PURPOSE:Confounding is a key concern in observational studies using healthcare databases. The high-dimensional propensity score (HDPS) algorithm is an approach for generating and prioritising proxy variables, leveraging all available information in a database to mitigate residual confounding. This study aims to implement HDPS approaches in a novel setting using primary and secondary data available from Hong Kong (HK). METHODS:Using data from HK, we implemented HDPS in a cohort study investigating the use of different antihypertensive drug classes and incident dementia risk. The top 250 HDPS covariates were included in inverse probability of treatment weighting in addition to investigator-specified variables. Diagnostics evaluated the performance of the HDPS. Sensitivity analyses included varying the number of HDPS covariates and removing potentially influential or inappropriate covariates. RESULTS:434 506 new-users of antihypertensives were included. With a traditional PS approach, no evidence for an association was observed for each antihypertensive comparison. After HDPS implementation, the estimate for beta-blockers shifted from no evidence (Hazard ratio (HR): 0.93, 95% confidence interval (CI): 0.86-1.02) to moderate evidence of a reduced hazard of incident dementia compared to angiotensin-converting enzyme inhibitors (HR: 0.90, 95% CI: 0.82-0.98). A greater overall covariate balance between comparison groups was achieved after the inclusion of HDPS covariates and potential frailty markers were identified as influential. CONCLUSIONS:We successfully implemented the HDPS in HK data, observing improved covariate balance across a wider set of potential confounders. HDPS also identified possible database-specific frailty markers which could be considered more widely when specifying adjustment variables in this setting.

Previous evidence suggests a potential protective effect of warfarin against cancer, compared to non-users. However, it may be prone to immortal time bias and residual confounding. We aimed to examine the association between cancer and warfarin, compared with active comparator (direct oral anticoagulants). We conducted studies using population-based databases from England and Hong Kong to investigate the association between warfarin and hazard of cancer using a new-user active-comparator cohort design. People with atrial fibrillation aged ≥ 18 years who had first received anticoagulant treatment during 01/01/2011–31/12/2019 were involved. No evidence supported the association between warfarin and hazard of overall cancer, compared with direct oral anticoagulants in both settings (England: hazard ratio [HR] = 1.03, 95

BACKGROUND:Bleeding is a side effect of direct oral anticoagulants (DOACs) and selective serotonin reuptake inhibitors (SSRIs). However, it is unknown whether their concomitant use would further exacerbate bleeding risk. AIM:To compare hazard of bleeding in patients with concomitant use of DOACs and SSRIs versus non-SSRI antidepressants. DESIGN & SETTING:Population-based cohort and case-crossover study using primary care data from the UK Clinical Practice Research Datalink (CPRD) Aurum between 1/1/2011 and 29/3/2021. METHOD:We used a cohort design to estimate hazard ratios (HRs) using propensity score weighting, comparing DOAC+SSRI and DOAC+non-SSRI users, and a 6-parameter model case-crossover design comparing odds of exposure to different drug initiation patterns for outcomes in hazard vs referent window within an individual to eliminate time-invariant confounding (confounding that do not change over time). RESULTS:There was no difference in bleeding risk in the cohort design (intracranial bleeding: HR1.16, 99% confidence interval [CI] 0.62-2.20; gastrointestinal bleeding: HR1.09, 99% CI 0.83-1.41; other bleeding: HR1.01, 99% CI 0.78-1.29). In the case-crossover design, we observed higher odds ratio (OR) of 1.64 (99%CI 1.14-2.35) for other bleeding associated with SSRI initiation while taking DOAC than SSRI monotherapy (OR1.06; 99% CI 1.01-1.11; p for Wald test=0.002), but greater odds ratio was not observed in DOAC users initiated non-SSRI (p for Wald test=0.83). CONCLUSION:We found no evidence of increased risk of intracranial and gastrointestinal bleeding during concomitant use of DOAC+SSRI in the cohort analysis. However, the case-crossover analysis suggested some evidence of a higher risk of other bleeding when initiating SSRIs (but not non-SSRIs) while taking DOACs.

