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 2005, the Food and Drug Administration (FDA) issued a decision memorandum regarding nonsteroidal anti-inflammatory drugs (NSAIDs). The memorandum recommended the withdrawal of certain NSAIDs due to potential cardiovascular adverse effects. It highlighted the issue of cardiovascular risk associated with NSAIDs as a class. The NSAID medication guide includes a wide range of adverse drug reactions (ADRs), such as increased blood pressure, liver failure, allergic reactions, heart attack, and intestinal bleeding. Although both sexes have an increased risk of ADRs with NSAID use, females have a greater risk than males due to differences in pharmacodynamics and higher medication concentrations (mg/kg). The prevalence of NSAIDs and the disparity in risk of ADRs by sex within this class of medications make this a significant public health issue. This study quantifies sex-specific differences and other factors associated with prescription NSAID use. Method: The data for this study was obtained from the National Health and Nutrition Examination Survey (NHANES), a complex survey conducted by the Centers for Disease Control and Prevention (CDC) in two-year cycles. NHANES is designed to make inferences about the health of the US civilian noninstitutionalized population. A survey-weighted logistic regression model was utilized to investigate potential sex differences with prescription NSAIDs in the context of other factors including kidney disease, hypertension, liver disease, insurance status, coronary heart disease, and age within the 2011-2018 NHANES survey data. Results: Females reported a slightly higher percentage of high blood pressure and kidney disease than males, while males reported a slightly higher percentage of coronary heart and liver disease than females. Furthermore, a larger percentage of females reported having health insurance coverage than males. Last, the model indicated that females were 58% more likely to have used a prescription NSAID than males. Conclusion: The results confirm that women and people with medical conditions, who would potentially suffer greater harm from NSAID ADRs, are more likely to use a prescription NSAID than individuals without these conditions. Therefore, it is crucial to continue investigating the safety and efficacy of medications, particularly in specific populations, to reduce the risk of harmful side effects from medication use.
Objective: Given difficulty in discontinuing prescribed benzodiazepines and potential harms to people from chronic benzodiazepine use, it is important to understand medical and mental health conditions associated with re-prescription. This study sought to estimate benzodiazepine re-prescription incidence rates among Veterans in the United States Veterans Health Administration (VHA) and identify predictors of re-prescription among Veterans who discontinued benzodiazepines. Methods: This longitudinal study used VHA administrative data from patients’ electronic health records in Fiscal Year 2019. Patients with chronic (>30 days) benzodiazepine prescriptions who were not prescribed benzodiazepines continuously for the entire year were identified based on pharmacy records (n=151,777). We used Kaplan-Meier methods and a Cox proportional hazards model to estimate benzodiazepine re-prescription incidence rates. Unadjusted and adjusted hazard ratios were used to examine demographic and clinical characteristics as predictors of benzodiazepine re-prescription. Results: Among 151,777 patients who did not refill a benzodiazepine prescription for ≥30 days, 50% were re-prescribed benzodiazepines within 2.5 months. Benzodiazepine re-prescription was associated with mental health conditions (e.g., anxiety, PTSD). Patients were less likely to be re-prescribed benzodiazepines if they had a history of an alcohol or drug use disorder, neurological disorder other than paralysis, chronic heart failure, dementia, and hospice care. Conclusions: The short gap between benzodiazepine prescriptions ending and being re-prescribed suggests patients have difficulty discontinuing prescribed benzodiazepines. More investigations are needed on the medical necessity of chronic benzodiazepines and strategies for increasing guideline concordant care.
Purpose To examine whether low-density lipoprotein cholesterol (LDL-C) levels influence the cardiovascular risk associated with non-aspirin non-steroidal anti-inflammatory drug (NSAID) use after myocardial infarction (MI). Methods Using Danish health registries, we conducted a population-based cohort study of all adult patients with first-time MI during 2010–2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and a high LDL-C group (<3.0 vs. ≥3.0 mmol/L). We used time varying Cox regression to compute hazard ratios (HRs) with 95% confidence intervals of the association between NSAID use and a major adverse cardiovascular event (MACE: recurrent MI, ischemic stroke, and all-cause death). Results We followed 50,573 patients for a median of 3.1 years. While exposed, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11–1.32) overall, 1.19 (1.06–1.33) in the low LDL-C group, and 1.23 (1.07–1.41) in the high LDL-group. The HRs for recurrent MI and ischemic stroke were comparable between the LDL-C subgroups. The HRs for all-cause death were 1.22 (1.07–1.39) in the low LDL-C group and 1.54 (1.30–1.83) in the high LDL-C group. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results. Conclusion In patients with MI, LDL-C levels did not influence the increased risk of MACE associated with NSAID use, but might influence the association between NSAID use and all-cause death.
