Pharmacoepidemiology and Drug Safety最新文献

Background: Valproate-containing medicines (VPA) are first-line treatments for epilepsy; however, they pose teratogenic risks, restricting their use in women of childbearing age. We aimed to estimate the secular trends in the use of VPA and alternative treatments in young women, and to characterise dose/strength, treatment duration, and indication in new VPA users.

Methods: We conducted a multi-national population-based cohort study using primary care records from the Netherlands, Spain, and the UK (IPCI, SIDIAP, CPRD GOLD), primary and outpatient specialist care records from Germany and Belgium (IQVIA DA Germany, IQVIA LPD Belgium), and hospital records from Finland (ACI VARHA), all mapped to the OMOP Common data model. All women present in the databases aged ≥ 12 and ≤ 55 years on the 1st of January of each year in the period 2010-2022 (or latest available), with at least 365 days of prior observation, were included.

Results: A total of 2 948 860 (CPRD GOLD), 718 835 (IPCI), 2 494 052 (SIDIAP), 157 361 (ACI VARHA), 218 250 (IQVIA LPD Belgium); and 5 152 752 (IQVIA DA Germany) women were included. Among those, 6416, 1241, 10 398, 1447, 945, and 4002 started treatments with VPA, respectively. Incidence and prevalence of VPA use in young women decreased between 2010 and 2021, while the prevalence of the alternative treatments pregabalin and gabapentin increased, especially in CPRD (it rises from 0.5% to 1.5%). Median age of new VPA users ranged between 40 and 43 years. Anxiety and depressive disorder were frequent comorbidities, and the use of hormonal contraceptives we were able to capture was low. Average treatment duration varied substantially across databases.

Conclusion: Incidences and prevalence of use of VPA among young women declined since 2015. Conversely, alternative antiepileptics have increased in uptake, particularly gabapentinoids. The use of standardized federated analytics allowed for a rapid assessment of VPA utilization, supporting the regulatory agencies in their decision-making and improving patient safety across Europe.

Introduction: Despite substantial investments in analytical infrastructure and scientific research related to the development and analysis of real-world evidence in support of signal management, the impact on routine pharmacovigilance activities has been limited. Most organizations still rely largely on analyses of individual case reports and pre-existing evidence - especially during signal detection and validation.

Objective: This paper presents a set of recommendations for efforts to enable broader use of real-world evidence throughout pharmacovigilance signal management, in the future.

Outcome: The recommendations regard streamlined data access, data harmonization and use of reproducible analytical workflows to enable rapid and robust evidence generation. They emphasize the need for cross-disciplinary collaboration and for organizational adaptations to ensure adequate competence and supporting processes, including principles for how to integrate new types of evidence in decision-making. The execution of pilot studies under realistic conditions and the dissemination of their findings are highlighted as important steps toward defining the proposed change and driving progress in this area. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).

Background: Research using real-world databases (RWD) often requires the development of computable phenotypes based on clinical reasoning-based algorithms or prediction models with validation through a reference standard such as chart review. While there are studies reporting different phenotypes for key prostate cancer (PC) disease or outcomes, these have not been summarized systematically.

Objectives: To conduct a systematic review (SR) to summarize validation statistics on PC-specific phenotypes, including metastasis, biochemical recurrence (BCR), castration-resistant prostate cancer (CRPC), hormone-sensitive prostate cancer (HSPC), progression-free survival, and performance status.

Methods: We conducted a SR in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies guidelines. We systematically searched PubMed/Medline and EMBASE for studies reporting algorithms and prediction models for PC phenotypes based on structured RWD published between 2012 and 2024. A summary of algorithms and prediction models, along with their respective estimates of diagnostic accuracy compared to reference standards and/or measures of uncertainty, was provided. An area under the curve (AUC) > 0.7 was considered an acceptable phenotype.

