Purpose Ascertainment of mortality is critical to epidemiologic studies. Secondary collected database studies face challenges given the need to record mortality data in health claims or electronic medical records. The National Death Index (NDI) is the gold standard for mortality data in the U.S. Methods This study is a secondary analysis of an advanced cancer cohort in the U.S. between January 2010 and December 2018, with an established NDI linkage. Mortality data sources, inpatient discharge, disenrollment, death master file (DMF), Center for Medicare and Medicaid Services (CMS), Utilization management data (U.M.), and online obituary data were compared to NDI. We calculated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and 95% confidence intervals (95% CI). Per each source, death identified 60 days before and 30 days after NDI death was deemed a match. Results Among 40,692 patients, 25,761 (63.3%) had a death date using NDI; the composite algorithm had a sensitivity of 88.9% (95% CI= 88.5%, 89.3%), specificity was 89.1% (95% CI= 88.6%, 89.6%). At the same time, PPV was 93.4% (95% CI= 93.1%, 93.7%), NPV was 82.3% (95% CI= 81.7%, 82.9%), and when comparing each individual source, each had a high PPV but limited sensitivity. Conclusion The composite algorithm was demonstrated to be a sensitive and precise measure of mortality in advanced cancer patients in the U.S. from 2010 to 2018, while individual database sources were accurate but had limited sensitivity compared to the NDI.

A document by Carla Rodriguez-Watson. Click on the document to view its contents.

Background: Several cases of renal complications including acute kidney injury (AKI) after influenza vaccination have been reported, but the association remains unproven. We evaluated the association between influenza vaccination and AKI occurrence among the Korean elderly in the 2018–2019 and 2019–2020 seasons. Methods: We used a large database that combined vaccination registration data from the Korea Disease Control and Prevention Agency and the claims data from the National Health Insurance Service. The study subjects were patients hospitalized with AKI for the first time following vaccination among those who received one influenza vaccine in the 2018–2019 or 2019–2020 season. Only those who were 65 or older at the date of vaccination were included in our study. We performed a self-controlled case series study in which the risk period was designated as 1 to 28 days after vaccination, and the observation period as each influenza season. We conducted sensitivity analyses with varied risk periods and observation periods. Results: A total of 16,713 and 16,272 AKI events were identified during each influenza season. The adjusted incidence rate ratio (aIRR) for AKI was 0.83 (95% confidence interval [CI]= 0.79–0.87) in the 2018–2019 season. The IRR of the 2019–2020 influenza vaccination was similar to the 2018–2019 season (aIRR=0.86; 95% CI=0.82–0.90). Sensitivity analyses showed similar results. Conclusions: We suggest that influenza vaccination is associated with a lower risk of AKI in the elderly over 65.

Introduction: Use observational methods to evaluate reliability of evidence generated by a study of the effect of glucagon-like peptide 1 receptor agonists (GLP-1RA) on chronic lower respiratory disease (CLRD) outcomes among type-2 diabetes mellites (T2DM) patients. Research Design and Methods: We independently reproduced a study comparing effects of GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP4-i) on CLRD outcome among patients with T2DM and prior CLRD. We reproduced inputs and outputs using the original study data (national administrative claims) and evaluated robustness to alternate design/analysis decisions. To evaluate generalizability, we applied the protocol and meta-analyzed across a research network including diverse array of populations and data sources. We also produced additional analyses evaluating individual drugs within the GLP-1RA class. Results: We confirmed alignment of study inputs and outputs and closely reproduced effect estimates and sensitivity analyses. Adjusted effect estimates were robust to empirical calibration. Network meta-analysis confirmed original findings, but indicated weaker effects than originally published. Meta-analyzing drugs within the GLP-1RA class against DPP4-I provided some evidence that effects vary within the GLP-1RA class, indicating stronger effects for exenatide and weaker effects of dulaglutide. Conclusions: This study supports the reliability of the original study by 1) confirming the findings in a range of alternate databases and populations 2) demonstrating effects for multiple drugs within the GLP-1RA class, and 3) independently confirming the reproducibility original study and its findings. We propose that clinicians treating patients with T2DM and a history of CLRD consider GLP-1RA in absence of strong motivating reasons to select another therapy.