INTRODUCTION:Disruption of gut microbiota by antibiotic use has been linked to the development of inflammatory bowel disease (IBD). This study aimed to evaluate the association between antibiotic use for nongastrointestinal (GI) infections and the risk of IBD flare-ups, and to examine whether route of administration, antimicrobial spectrum, and antibiotic class modulate this risk. METHODS:We conducted a self-controlled case series study using territory-wide electronic medical records from Hong Kong. Adults with IBD who experienced at least 1 flare-up and received at least 1 course of antibiotics for infections outside the GI tract between 2000 and 2024 were included, to reduce indication bias related to GI symptoms. Conditional Poisson regression models were used to estimate incidence rate ratios (IRRs) by comparing across predefined risk periods to the baseline period. RESULTS:Among 810 patients, IBD flare incidence was elevated during the month preceding antibiotics (IRR 2.85), increased further during treatment (IRR 3.44), and peaked within 2 weeks after treatment (IRR 4.79), and returned to baseline levels within 6 months, vs baseline. Increased incidences were observed for oral antibiotics during and 2 weeks after treatment (IRRs 3.91 and 3.70), but not for injectable antibiotics (interaction P values <0.01). The IRRs for broad-spectrum antibiotics were higher than those for narrow-spectrum agents from 1 month before to 6 weeks after antibiotic use, vs baseline. DISCUSSION:Antibiotic use for non-GI infections was associated with a short-term increase in IBD flare risk. Injectable or narrow-spectrum antibiotics may have a relatively smaller impact on potential IBD flare-ups.

BACKGROUND:Differences in performance of the Self-Controlled Case Series (SCCS) for signal detection have been reported across different databases. However, there has been limited comparative analysis of performance and it remains unknown whether combinations of databases could enable more effective signal detection. OBJECTIVES:This study aims to compare the performance of the SCCS for signal detection across several data sources, and to determine whether combinations of databases can improve SCCS performance. METHODS:We applied the SCCS to macrolides and fluoroquinolone antibiotics, in four databases: Merative MarketScan Commercial Claims and Medicare, the Clinical Practice Research Datalink (CPRD) Aurum and the Système National des Données de Santé. 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, specificity and area under the receiver operating curve (AUC) with respect to the product labels, both for individual and combinations of databases. RESULTS:The sensitivity of the SCCS ranged from 0.57-0.89 across individual databases, and the specificity from 0.43-0.77 when limited to drug-outcome pairs sufficiently powered. The combination of all databases achieved the maximum sensitivity of 0.89 (0.41 specificity) for the full reference set, and a sensitivity of 1 (0.35 specificity) for drug outcome pairs with enough power. Whilst AUCs ranged from 0.66 to 0.71 across individual databases, the highest performing combination was CPRD plus MarketScan Commercial Claims (0.76 AUC). CONCLUSIONS:Using a carefully designed reference set of drug-outcome pairs well suited to the study design, the SCCS performance varied substantially by database due to differences in population, reporting, healthcare and coding systems and prescribing patterns. Multi-database studies showed increased performance of SCCS for signal detection.

Survivors of breast cancer (BC) have a higher risk of developing herpes zoster (HZ), but it remains unclear how this risk is affected by time since BC diagnosis and treatment regimen. This matched cohort study used a large health-insurance claims database including Japanese employees and their families. Between January 2005 and December 2019, women aged 18–74 years with and without incident BC were matched 1:4 by age and timing of database entry, in the month of BC diagnosis. This study aimed to evaluate the risk of developing HZ in female BC survivors compared with women without BC, to examine temporal variations in risk during survivorship, and to assess the impact of different BC treatments on this risk. We compared the first HZ incidence using stratified Cox regression analyses over the study period, divided by follow-up length. We then estimated HZ risk by treatment regimen using unstratified Cox regression analysis, with follow-up beginning 1 year after matching. Comparing 23,169 BC survivors vs 92,801 matched women without BC (median age: 49.4 years, interquartile range: 44.7–56.0 years), the HZ incidence rate (95

