Pharmacoepidemiology and Drug Safety最新文献

Purpose: Japanese traditional (Kampo) medicines containing ephedra are used to relieve symptoms of the common cold during pregnancy. The risks associated with perinatal outcomes, however, remain unclear. Thus, we evaluated the risk of adverse perinatal outcomes associated with the use of Kampo medicines containing ephedra during pregnancy using data from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study).

Methods: Questionnaires were distributed to pregnant women who participated in the TMM BirThree Cohort Study at approximately weeks 12 and 26 of pregnancy. Adverse perinatal outcomes in women who used Kampo medicines containing ephedra or acetaminophen during pregnancy were assessed. Odds ratios (ORs) were estimated using weighted logistic regression analyses.

Results: Among 20 083 pregnant women, acetaminophen and Kampo medicines containing ephedra were used by 5.3% and 3.5% of women, respectively. The OR for caesarean section was 0.95 (95% confidence interval [CI], 0.75-1.20), for preterm birth (PTB) was0.99 (95% CI, 0.63-1.55), for low birth weight (LBW) was 1.04 (95% CI, 0.72-1.49), for small for gestational age (SGA) was 0.98 (95% CI, 0.58-1.65), and for low Apgar scores at 5 min was 0.85 (95% CI, 0.25-2.93) in the women who used Kampo medicines containing ephedra during pregnancy.

Conclusions: No statistically significant association was seen between the use of Kampo medicines containing ephedra during pregnancy and an increased risk of needing a caesarean section, PTB, LBW, SGA, or low Apgar scores. Although further research is needed, this study may assist in clinical decision-making.

Background: Inverse probability weighting (IPW) is a widely used method to estimate the causal effect of treatment from observational data. However, it can be unstable when extreme propensity score (PS) values lead to very large weights. Overlap weights (OW), which emphasize subjects in areas of covariate overlap, reduce the influence of extreme PS without excluding participants. While the OW method has shown strong performance in simulations with continuous outcomes, its utility in binary outcome settings-common in health research-has not been thoroughly evaluated.

Methods: We conducted simulation studies to evaluate the performance of OW in comparison to other PS weighting methods including IPW, trimmed IPW, and matching weights, in settings with extreme PS values and a binary outcome. Using simulated datasets with varying degrees of PS overlap and treatment prevalence, we assessed covariate balance and treatment effect estimation performance. The performance of the PS weighting methods was further illustrated through an application to data from a study on pancreatic ductal adenocarcinoma.

Results: In simulation studies, IPW's performance deteriorated markedly as the overlap in the covariate distribution decreased. In contrast, OW achieved exact covariate balance and consistently showed the highest efficiency among all methods evaluated. In the application to real-world data characterized by low treatment prevalence and substantial covariate imbalance, OW also outperformed the other methods in terms of both standard error and covariate balance.

Conclusion: These findings suggest superior performance of OW in terms of covariate balance and estimation efficiency in settings with extreme PS and a binary outcome.

Purpose: Self-medication carries the potential for significant adverse events when practiced irresponsibly. The indiscriminate use of medicines notably intensified during the COVID-19 pandemic. This study aimed to investigate the epidemiological profile of exogenous intoxications due to self-medication among Brazilians from 2014 to 2023.

Methods: This was a cross-sectional, descriptive, and exploratory study utilizing secondary data from the Brazilian Ministry of Health's Notifiable Diseases Information System. Confirmed cases of self-medication intoxication reported between 2014 and 2023 were included. Descriptive analysis, incidence and lethality rate calculations, chi-squared tests (p ≤ 0.05), and Multiple Correspondence Analysis (MCA) were performed to explore potential associations between sociodemographic and clinical variables.

Results: A total of 23 859 cases were analyzed. The study observed a predominance of adults (20-59 years), women (70.8%), and individuals self-identifying as White or Brown (mixed-race). Most cases resulted from an acute-single exposure to the medication and resolved with complete recovery without sequelae. There was a national increase in incidence, particularly in 2022 and 2023, and significant variations among Brazilian Federative Units. The MCA identified associations between advanced age and the type of exposure (repeated or chronic) and the severity of outcomes. It also revealed changes in the sociodemographic profile of self-medication intoxications during the COVID-19 pandemic.

Conclusions: These findings underscore the pandemic's impact on self-medication patterns and intoxication notifications. The study highlights the need for public policies focused on health education, appropriate medicine use, and strengthening the culture of reporting in Brazil.

Background: Despite testing of epidemiological methods in US Claims databases for signal detection, such data sources have not become a routine capability. The Self Controlled Case Series (SCCS) is one of the most promising methods for drug safety signal detection using Real World Data, and incorporating active comparators could potentially improve its performance by addressing confounding by indication.