Background: Despite cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD), their utilization remains low globally. This study aimed to evaluate the utilization of SGLT2i and GLP1RA in patients with T2DM and ASCVD, as well as the factors associated with medications in South Korea. Methods: This retrospective study was conducted from 2015 to 2020, using National Patient Sample claims data. The study population included adult patients with confirmed T2DM and ASCVD diagnosed between March 1 and October 31 each year. Demographic and clinical characteristics, and influencing factors were investigated. Results: Among 57,576 study participants, SGLT2i use increased from 1.2 % to 10.51 % during the study period, whereas GLP1RA use increased slightly from 0 % to 1.17 %. Older age, comorbid chronic kidney disease, concurrent use of dipeptidyl peptidase 4 inhibitors (DPP4i), and prescriptions from specific physician specialties negatively influenced SGLT2i use. Conversely, comorbid dyslipidemia, heart failure, concurrent use of sulfonylurea (SU), and prescriptions from cardiologists positively influenced SGLT2i use. For GLP1RA, older age, concurrent DPP4i use, and specific physician specialty were negative factors, whereas female sex, dyslipidemia, insulin, and SU use were positive factors. Conclusions: Despite increasing utilization, 88.35 % of eligible patients remained untreated with SGLT2i and GLP1RA as of 2020. This study highlights the disparities in utilization based on patient characteristics and physician specialties, emphasizing the need to remove barriers and enhance clinical benefits for high-risk patients.

Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic. Methods: We conducted a literature review identifying all studies published in “Pharmacoepidemiology and Drug Safety” (PDS) between 2017 and 2022, Data was extracted on the frequency and types of programming code shared, and other key open science practices (clinical codelist sharing, data sharing, study pre-registration, and use of reporting guidelines). We developed six recommendations for investigators who choose to share to programming code and gathered feedback from members of the International Society of Pharmacoepidemiology (ISPE). Results: Programming code sharing by articles published in PDS ranged from 2.4% in 2017 to 13.4% in 2022. It was more prevalent among articles with a methodological focus, simulation studies, and papers which also shared record-level data. We recommend that reporting of open science practices, including code sharing, is standardised to enable continued monitoring. When sharing programming code, we recommend the use of permanent digital identifiers, appropriate licenses, and, where possible, adherence to good software practices around the provision of metadata and documentation, computational reproducibility, and data privacy. Conclusion: Programming code sharing is rare but increasing in pharmacoepidemiology studies published in Pharmacoepidemiology and Drug Safety. We recommend improved and consistent reporting of code sharing, and adherence to good programming practices in order to maximize the utility of code when this is shared.

Purpose: Removing medicines from market may benefit public health by preventing adverse drug reactions (ADRs), which should be quantified. This study’s aim was to identify a model to quantify the impact of medicines’ marketing authorisation (MA) withdrawal and revocation in terms of morbidity and mortality. Methods: MA withdrawals and revocations for safety reasons in France, Germany, and/or the United Kingdom (UK) between July 2012 and December 2016 were identified for prescription medicines. Annual exposure was estimated for each medicine, using IQVIA Medical Research Data (IMRD)-France, IMRD-Germany, and IMRD-UK primary care electronic health record databases. European Medicines Agency records provided reasons for regulatory action for each medicine. Absolute risks of ADRs in patients exposed to each medicine were estimated by systematic review of quantitative research. Public health impact, expressed as annual number of ADRs avoided, was estimated by modelling exposure and ADR risk. Results: Four MA withdrawals and two revocations met study inclusion criteria. Each product’s usage decreased following MA withdrawal or revocation. Absolute risk for ADRs was 0.1-41.25%. To estimate impact of each withdrawal or revocation, its average annual exposure within each IMRD population was multiplied by the absolute risk to give the crude number of ADRs prevented annually due to regulatory action. Conclusions: This model quantifies the public health impact of MA withdrawal and revocation in terms of serious morbidity, resulting from eliminated or reduced usage of medicines. This method can be applied to products in other settings to quantify the impact of other pharmacovigilance actions.

Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined. Methods: Of 7,538 participants of the Tsuruoka Metabolomics Cohort Study, 3,737（HT: 2,724, DL: 2,137, DM: 665) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥ 0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression. Results: Medication adherence differed by medication groups. Those with DL-only showed the lowest adherence (79.6%), followed by those with DM-only (81.7%) and those with HT-only (89.8%). The associations were observed especially among those with no comorbidities. Determinants associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT, females, having comorbidities, having the medical history of stroke, and drinking habit among those with DL, and skipping breakfast among those with DM. Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support.

Objective To identify primary care recorded factors associated with the short-term human papillomavirus (HPV) vaccination among girls and female adolescents. Methods We used the Spanish Pharmacoepidemiological Research Database for Public Health System to identify girls aged 9-18 years in 2007-2016 with ≥1 year of primary care data (start date) and collect baseline characteristics and consultations. The link between those factors and the 1-year HPV vaccination was assessed through multivariate adjusted Odds Ratios (OR; 95% CI). Results Among 388,669 girls identified, 14,999 were vaccinated against HPV during the first year. The vaccination decreased among girls consulting for social (0.62; 0.55-0.70) or adaptation (0.60; 0.38-0.93) problems, prescriptions of benzodiazepines (0.58; 0.35-0.94) or drugs for gastrointestinal symptoms (0.58; 0.38-0.89), with recorded tuberculosis test (0.68; 0.52-0.87), B and C meningitis (0.46; 0.43-0.50) vaccination, consulting the doctor in the last 3 months (0.92; 0.87-0.98) and with severe thinness (0.68; 0.59-0.78) or obesity (0.88; 0.78-0.99). The odds increased among girls with abdominal pain (1.10; 1.04-1.16), prescriptions in the last 3 months (1.17; 1.10-1.25), and vaccinations against chickenpox (1.16; 1.07-1.27), influenza (1.23; 1.08-1.40), hepatitis (1.46; 1.35-1.58) and diphtheria-tetanus (1.91; 1.82-2.01). Conclusions The correlation between the HPV and other vaccinations suggested medical (contra)indications or willingness and knowledge/beliefs that might affect different vaccinations similarly. The higher frequency of the HPV vaccination among females requiring specific treatments or with abdominal pain suggested vulnerability to HPV complications. While a decreased HPV vaccination linked to certain social and personal situations (and benzodiazepines treatment) requires further research.

Purpose Exposure of hydrochlorothiazide (HCTZ) has been linked to the increase of skin cancer in the Caucasian population, especially for the squamous cell carcinoma (SCC) but not for basal cell carcinoma (BCC). This study aimed to evaluate the risks of skin cancer between patients receiving HCTZ and those receiving other antihypertensives. Methods This retrospective cohort study was derived from the National Health Insurance Database in Taiwan. We enrolled patients aged 20 years and older who newly receiving antihypertensive medications between 2004 - 2015. We calculated the medication possession ratio (MPR) of the first two years of treatment for patient enrollment and treatment classification, in which patients with MPR above 80% were enrolled and patients were subsequently categorized into receiving HCTZ, other thiazide diuretics, non-thiazide diuretics, and non-diuretic antihypertensives. The Cox proportional hazards model was used to evaluate the risk of skin cancer, and further divided into SCC, and BCC. Results Our study enrolled 41,086, 27,402, 19,613, and 856,782 patients receiving HCTZ, other thiazide diuretics, non-thiazide diuretics, and non-diuretic antihypertensives, respectively. We found BCC risks were similar when comparing HCTZ with other thiazides (adjusted hazard ratio, 0.84; 95% CI: 0.54-1.33), non-thiazide diuretics (0.93; 0.51-1.67), and non-diuretic antihypertensives (0.91; 0.66-1.26). Higher SCC risk was observed in the HCTZ group, compared to other thiazide (1.24; 0.74-2.08), non-thiazide diuretics (1.32; 0.70- 2.51), and non-diuretic antihypertensives (1.23; 0.87-1.73), although the differences were not statistically significant. Conclusions We conclude that skin cancer need not be of major concern to physicians when prescribing antihypertensives for an Asian population.