OBJECTIVES:Direct oral anticoagulants (DOACs) are commonly co-prescribed with digoxin, but whether there is a drug interaction between them is unclear. We aimed to investigate potential drug interactions between DOACs and digoxin. STUDY DESIGN AND SETTING:We identified DOAC users during January 1, 2011-December 31, 2019 using data from Clinical Practice Research Datalink Aurum in cohort design with propensity score to compare the hazards of effectiveness cardiovascular and mortality outcomes and safety bleeding outcomes, respectively, in DOAC + digoxin users versus DOAC + beta-blocker users. A case-crossover design was conducted to compare odds of exposure to different drug initiation patterns in hazard period versus referent period. RESULTS:Of 397,459 DOAC users, we identified 25,251 co-prescribed digoxin and 109,779 co-prescribed beta-blockers in cohort study. A lower proportion of DOAC + digoxin users were men (46%) in contrast with that of DOAC + beta-blocker users (53%). Mean age of DOAC + digoxin users (77.1 years) were higher than DOAC + beta-blocker users (74.5 years). No increased risk of pharmacologically predictable DOAC safety outcomes or specific effectiveness outcomes was seen with DOAC + digoxin. A higher risk of all-cause mortality (hazard ratio: 1.35; 99% confidence interval [CI]: 1.14-1.61) was observed with DOAC + digoxin versus DOAC + beta-blockers. In the case-crossover study, a 24% higher odds of all-cause mortality was seen with initiating digoxin while taking DOAC (odds ratio: 1.24; 99% CI: 1.06-1.45); and a 63% higher odds was also seen with initiating DOAC while taking digoxin (odds ratio: 1.63; 99% CI: 1.41-1.88). CONCLUSION:We found no increased risk of bleeding when DOACs are used with digoxin, suggesting combined use does not lead to drug-drug interaction. Future work is recommended to investigate the underlying mechanism of association with all-cause mortality. PLAIN LANGUAGE SUMMARY:This study aimed to examine potential drug interactions between direct oral anticoagulants (DOACs) (a drug class to prevent blood clots) and digoxin (treatment of abnormal heart rhythms). We compared a range of clinical outcomes in people prescribed DOAC and digoxin with people prescribed DOAC and beta-blockers (a treatment alternative to digoxin). We also used a new study design (case-crossover design) to compare the risk of clinical outcomes between different periods within a person as a validation. In both study designs, we found no increased risk of bleeding when DOACs are used with digoxin, suggesting combined use does not lead to drug-drug interaction. However, we found an increased risk of all-cause death associated with digoxin in DOAC users which requires further investigation.

BACKGROUND:Direct oral anticoagulants (DOACs) are commonly co-prescribed with statins. Although biologically plausible, whether there is a drug interaction between DOACs and atorvastatin/simvastatin is unclear. AIM:To investigate the association between co-prescribed DOACs and atorvastatin/simvastatin and bleeding, cardiovascular disease, and mortality. DESIGN AND SETTING:Cohort and case-crossover study using data from English general practices in the Clinical Practice Research Datalink Aurum from 1 January 2011 to 31 December 2019. METHOD:A cohort design was used to estimate hazard ratios for clinically relevant pharmacological interaction safety outcomes (intracranial bleeding, gastrointestinal bleeding, and other bleeding) comparing DOACs and atorvastatin/simvastatin with DOACs and other statins (fluvastatin, pravastatin, and rosuvastatin that are not anticipated to interact with DOACs). Effectiveness outcomes (ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality, and all-cause mortality) were also included. In addition, a case-crossover design was used to compare the odds of exposure to different drug initiation patterns in the hazard window versus the referent window within an individual. RESULTS:Of 397 459 patients who were prescribed DOACs, 70 318 people co-prescribed atorvastatin and 38 724 co-prescribed simvastatin were selected. The cohort analysis showed no difference in risk of all outcomes comparing patients prescribed DOACs and atorvastatin/simvastatin versus those prescribed DOACs and other statins. In the case-crossover analysis, odds ratios (ORs) for other bleeding (OR 5.06, 99% confidence interval [CI] = 3.79 to 6.76) among those initiating DOACs while taking atorvastatin and the ORs for gastrointestinal bleeding (OR 6.05, 99% CI = 4.28 to 8.54) and other bleeding (OR 6.81, 99% CI = 4.74 to 9.78) among those initiating DOACs while taking simvastatin were greater than those initiating DOAC monotherapy. Similar patterns were also observed for cardiovascular mortality and all-cause mortality. CONCLUSION:This study shows no evidence of interaction between DOACs and atorvastatin/simvastatin. However, people starting a DOAC while taking atorvastatin/simvastatin were at high risk of bleeding and mortality, likely because of temporal clinical vulnerability.

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.