Results: Out of 7427 retrieved citations, 29 unique retrospective studies (31 citations) were included. Both claims-based codes and prediction model-based classification for any metastasis and bone metastases had an acceptable performance with high AUC (0.88 and > 0.7, respectively) and high specificity (above 90%) with a few having moderate sensitivity (60% to 100%). The prediction model-based BCR classification had acceptable performance (AUC > 0.7); however, claims-based BCR had moderate performance statistics with sensitivity in the range of 3%-19% and specificity in the range of 83%-98%. One claims-based algorithm for metastatic CRPC had high sensitivity (77%) and specificity (100%). Studies for mHSPC were based on clinical reasoning without assessing their diagnostic accuracy. Claims-based algorithms for performance status had at least 75% sensitivity and relatively high specificity.

Conclusions: Our SR highlights the acceptable accuracy of computable phenotypes for PC, including (bone) metastasis, BCR, and performance status within RWD. Further validation studies are needed for RWD-based phenotypes to account for changes in therapeutic options in PC.

This study aimed to identify and describe trajectories of adherence to biologics in patients with IBDs and to identify adherence determinants in the Italian real-world setting. We conducted a retrospective cohort study across 12 Italian regions, including new users of biologics with inflammatory bowel diseases (IBDs), between 2010 and 2019 and followed them for 3 years. We assessed adherence longitudinally, and we identified trajectories using nonparametric methods. To identify determinants of adherence, we used multinomial multivariate regression models. We included 20 150 subjects in the final cohort, mostly male (56%), < 65 years old (92%), and with Crohn's disease (58%). We identified three trajectories of adherence to biologics for IBDs: one group (19% of the cohort) maintained high adherence throughout the observation period, while the largest group (46%) initially reduced adherence, stabilizing around 70%. The remaining group (35%) gradually decreased adherence over the entire follow-up, reaching 20%. Being female (odds ratio (OR) 1.52, 95% confidence interval (CI) 1.40-1.65), older (OR 1.44, 95% CI 1.21-1.70), and having adalimumab as index drug were each positively associated with low adherence compared to high adherence. In contrast, starting treatment with a biosimilar (OR 0.47, 95% CI 0.42-0.52) was negatively associated with low adherence. Our findings highlight that one in three patients with IBDs gradually reduced adherence to biologics within the first 3 years of treatment. Differences were observed according to the initial biologic dispensed and patient characteristics such as sex and age, with females and older patients positively associated with low adherence.

Purpose: To assess changes in study results in self-controlled case series (SCCS) studies and explore potential biases when applying incident and prevalent exposure and outcome scenarios.

Methods: We used the National Health Insurance Service database in South Korea to conduct two SCCS studies: (1) the risk of retinal detachment following fluoroquinolone use (expected elevated risk), and (2) the risk of acute cardiovascular disease following ranibizumab use (expected null association). Exposure and outcome scenarios were classified based on a washout period of 2 and 1 year, respectively, before the observation period: incident exposure-incident outcome, incident exposure-prevalent outcome, prevalent exposure-incident outcome, and prevalent exposure-prevalent outcome. For each scenario, conditional Poisson regression models, adjusted for time-varying age, estimated incidence rate ratios (IRRs) with 95% confidence intervals (CIs).

Results: In the fluoroquinolone study, IRRs of retinal detachment were as follows: 1.83 (95% CI 1.72-1.96) for incident exposure-incident outcome, 1.83 (1.71-1.95) for incident exposure-prevalent outcome, 1.71 (1.62-1.80) for prevalent exposure-incident outcome, and 1.70 (1.62-1.79) for prevalent exposure-prevalent outcome scenario. In the ranibizumab study, IRRs of acute cardiovascular disease were 0.91 (0.84-0.99), 0.89 (0.82-0.97), 1.02 (0.94-1.10), and 1.00 (0.93-1.08), respectively.