Objectives: This study aims to evaluate the performance of the SCCS with and without active comparators for signal detection using US Merative MarketScan Commercial Claims and Medicare databases.

Methods: We applied the SCCS to macrolide and fluoroquinolone antibiotics, using amoxicillin and cefalexin as active comparators. In total, 7 drugs and 30 outcomes from all organ classes were selected. We developed a reference set of 104 positive controls and 58 negative controls, using a taxonomy framework to ensure the selected drug outcome pairs are theoretically well suited to the SCCS design. A two-year observation period with a 30-day risk window after each dispensing was used. Diagnostic performance was measured using sensitivity and specificity with respect to the product labels.

Results: The SCCS without active comparators achieved sensitivities of 0.73 and 0.72 and specificities of 0.68 and 0.62 in commercial and Medicare claims, respectively, for pairs with sufficient power. Active comparators increased specificity up to 0.84 and 0.86, respectively, in Commercial Claims and Medicare but decreased sensitivity to 0.45 and 0.36.

Conclusions: MarketScan databases are potentially suitable for drug safety signal detection due to their large size and information contained. Using a carefully designed reference set of drug-outcome pairs well suited to the study design, the SCCS, while imperfect, performed comparably to optimal settings identified in previously published studies. Active comparators did not enhance overall performance but showed improved specificity by better controlling confounding by indication at the cost of reduced sensitivity.

Purpose: Combined oral contraceptives (COCs) are contraindicated in migraine with aura due to stroke risk, and some hormone therapy for menopause guidelines recommend caution in this population. However, this guidance is informed by sparse or older evidence reflective of higher doses than typically prescribed today. This study aimed to describe modern-day utilization of COCs and hormone therapy among female individuals with migraine with aura from 2000 to 2024.

Methods: Using United Kingdom medical record data, this study evaluated the use of COCs and progestogen-only pills (POPs) among reproductive-age individuals and hormone therapy among post-reproductive age individuals, before and after migraine with aura diagnosis. Post-diagnosis medication utilization was described relative to baseline characteristics and pre-diagnosis use of each medication, overall and longitudinally.

Results: Among 142 867 individuals of reproductive age, 84 374 (59%) used oral contraceptives on or after migraine with aura diagnosis, predominantly POPs (n = 75 823, 53% of those with any oral contraceptive) over COCs (n = 21 968, 15%). Most oral contraceptive users in the year pre-diagnosis used COCs (n = 36 909/56760, 66%). Among 46 913 individuals of post-reproductive age, 20 990 (45%) had a prescription for hormone therapy after migraine with aura diagnosis, with transdermal formulations used increasingly over calendar time.

Conclusions: Utilization of COCs declined but did not fully cease after migraine with aura diagnosis. Post-diagnosis utilization of hormone therapy for menopause was common. Given this utilization among individuals with migraine with aura, high-quality evidence quantifying the risk of stroke associated with modern-day use of these medications in this population is needed to inform patient and provider decision making.

Purpose: Pharmacotherapy during pregnancy should be approached with caution due to the potential risk of adverse effects, including birth defects, in the fetus. Appropriate post-marketing surveillance and perinatal pharmacoepidemiology are essential to ensure the safety of pharmacotherapy during pregnancy. However, due to limited research infrastructure in pharmacoepidemiology, collecting reliable data on drug safety in pregnant women and infants remains a challenge in Japan. Thus, we examined the suitability (fitness for purpose) of Japanese medical databases for perinatal studies to establish infrastructure in this field.

Methods: We assessed seven available databases in Japan: the DeSC database, EBM provider, Japanese Adverse Drug Event Report database, JMDC claims database, MDV analyzer, the National Database of Health Insurance Claims, and Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). To assess the quality of databases for maternal studies, we evaluated the content of each mother-infant linkable database based on the core data elements recommended for perinatal pharmacoepidemiology.

Results: Three of the databases were found to be mother-infant linkable: the DeSC database, JMDC claims database, and the TMM BirThree Cohort Study. The coverage of core data elements in perinatal pharmacoepidemiology was 73.5% in the DeSC and JMDC claims databases and 92.9% in the TMM BirThree Cohort Study.

Conclusion: Some representative medical databases in Japan are well suited for use in perinatal pharmacoepidemiologic research on infant outcomes.

Key changes in the pharmacoepidemiological research environment had a significant influence on the activities of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) over the last decade. These changes included the SARS-CoV-2 pandemic, the increased access to anonymized real-world data (RWD) sources, the integration of real-world evidence (RWE) into regulatory and public health decision-making, and the emergence of new technologies and methods. This paper describes how ENCePP has evolved in this changing environment to strengthen pharmacoepidemiological methods and practice in Europe and globally. It also provides future perspectives for the network. Through a collaborative approach in non-interventional research, ENCePP will collectively continue to promote excellence for RWE generation, supporting the safe and effective use of medicines.