Breast cancer (BC) survivors may have an increased risk of endometrial cancer due to shared risk factors and tamoxifen use. However, the risk among women in Japan and that for each endocrine therapy regimen remains unknown when comparing BC survivors to women without BC. We conducted a matched-cohort study using the JMDC claims database, covering company employees and their family members in Japan. Between January 2005 and December 2019, women aged 18–74 years with BC were matched to women without BC in a 1:4 ratio by age and database entry timing. Endometrial cancer risk was compared using stratified Cox regression. In addition, starting the follow-up at one year after matching, we assessed risk by endocrine treatment (tamoxifen, aromatase inhibitor [AI], and no endocrine therapy) using unstratified Cox regression. Among 23,729 BC survivors and 95,659 matched women (median age, 49.5 years), there were 56 vs 40 endometrial cancer cases (0.73 vs 0.13 cases/1,000 person-years, respectively), with adjusted hazard ratios of 7.71 (95

Background:The number of breast cancer (BC) survivors has increased worldwide, but the landscape of their non-cancer disease risks remains unclear, especially among Asian women. Methods:In the JMDC claims database, which covers company employees and their family members in Japan, women aged 18-74 years with and without an incident BC were matched in a 1:4 ratio for age and entry timing to the database between January 2005 and December 2019. The risks for six cardiovascular diseases (myocardial infarction, heart failure, atrial fibrillation/flutter, ischaemic stroke, intracranial haemorrhage, and pulmonary embolism) and six non-cardiovascular diseases (major osteoporotic fractures, other fractures, gastrointestinal bleeding, urinary tract infection, infectious pneumonia, and anxiety/depression) were compared between the groups. Findings:Comparing 24,017 BC survivors and 96,068 matched women (mean age, 50.5 years, standard deviation, 8.7 years), the incidence rates of heart failure, atrial fibrillation/flutter, and all non-cardiovascular diseases were higher in the BC survivor group. The highest adjusted hazard ratio (HR) was noted for heart failure (3.99 [95% confidence interval 2.58-6.16]), followed by gastrointestinal bleeding (3.55 [3.10-4.06]), and anxiety/depression (3.06 [2.86-3.28]). The HRs in the first year were larger than those for 1-10 years for most outcomes, whereas the HRs for fracture outcomes were larger for 1-10 years. Interpretation:BC survivors in Japan showed an increased risk of many non-cancer diseases compared to women without BC. Most risks increased more steeply during the first year following diagnosis, whereas the risk of fractures increased later. Funding:Competitive research funding from Pfizer Health Research Foundation in Japan.

Background: With improvements in the detection and treatment of breast cancer (BC), the number of BC survivors has increased worldwide. However, the landscape of their non-cancer disease risks, including cardiovascular and non-cardiovascular risks remains unclear, especially among Asian women. Methods: We conducted a matched cohort study using data from the JMDC claims database (https://www.jmdc.co.jp/en/) that covers company employees and their family members in Japan. Between January 2005 and December 2019, women aged 18–74 years with and without an incident BC (defined as the BC diagnosis and surgery) were matched with 1:4 ratio for age and entry timing to the database. Using stratified Cox regression analysis, we estimated and compared the risks for six cardiovascular diseases (acute myocardial infarction, acute heart failure, atrial fibrillation/flutter, ischemic stroke, intracranial hemorrhage, and pulmonary embolism) and six non-cardiovascular diseases (major osteoporotic fractures, other fractures, gastrointestinal bleeding, urinary tract infection, infectious pneumonia, and anxiety/depression) between the groups, overall and by follow-up time (<1 year and 1-10 year from the BC diagnosis, separately). In addition, risk by chemotherapy (anthracycline, taxane, anthracycline&taxane, and no anthracycline/taxane) and hormone therapy (tamoxifen, aromatase inhibitors, no tamoxifen/aromatase inhibitors) were estimated using non-stratified Cox regression analysis, with the reference group being women without BC. The treatment regimens were identified and classified during the first year from the BC diagnosis and follow-up was started at 1 year from the diagnosis. For this analysis, we adjusted for hormone therapy (tamoxifen and aromatase inhibitors) when analyzed by chemotherapy, and chemotherapy (anthracyclines and taxanes) when analyzed by hormone therapy. Results: We included 24,017 BC survivors and 96,068 matched women in the analysis. The incidence rates of acute heart failure, atrial fibrillation/flutter, and all non-cardiovascular diseases were higher in the BC survivors than in the matched cohort group. For cardiovascular diseases, the highest adjusted hazard ratio was marked by heart failure (3·88, [95% confidence interval 2·55–5·90]), followed by atrial fibrillation/flutter (1·83, [1·40–2·39]). For non-cardiovascular diseases, the highest adjusted hazard ratio was marked by gastrointestinal bleeding (3·55, [3·10–4·06]), followed by anxiety/depression (3·06, [2·86–3·28]). Of the diseases with significant increases over the entire period, the hazard ratio at <1 year was larger than that at 1–10 years from the BC diagnosis in most outcomes; however, major osteoporotic fractures and other fractures had a larger hazard ratio in 1–10 years than in <1 year. For osteoporotic fracture and other fractures, the hazard ratio in 1–10 years was 1·77 (1·46–2·15) and 2·09 (1·86–2·34) respectively, whereas that in < 1 year was 1·30 (0·92–1·85), and 1·28 (1·05–1·56), respectively. By chemotherapy, hazard ratios for acute heart failure, atrial fibrillation/flutter, other fractures, gastrointestinal bleeding, infectious pneumonia, and anxiety/depression tended to be higher in the anthracycline&taxane group than in the other groups. By hormone therapy, a higher risk of fractures and gastrointestinal bleeding was observed among aromatase inhibitor users. Conclusion: The BC survivors in Japan showed an increased risk of acute heart failure, atrial fibrillation/flutter, and six non-cardiovascular diseases than women without BC. Most risks increased more steeply during the first year of intensive multidisciplinary care of BC, whereas the risk of fractures increased later. It is important for healthcare providers and patients to understand the risks of these diseases and link them to screening, prevention, and early treatment. Citation Format: Chitose Kawamura, Krishnan Bhaskaran, Takaaki Konishi, Yasuaki Sagara, Yasuaki Sagara, Angel YS Wong, Nanako Tamiya, Masao Iwagami. Cardiovascular and Non-cardiovascular Risks among Female Breast Cancer Survivors in Japan: A Matched Cohort Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-01.

