjustment by PS matching should be used carefully.

Characteristics of hospital differences in missing of clinical laboratory test results in a multi-hospital observational database contributing to MID-NET® in Japan.

BACKGROUND: In Japan, a multiple-hospital observational database system, the Medical Information Database Network (MID-NET®), was launched for post-marketing drug safety assessments. These assessments will be based on datasets with missing laboratory results. The characteristics of missing data considering hospital differences have not been evaluated. We assessed the missing proportion and the association between missingness and a factor through case studies using a database system, a part of MID-NET®. METHODS: Seven scenarios using laboratory results before the prescription of the assessed drug as baseline covariates and data from 10 hospitals of Tokushukai Medical Group were used. The missing proportion and the association between missingness and patient background were investigated per hospital. The associations were assessed using the log of adjusted odds ratio (log-aOR). Additionally, an ad hoc survey was conducted to explore other factors affecting the missingness. RESULTS: For some laboratory tests, missing proportions varied among hospitals, such as 7.4-44.4% of alkaline phosphatase (ALP) and 8.1-31.2% of triglyceride (TG) among statin users. The association between missingness and affecting factors also differed among hospitals for some factors; example, the log-aOR of hospitalization associated with missingness of TG was - 0.41 (95% CI, - 1.06 to 0.24) in hospital 3 and 1.84 (95% CI, 1.34 to 2.34) in hospital 4. In the ad hoc survey focusing on ALP, hospital-dependent differences in the ordering system settings were observed. CONCLUSIONS: Hospital differences in missing data appeared in some laboratory tests in our multi-hospital observational database, which could be attributed to the affecting factors, including the patient background.

Cardiovascular risks associated with dipeptidyl peptidase-4 inhibitors monotherapy compared with other antidiabetes drugs in the Japanese population: A nationwide cohort study.

PURPOSE: We evaluated the cardiovascular risk associated with dipeptidyl peptidase-4 inhibitors (DPP-4Is) as monotherapy compared with other antidiabetic drugs in Japan. METHODS: We conducted a nationwide cohort study involving 2 716 000 diabetes patients in Japan. New users of any antidiabetic drug as monotherapy between 1 April 2010 and 31 October 2014 were identified. Occurrences of myocardial infarction (MI), heart failure (HF), and stroke requiring hospitalization associated with DPP-4Is were compared with those associated with biguanides (BGs), sulfonylureas (SUs), or α-glucosidase inhibitors (α-GIs). Adjusted hazard ratios (aHRs) for these outcomes were estimated by Cox proportional hazards model. Propensity score standardization was used to control for confounding. RESULTS: We identified 1 105 103 patients using DPP-4Is, 278 280 patients using BGs, 273 449 patients using SUs, and 217 026 patients using α-GIs. The risks of MI and HF for DPP-4I users were significantly higher than those for BG users (MI: aHR, 1.48 [95%CI, 1.20-1.82], HF: aHR, 1.46 [95%CI, 1.31-1.62]), while significantly lower than those for SU users (MI: aHR, 0.84 [95%CI, 0.72-0.98], HF: aHR, 0.86 [95%CI, 0.81-0.92]). The risk of MI for DPP-4I users was similar to that for α-GI users, while the risk of HF for DPP-4I users was slightly higher than for α-GI users (MI: aHR, 0.98 [95%CI, 0.82-1.17], HF: aHR, 1.12[95%CI, 1.04-1.21]). CONCLUSIONS: Risk of MI and HF requiring hospitalization associated with DPP-4Is as monotherapy was significantly higher than BGs, significantly lower than SUs, and similar to α-GIs.