Conclusions: In prevalent exposure scenarios, IRRs in both studies were attenuated, consistent with prevalent user bias. In prevalent outcome scenarios, where survivor bias was anticipated, no notable shifts in IRRs were observed, possibly due to the high severity and low recurrence of the outcomes associated with the respective exposures. Further consideration of prevalent user and survivor bias is important when interpreting SCCS results. Additional research is needed to quantify the impact of varying exposure and outcome definitions on SCCS estimates.

Purpose: Oral glucocorticoids (OGCs) have a broad range of uses and are effective in treating numerous conditions. However, it is commonly acknowledged that OGCs at high doses or over long periods have a burden of toxicity. Despite the use of steroid-sparing therapies, OGCs continue to be prescribed to treat a wide range of immune and inflammatory conditions. We aimed to address the following research questions: (1) what are the contemporary indications for high dose and/or long-term OGCs? (2) what patterns of use are described in the literature for high dose and/or long-term OGCs? (3) which evidence do we have for chronic conditions related to well-established steroid-sparing strategies and tapering regimes for OGCs? (4) what adverse effects have been reported with high dose and/or long-term OGCs?

Methods: A rapid scoping review was conducted using the Joanna Briggs Institute guidelines. The Protocol has been published on the Open Science Framework. A systematic search of MEDLINE (Sep 2014 to Sep 2024) identified systematic reviews and scoping reviews involving adults (≥ 18 years) treated with high doses and/or long-term OGCs for chronic inflammatory conditions. Studies involving pregnant women were excluded.

Results: In total, 137 reviews were included. OGCs were indicated in 47 different conditions in dermatology, respiratory, gastrointestinal, hematology, immunology, rheumatology, and other miscellaneous categories. Across all specialties, OGCs were used either at high doses (at least 20 mg prednisone equivalent per day) or for long durations (for at least 3 months). For types of adverse effects reported in the included reviews, 20 were labeled as endocrine, 13 as immunological, 21 as musculoskeletal, 30 as gastrointestinal, and 16 as cardiovascular. Sixty-four reviews looked for/reported unspecified adverse events. One hundred and fifteen reviews had evidence of steroid-sparing/tapering regimes, indicating the wide use of these strategies to mitigate the harmful effects of OGCs.

Conclusion: OGCs are used for a broad range of inflammatory conditions across multiple specialties. There is evidence related to a broad range of potential adverse effects across multiple body systems regardless of the indication of use. Further research is needed using a combined cross-condition approach to their measurement and reduction, alongside gaining more insight into the impact of OGCs on patients' quality of life.

Objectives: The safety of the BNT162b2 mRNA COVID-19 vaccine has been extensively evaluated since the global rollout began. While serious adverse events are rare, safety issues continue to arise. This study evaluates the claim that earlier small vaccine batches were associated with higher rates of serious adverse events compared to later batches.

Design, participants, setting: A nationwide cohort study was conducted in Denmark, comprising individuals vaccinated with the BNT162b2 vaccine from 52 pre-defined batches classified into three pre-defined groups. Vaccinated individuals were matched 1:1 between batch groups on age, sex, and vaccination priority group. The study outcomes included 27 serious adverse events, two negative control outcomes, and all-cause mortality. Cox regression was used to estimate hazard ratios (HRs) comparing rates between batch groups in the 28 days following vaccination. We conducted two comparisons of the early small batches to two groups of larger batches used later in the pandemic.

Results: In the study period, 9 983 728 vaccinations were administered from batches in the three pre-defined groups. Slightly increased rates of arrhythmia were observed in both study comparisons, HRs 1.25 (95% CI, 1.05-1.50) and 1.15 (1.00-1.31), respectively, but sensitivity analyses did not robustly support these associations. For the remaining outcomes, increased rates in both study comparisons were not observed.

Conclusion: This nationwide cohort study provides reassurance regarding the safety of the BNT162b2 vaccine across different batches used in Denmark. The findings support the overall safety of the vaccine, with no clinically relevant variations in serious adverse event rates between batches.