BACKGROUND Although drug interactions between clarithromycin/erythromycin/fluconazole and direct oral anticoagulants (DOACs) are mechanistically plausible, it is uncertain whether they are clinically relevant. OBJECTIVE This study aims to investigate the association among coprescribed DOACs and antimicrobials and bleeding, cardiovascular disease and mortality. METHODS We identified DOAC users in the Clinical Practice Research DatalinkAurum from January 1, 2011 to March 29, 2021. We used a cohort design to estimate hazard ratios (HRs) for bleeding outcomes (intracranial bleeding, gastrointestinal bleeding, other bleeding), comparing DOACs + clarithromycin/erythromycin/fluconazole users with DOACs users not receiving these antimicrobials. Cardiovascular outcomes were ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality, and all-cause mortality. A 6-parameter case-crossover design comparing odds of exposure with different drug initiation patterns for all outcomes in hazard window vs referent window within an individual was also conducted. RESULTS Of 483,815 DOAC users, we identified 21,701 coprescribed clarithromycin, 4532 coprescribed erythromycin, and 4840 coprescribed fluconazole. We observed an increased risk of gastrointestinal bleeding over 7 days following coprescription of DOAC + erythromycin vs DOAC alone (HR 3.66; 99% confidence interval [CI] 1.27-10.51), with wide CIs in case-crossover analysis. No evidence of increased risk of bleeding outcomes was seen for DOAC + clarithromycin/fluconazole in cohort and case-crossover analyses. For cardiovascular outcomes, compared with DOAC alone, an increased risk of cardiovascular mortality with DOAC + clarithromycin (HR 3.36; 99% CI 1.73-6.52) and increased risk of all-cause mortality with DOAC + clarithromycin/ erythromycin/fluconazole were observed in cohort analysis. However, similar risks were found when initiating erythromycin/flu-conazole with and without DOACs. CONCLUSION We found no strong evidence of increased risks of bleeding and cardiovascular outcomes in DOACs + clarithromycin/fluconazole/erythromycin users except a possible short-term increased risk of gastrointestinal bleeding in DOACs + erythromycin users.

One of the key challenges in pharmacoepidemiological studies is that of uncontrolled confounding, which occurs when confounders are poorly measured, unmeasured or unknown. Self-controlled designs can help address this issue, as their key comparison is not between people, but periods of time within the same person. This controls for all time-stable confounders (genetics) and in the absence of time-varying confounding negates the need for an external control group. However, these benefits come at the cost of strong assumptions, not all of which are verifiable. This review briefly introduces the reader to different types of self-controlled study designs, their terminology and highlights key publications through an annotated reference list. We include a practical description of how these designs can be implemented and visualised using recent examples, and finish by discussing recent developments. We hope this review will serve as a starting point for researchers looking to apply self-controlled designs in their own work.