Letter to the Editor Pharmacoepidemiology and Drug SafetyAuthors: Christopher Lee1, Silvia Rizzi 1, Ana Luiza Bierrenbach1, Luis Antunes1, Niina-Maria Nissinen1, Olga Rocha1, Jennifer Campbell2, Caroline Minassian3, Susan Hodgson2, Anne Broe1

Background: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives. Methods: We conducted a cohort study of Optum’s de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups. Results: Of the 87,130 patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95%CI 0.96–1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95%CI 0.97–1.12). Conclusions: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system.

Purpose: In drug studies, research designs requiring no prior exposure to certain drug classes may restrict important populations. Since abuse-deterrent formulations (ADF) of opioids are routinely prescribed after other opioids, choice of study design, identification of appropriate comparators, and addressing confounding by “indication” are important considerations in ADF post-marketing studies. Methods: In a retrospective cohort study using claims data (2006-2018) from a North Carolina private insurer [NC claims] and Merative MarketScan [MarketScan], we identified patients (18-64 years old) initiating ADF or non-ADF extended-release/long-acting (ER/LA) opioids. We compared patient characteristics and described opioid treatment history between treatment groups, classifying patients as traditional (no opioid claims during prior six-month washout period) or prevalent new users. Results: We identified 8,415 (NC claims) and 147,978 (MarketScan) ADF, and 10,114 (NC claims) and 232,028 (MarketScan) non-ADF ER/LA opioid initiators. Most had prior opioid exposure (ranging 64-74%), and key clinical differences included higher prevalence of recent acute or chronic pain and surgery among patients initiating ADFs compared to non-ADF ER/LA initiators. Concurrent immediate-release opioid prescriptions at initiation were more common in prevalent new users than traditional new users. Conclusions: Careful consideration of the study design, comparator choice, and confounding by “indication” is crucial when examining ADF opioid use-related outcomes.

Transparency and reproducibility are major prerequisites for conducting meaningful real-world evidence (RWE) studies that are fit for decision-making. Many advances have been made in the documentation and reporting of study protocols and results, but the principles for version control and sharing of analytic code in RWE are not yet as established as in other quantitative disciplines like computational biology and health informatics. In this practical tutorial, we aim to give an introduction to distributed version control systems (VCS) tailored towards the FAIR ( Findable, Accessible, Interoperable and Reproducible) implementation of RWE studies. To ease adoption, we provide detailed step-by-step instructions with practical examples on how the Git VCS and R programming language can be implemented into RWE study workflows to facilitate reproducible analyses. We further discuss and showcase how these tools can be used to track changes, collaborate, disseminate and archive RWE studies through dedicated project repositories that maintain a complete audit trail of all relevant study documents.

A document by Nicolas Thurin. Click on the document to view its contents.

Purpose Guidelines recommend low-molecular-weight heparins (LMWHs) for patients with cancer associated thrombosis. However, until recently, only dalteparin and tinzaparin were approved in the European Economic Area (EEA) for these patients. This study compares the benefit–risk profile of enoxaparin with dalteparin and tinzaparin, based on real-world evidence (RWE) for the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrence in adult patients with active cancer. Methods A semi-quantitative structured benefit–risk assessment was conducted for the label-extension application of enoxaparin employing the following steps of the benefit–risk action team descriptive framework: define decision context; determine key benefit and risk outcomes; identify data sources; extract data; interpret results. Results The key benefits were defined as reduced all-cause mortality and VTE recurrence (including symptomatic DVT, fatal PE and non-fatal PE); the key risks were major and non-major bleeding of clinical significance. When compared with other EEA-approved LMWHs (dalteparin, tinzaparin), enoxaparin demonstrated a trend toward favourable effects for the reduction of VTE recurrence and all-cause mortality. There was a trend in favour of other LMWHs for major bleeding, and a trend in favour of enoxaparin for non-major bleeding with no evidence of significant difference between enoxaparin and the comparator groups. Conclusions The assessment using RWE demonstrated a favourable benefit–risk profile for enoxaparin similar to that of other EEA-approved LMWHs for the treatment of DVT and PE and the prevention of recurrence in patients with active cancer and thus supported the label-extension approval.