Background: The self controlled case series (SCCS) is one of the most promising methods for drug safety signal detection using real world data (RWD), and incorporating active comparators could potentially improve its performance by addressing time-varying confounding by indication. The 'Système National des Données de Santé' (SNDS) is a large nationwide administrative claims database, which has not been used extensively for drug safety signal detection. While comparable in size to other RWD sources, it is unclear to what extent the performance of SCCS correlates with that in other sources.

Objectives: This study aims to evaluate the performance of the SCCS with and without active comparators for signal detection in the French administrative healthcare database SNDS.

Methods: We applied the SCCS to macrolide and fluoroquinolone antibiotics, using amoxicillin as the active comparator. Amoxicillin was chosen as an active comparator with similar indications. In total, 7 drugs and 30 outcomes from all organ classes were selected. We developed a reference set of 104 positive controls and 58 negative controls, using a taxonomy framework to ensure the selected drug outcome pairs are theoretically well suited to the SCCS design. The observation period lasted 2 years, with a 30-day risk window after each dispensing. Diagnostic performance was measured using sensitivity and specificity with respect to the product labels.

Results: The sensitivity and specificity of the SCCS without active comparator were 0.89 and 0.43, respectively, when limited to pairs with satisfactory power. Specificity increased up to 0.91 with active comparators; however, sensitivity decreased to 0.52.

Conclusions: The SNDS is a useful data source for signal detection, particularly for outcomes captured in hospitals. Using a carefully designed reference set of drug-outcome pairs well suited to the study design, the SCCS achieved satisfactory performance for signal detection in this database. In this study, the use of active comparators improved overall performance at the expense of greatly reduced sensitivity.

Purpose: This study aims to compare the effectiveness and safety of standard and reduced initial doses of regorafenib in patients with metastatic colorectal cancer (mCRC).

Materials and methods: This retrospective observational study was conducted using the Taipei Medical University Clinical Research Database. Patients aged 20 years or older who received regorafenib for mCRC between January 2014 and December 2021 were included. Patients were divided into standard initial dose (160 mg) and reduced initial dose (< 160 mg) groups. Time-to-treatment discontinuation (TTD), overall survival (OS), and the incidence of five common adverse events were compared between groups.

Results: Among 266 patients, 58 received the standard initial dose and 208 received the reduced initial dose; the median TTD was 68.0 days and 64.5 days, respectively (p = 0.25). The median OS was 9.7 months for the standard-dose group and 6.7 months for the reduced-dose group (p = 0.01). In the multivariate Cox analysis, the reduced initial dose was associated with shorter survival (hazard ratio 1.66 [95% confidence interval 1.22-2.30]). Hand-foot skin reaction and total bilirubin elevation were less common in the reduced-dose group (p = 0.01 and 0.03, respectively). Excluding concurrent anti-cancer drug users led to a similar median OS between the two dosing groups (p = 0.12).

Conclusion: No difference in TTD was observed between the dosing groups. The reduced-dose group had a shorter OS but fewer adverse events. For patients who can tolerate standard doses of regorafenib, a combination of regorafenib and other anti-cancer drugs may be beneficial but would require further investigation.

Purpose: Leukotriene receptor antagonists (LTRAs) are widely prescribed as controller medications for pediatric asthma. However, there have been increasing concerns about potential neuropsychiatric adverse reactions associated with LTRAs. Findings from observational studies have been inconsistent, and direct comparisons of the risk of neuropsychiatric events (NPEs) between LTRAs and inhaled corticosteroids (ICS) remain limited in the pediatric population.

Methods: A retrospective cohort study was conducted utilizing a nationwide claims database (January 2018-April 2022) and a multicenter electronic health record (EHR) database (January 2006-March 2022) from South Korea. Patients aged 5-18 years diagnosed with asthma before initiating LTRA or ICS were included. The primary outcome was NPEs within 90 days of exposure, defined using two methods: diagnostic code-based analysis and natural language processing (NLP)-based analysis using clinical notes. After propensity score stratification, Cox proportional hazards models were used to estimate risks.

Results: The diagnostic code-based analysis on the claims database included 169 636 LTRA users and 28 845 ICS users. There was no statistically significant difference in the risk of NPEs between LTRA and ICS (calibrated hazard ratios [HRs], 1.14 [95% CI, 0.92-1.42]). In the NLP-based analysis using EHR database, 1641 LTRA users and 1607 ICS users were included. The results were consistent with those of the diagnostic code-based analysis (calibrated HR, 1.33 [95% CI, 0.66-2.68]).

Conclusions: LTRA use was not found to be associated with a significantly increased risk of NPEs in children with asthma. These findings offer valuable insights to support clinical decision-making in pediatric asthma treatment.