BACKGROUND:Current treatment guidelines recommend fidaxomicin and oral vancomycin as first-line treatments for Clostridioides difficile infection (CDI). Disparities in the prevalence of CDI and the availability of novel treatments necessitate understanding the contemporary trends in their consumption at the global level. METHODS:This longitudinal study used global pharmaceutical sales from IQVIA-MIDAS for fidaxomicin and oral vancomycin in 43 countries from 2012 to 2023. We measured defined daily doses per 100,000 inhabitants per year (DDD/100K) and manufacture-level prices, calculating changes using compound annual growth rates (CAGR). We conducted interrupted time-series analyses to assess the impact of guideline updates by Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (IDSA/SHEA) on quarterly consumption. RESULTS:Overall fidaxomicin consumption increased from 21.68 DDD/100K in 2012 to 126.86 DDD/100K in 2023 (CAGR = 17.42%) and similar increases in expenditure (0.07-0.34 USD/capita; CAGR = 14.96%). Oral vancomycin consumption increased from 71.61 to 120.82 DDD/100K (CAGR = 4.87%), although with a decreasing trend in expenditure (0.20-0.03 USD/capita; CAGR = -15.16%). The earliest adoption of fidaxomicin in middle-income economies occurred five years later than in high-income economies. Despite higher CAGRs, consumption of fidaxomicin and oral vancomycin in middle-income economies was only 1.9% and 2.3%, respectively, of that in high-income economies in 2023. Following the IDSA/SHEA guideline updates, fidaxomicin consumption in Northern America increased immediately. CONCLUSION:Consumption of fidaxomicin and oral vancomycin continues to increase globally; however, significant economic and geographical disparities in utilization highlight inequitable access to first-line CDI treatments.

This article introduces the basic concept of a novel 6-parameter model case-crossover study with active comparator design. While case-crossover study design eliminates time-invariant confounding, the 6-parameter model as a modified version also allows studying the effect of drug initiation patterns between two interacting drugs. The implementation of the case-crossover study is illustrated, including the generation of the dataset for data analysis and performing the 6-parameter model using conditional logistic regression. Potential interpretation framework is proposed using eight combinations based on three scenarios shown in the results of the 6-parameter case-crossover study design.

BACKGROUND:There is little evidence about signal detection using UK primary care electronic health records (EHRs). 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 the UK Clinical Practice Research Datalink (CPRD) Aurum. METHODS:We applied the SCCS to macrolide and fluoroquinolone antibiotics, using amoxicillin and cefalexin as active comparators. In total seven 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. Two-year observation periods with a 30-day risk window after each dispensing were used. 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 in the 2017/2018 observation period were 0.57 and 0.77 when limited to pairs with satisfactory power. Specificity increased up to 0.89 with active comparators, however sensitivity decreased to 0.18. Five drug-outcome pairs were signals of disproportionality before they were present on labels. CONCLUSIONS:Using a carefully designed reference set of drug-outcome pairs well suited to the study design, the SCCS performed moderately well for signal detection in CPRD. Whilst active comparators effectively reduced confounding by indication, they also reduced the number of correctly identified positive controls, due to a reduction in power. We showed some evidence that SCCS is able to highlight SDRs before they were present on labels.

BACKGROUND:The conflicting findings on the association between proton pump inhibitors (PPIs) and ischaemic stroke could be due to residual confounding. Self-controlled case series (SCCS) can be used to avoid time-invariant confounding. Additionally, different baseline risks of stroke should be considered, as some individuals may be prescribed PPIs for gastroprotection from bleeding with antithrombotic drugs. METHODS:We identified adult patients with incident ischaemic stroke from 2003 to 2014 in Hong Kong and applied the modified SCCS. The exposure window was pre-defined as Days 1-30, 31-60, 61-90, and 91 to the prescription end, since the PPI prescription. All other periods were referent windows. We estimated incidence rate ratios (IRR) and stratified them further using antithrombotic drugs. RESULTS:A total of 18 170 patients were included. The IRRs for ischaemic stroke were 1.55 (95% CI: 1.00-2.42) during days 61 to 90, 1.51 (95% CI: 1.14-2.00) during days 91 to end, versus the referent window. There was no evidence of an increased risk in other risk windows versus the referent windows. In the stratified analysis, we observed an increased risk in people co-prescribed PPIs with antithrombotic drugs in all risk periods, but no increased risks among those with PPI monotherapy versus the referent window. CONCLUSION:No evidence of a higher ischaemic stroke after monotherapy of PPI use. The increased risk of ischaemic stroke associated with PPIs could be due to their high baseline risk prescribed with antithrombotic drugs for primary prevention. Clinical monitoring of ischaemic stroke is recommended in these people.