Purpose: To determine the proportion of Australians dispensed psychotropic medications between 2013 and 2022 according to their age. Methods: Services Australia provided a de-identified 10% random Pharmaceutical Benefits Scheme (PBS) sample that allowed us to determine the proportion of Australians dispensed at least one script per year for the use of antipsychotics, antidepressants, anxiolytics, and hypnotics. The classification of medications followed Anatomical Therapeutic Chemical (ATC) coding. Participants were stratified into 10-year age groups from 0-9 to ≥90 years, and sex was coded as male/female. We used logit models to analyse the data. Results: The number of records per year ranged from 1,540,520 to 1,746,402, and 54.10% were for females. A greater proportion of older adults, particularly those aged ≥70 years, were dispensed antipsychotics, antidepressants, anxiolytics, and hypnotics than any other age-group. The proportion of people dispensed antipsychotics, anxiolytics, and hypnotics declined between 2013 and 2022, but increased for antidepressants, most markedly for adolescents and young adults. Females were more frequently dispensed antidepressants, anxiolytics, and hypnotics than males, but males were more frequently dispensed antipsychotics than females. Conclusions: Older age groups and females are the most frequent recipients of psychotropic medications dispensed in Australia. The organisation and resourcing of health services should reflect this reality.
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.
Purpose TransCelerate BioPharma conducted a survey of biopharmaceutical companies to evaluate current practice and identify opportunities to complement safety signal assessment with rapid real-world data (RWD) analysis. Methods A voluntary 30-question survey regarding use of RWD in safety signal assessment was disseminated to subject matter experts at all TransCelerate member companies in July 2022. Responses were blinded, aggregated, summarized, and presented. Results Eighteen of 20 member companies participated in the survey. Sixteen (89%) companies reported actively leveraging RWD in their signal assessment processes. Of 18 respondent companies, 8 (44%) routinely use rapid approaches to RWD analysis, 7 (39%) utilize rapid RWD analysis non-routinely or in a pilot setting, 2 (11%) are considering using rapid RWD analysis, and 1 (6%) has no plans to use rapid RWD analysis for their signal assessment. Most companies reported that RWD adds context to and improves quality of signal assessments. To conduct RWD analysis for signal assessment, 16 of 17 (94%) respondent companies utilize or plan to utilize internally available data, 8 (47%) utilize both internal and external data, and 3 (18%) utilize data networks. Respondents identified key challenges to rapidly performing RWD analyses, including data access/availability, time for analysis execution, and uncertainties regarding acceptance of minimal or non-protocolized approaches by health authorities. Conclusion Biopharmaceutical companies reported that they see value in the use of rapid RWD analyses for complementing signal assessments. Future work is recommended to offer a framework and process for use of rapid use of RWD analyses in signal assessment.
Purpose: To explore the differences among erectile aids (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal drugs) of the relative risk of priapism and identify age groups at risk. Methods: We queried the World Health Organization global database of individual case safety reports (VigiBase) for records of the ADR with sildenafil, tadalafil, avanafil, vardenafil, papaverine, and alprostadil. Disproportionality analyses (case/non-case approach) were performed to assess the relative risk of priapism reporting in PDE5i consumers compared to intracavernousal drug recipients. Results: From a total of 133,819 ADR events for erectogenic medications, 632 were priapism (PDE5is: n=550, 0.41%; intracavernousal drugs: n=82, 9.92%). We observed a strong signal for priapism induction for intracavernousal drugs than PDE5is (reporting odds ratio [ROR]=34.7; confidence interval [CI] 95%: 27.12 - 43.94 vs. ROR= 1.38; CI 95%: 1.24 - 1.54). For all PDE5i agents, the 12-17 years age group had the highest highest ROR (ROR=9.49, CI 95%: 3.76 - 19.93) followed by 2-11 years (ROR=4.31, CI 95%: 1.57 - 9.4). Disproportionality signals for consumers under eighteen for both all PDE5is as a whole (ROR=4.57, CI 95%: 2.48 - 7.73) and sildenafil (ROR=4.89, CI 95%: 2.51 - 8.62) were significantly stronger than individuals eighteen or older (ROR=1.06, CI 95%: 0.93 - 1.21 and ROR=1.08, CI 95%: 0.91 - 1.26, respectively). Conclusions: While the overall risk of priapism following the oral administration of PDE5is is extremely low compared with intracavernousal remedies, adolescents are at a higher risk of priapism than older men.
Purpose: With the expansion of research utilizing electronic healthcare data to identify transgender (TG) population health trends, the validity of computational phenotype algorithms to identify TG patients is not well understood. We aim to identify the current state of the literature that has utilized CPs to identify TG people within electronic healthcare data and their validity, potential gaps, and a synthesis of future recommendations based on past studies. Methods: Authors searched the National Library of Medicine’s PubMed, Scopus, and the American Psychological Association Psyc Info’s databases to identify studies published in the United States that applied CPs to identify TG people within electronic health care data. Results: Twelve studies were able to validate or enhance the positive predictive value (PPV) of their CP through manual chart reviews (n=5), hierarchy of code mechanisms (n=4), key text-strings (n=2), or self-surveys (n=1). CPs with the highest PPV to identify TG patients within their study population contained diagnosis codes and other components such as key text-strings. However, if key text-strings were not available, researchers have been able to find most TG patients within their electronic healthcare databases through diagnosis codes alone. Conclusion: CPs with the highest accuracy to identify TG patients contained diagnosis codes along with components such as procedural codes or key text-strings. CPs with high validity are essential to identifying TG patients when self-reported gender identity is not available. Still, self-reported gender identity information should be collected within electronic healthcare data as it is the gold standard method to better understand TG population health patterns.
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.