Pharmacoepidemiology and Drug Safety最新文献

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.

Purpose: The use of common data models (CDMs) is increasing; however, the complexity of many CDM frameworks constitutes a barrier for their use. For many local and collaborative use cases, simpler CDMs can suffice. Here, we propose the EpiCore CDM, a simple CDM framework for use in Scandinavian pharmacoepidemiological studies.

Methods: The EpiCore CDM was developed based on a set of guiding principles. It should (i) accommodate the most common elements of typical data sources in the field and region, (ii) be accessible to users without needing advanced technical expertise or database infrastructure, (iii) prioritize structural and syntactic harmonization of data and defer clinical concept mapping to the analytical phase, (iv) be usable in both collaborative and single site settings, and (v) include support for quality control procedures.

Results: The EpiCore CDM comprises two mandatory administrative tables (person and observation), six optional event tables (diagnosis, procedure, encounter, drug, primcare, and cancer) and three optional lookup tables (drug_info, organisation_info, and prescriber_info). Each table, along with its columns and constraints is specified according to an EpiCore CDM specification template. This provides easy documentation and integrates with an R-package called EpiCoreAssistant, which provides quality control tools for testing the compliance of a CDM instance with the EpiCore specification. In the event that a project requires customization of the CDM, this is easily implemented in the template and testing. A step-by-step description is presented, demonstrating the steps involved in a typical CDM-based collaborative pharmacoepidemiological study using the EpiCore CDM.

Conclusions: We present the EpiCore CDM, a specification template and an R package that offers a simple framework for improved workflows, standardizations and collaboration, focused on Scandinavian pharmacoepidemiological studies and with relevance for a broad palette of register-based health care researchers.

Purpose: To study the effect of tricyclic antidepressant (TCA)/selective serotonin-norepinephrine reuptake inhibitor (SNRI) versus selective serotonin reuptake inhibitor (SSRI) on the risk of urinary tract infection (UTI) among people with multiple sclerosis (MS).

Methods: A case-control study was conducted using data from the UK Clinical Practice Research Datalink Aurum, nested within a cohort of people with MS. Each person with a UTI was matched to ≤ 4 controls on sex, region, age (±2 years), and time since MS diagnosis (±20%). Conditional logistic regression analyses were conducted to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs) to compare TCA/SNRI to SSRI use and each antidepressant group to no antidepressant use. ORs were adjusted for smoking status, BMI, comorbidities, and recent drug prescriptions.

Results: Two thousand six hundred and sixty-four cases were matched to 3722 controls. TCA/SNRI versus SSRI use did not increase the risk of UTI (conditional aOR 1.21 [95% CI: 0.84-1.75]). TCA/SNRI use versus no antidepressant use did show an increased risk (conditional aOR [95% CI: 1.43 [1.21-1.69]), but SSRI versus no use did not (conditional aOR 1.15 [0.96-1.37]).

Conclusions: This study showed no increased risk of UTI for TCA/SNRI versus SSRI use among people with MS. However, effect estimates were imprecise due to small sample sizes.

Purpose: Observational comparative studies can be analyzed using intention-to-treat (ITT) (i.e., initial-treatment) or as-treated (AT) (i.e., per-protocol) approaches to estimate distinct treatment effects. Unfortunately, AT analyses have an increased vulnerability to selection bias from informative censoring. While methods for informative censoring adjustment are well established, the nuances of their implementation are less well documented.

Methods: We compared marginal hazard ratios for all-cause mortality from ITT and AT analyses comparing new users of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in the clinical practice research datalink from 2019 to 2022 using inverse probability of treatment weights. We created inverse probability of censoring weights (IPCW) using (A) non-lagged and (B) lagged models to adjust for informative censoring in the AT analyses. We replicated analyses comparing acetylcholinesterase inhibitor and angiotensin receptor blocker initiators to assess the impact of IPCW in a different context.

Results: We identified 335 469 SSRI initiators and 24 318 SNRI initiators. While AT estimates (HR: 1.50, 95% CI: 1.30-1.74) were further from the null than ITT estimates (HR: 1.22, 95% CI: 1.12-1.32), applying IPCW attenuated AT estimates using both lagged and non-lagged models (lagged HR: 1.24, 95% CI: 1.08-1.44; non-lagged HR: 1.16, 95% CI: 1.00-1.33). In the 337 981 antihypertensive initiators, however, IPCW did not influence AT estimates.

Conclusions: Younger patients were more likely to discontinue SSRIs than SNRIs, resulting in biased AT estimates closer to estimates in older patients. IPCW attenuated this bias, highlighting the utility of weighting when censoring is linked to patient characteristics.

Objective: The COVID-19 pandemic caused disruptions in in-person mental health (MH) care and a rapid uptake of virtual MH care, but there is little research on the impacts of this on patients' ability to continue their MH medications. This study used population-level data to examine the impact of the pandemic on MH medication nonadherence.

Methods: This retrospective study used electronic health record and claims data to identify 149,977 patients with MH diagnoses at three U.S. health systems who filled at least one MH medication in the 9 months before and after 3/14/2020. The primary outcome was nonadherence to MH medications (i.e., a disruption in coverage ≥ 25%) during the pandemic.

Results: Pre-pandemic, 39% of patients had MH medication nonadherence, while 35% had nonadherence during the pandemic. Nonadherence during the pandemic improved for nearly all patient subgroups, with the exception of Black patients, for whom MH medication nonadherence increased from 47% to 49%. Asian, Black, and Hispanic patients were less adherent to MH medications during the pandemic than White patients, and patients with lower education or income were less adherent than patients with higher education or income. Non-rural patients were less adherent to MH medication than rural patients.

Conclusions: Adherence to MH medications improved during the pandemic for all subgroups except Black patients. Despite these improvements, disparities in MH medication adherence persisted for Asian, Black, and Hispanic patients and for patients with lower education or income, suggesting these populations may need additional outreach and support.

Purpose: Clopidogrel, an antiplatelet agent used to prevent ischemic events, may interact with proton pump inhibitors (PPIs), especially omeprazole and esomeprazole, and reduce its effectiveness. The evidence surrounding this interaction remains controversial. This study investigates whether co-prescribing clopidogrel with PPIs is associated with a higher incidence of major adverse cardiovascular events (MACEs) compared to clopidogrel monotherapy.

Methods: We conducted a retrospective cohort study analyzing data from the Real-world Evidence Research Network in Saudi Arabia from 2016 to 2023. Patients were followed from their initial clopidogrel prescription until the occurrence of MACEs or the end of follow-up. We employed stabilized inverse probability of treatment weighting (SIPTW) to adjust for potential confounders and the Cox proportional hazards model to assess risks.

Results: A total of 29 572 patients were included, with 21 480 in the clopidogrel + PPI group and 8092 in the clopidogrel-only group. Baseline characteristics were balanced post SIPTW, with similar mean ages (clopidogrel + PPI: 65.9 years; clopidogrel only: 66.1 years) and 64% male representation. The incidence rate of MACE was 3.22 versus 2.92 per 10 000 person-days in the clopidogrel + PPI and clopidogrel-only groups, respectively. The weighted hazard ratio for MACE was 1.20 (95% CI, 1.01-1.43).

Conclusions: In this large real-world cohort study, we observed a modest but statistically significant increase in the risk of MACEs among patients who received concomitant clopidogrel and proton pump inhibitor therapy. Given the widespread use of these medications, these findings emphasize the need for individualized risk assessments when co-prescribing PPIs and clopidogrel.