Earl J. Morris

Objectives: To evaluate whether an electronic health record (EHR) cohort has sufficient data quality to support target trial emulation design elements, using Medicare claims as a reference for billing-derived domains and linked EHR-claims data to illustrate the incremental value of linkage. Materials and Methods: We constructed annual University of Florida Health EHR-Medicare linked cohorts of patients ≥65 years with type 2 diabetes (T2D) from 2013 to 2020. Using Medicare claims as the reference, we assessed EHR data quality for target trial emulation-relevant elements across completeness, accuracy, plausibility, and concordance, spanning eligibility, exposure/new-user ascertainment, baseline covariates, outcomes, and follow-up. We also descriptively compared capture of target trial emulation elements across EHR-only, claims-only, and linked data. Results: The mean annual EHR-Medicare linked cohort included 12 895 patients (mean age 74.9 years; 58.0% female). Demographics were complete and highly accurate. In the EHR-only cohort, completeness ranged 34.1%-78.4% for conditions and 53.7%-63.4% for glucose-lowering drugs (GLDs). Accuracy was high for prevalent conditions and GLD use but low for incident measures. Plausible values were common (>98.5%), and hemoglobin A1c-T2D concordance was strong (98.6%). Linking EHR and claims substantially improved completeness and accuracy, especially for encounters, mortality, incident diagnoses, and medications. Discussion: The linked dataset addressed major limitations of EHR-only data and provided enhanced granularity compared to claims alone, offering a comprehensive resource for real-world target trial emulation research. Conclusion: Electronic health records offer valuable clinical details but face data quality challenges. Robust quality assurance strategies and linkage with external data are essential to strengthen real-world evidence and support target trial emulation.

Background: In older adults with osteoarthritis (OA) and hypertension (HTN), analgesic use may elevate blood pressure and cardiovascular risk. Whether comorbid HTN influences initial analgesic choice remains unclear; we examined initial analgesic use in Medicare beneficiaries with incident OA, comparing those with and without HTN. Methods: We conducted a retrospective cohort study using 2011–2022 nationally representative Medicare beneficiaries (≥ 65 years) with incident OA who initiated an analgesic within 30 days of diagnosis and had continuous enrollment for ≥ 365 days prior through ≥ 30 days post‐index. Patients with baseline HTN were classified as OA + HTN; others as OA‐only. We assessed overall analgesic trends using the Cochran‐Armitage test and evaluated differences by HTN status using logistic regression with year as an interaction term. For stratified analyses by joint type, we applied weighted logistic regression. Results: Among 179,033 beneficiaries (mean age 75 ± 7.3 years; 62.7% women; 80.7% White), 57.1% had baseline HTN. Overall, the most commonly initiated analgesic classes were intra‐articular injections (30.3%), and oral NSAIDs only (28.2%). Notable changes from 2012 to 2022 were increase in topical NSAIDs use (3.1%–5.7%) and decrease in opioid combination use (25.4%–13.9%), with no significant trend differences by HTN status. In joint‐specific analyses, OA + HTN versus OA‐only showed no differences in odds of initiating oral opioids (OR: 0.97, 95% CI: 0.92–1.03), intra‐articular injections (OR: 1.01, 95% CI: 0.96–1.07) or topical NSAIDs (OR: 0.88, 95% CI: 0.78–1.01) versus oral NSAIDs. Conclusion: Baseline HTN did not influence the choice of initial analgesic in incident OA patients. Safer, evidence‐based alternatives are needed for older adults with comorbid HTN.

Aims: Predetermined treatment duration limits (PTDLs) are often used by Taiwan's National Health Insurance Administration to contain healthcare costs, but they may compromise patient outcomes. Therefore, we studied Taiwan's 2017 extension of the bevacizumab PTDL from 24 to 36 weeks in metastatic colorectal cancer (mCRC) to evaluate whether prolonged treatment duration improves clinical outcomes, specifically treatment continuity, therapy duration and survival. Methods: We identified two cohorts based on initial bevacizumab prescription dates from the Taiwan Health and Welfare Database: PTDL‐24 weeks (1 April 2013–31 March 2016; n = 2051) and PTDL‐36 weeks (1 April 2017–31 March 2020; n = 2484). We assessed overall survival (OS), progression‐free survival (PFS) and time on treatment (ToT) for first‐line therapy over 2 years. A doubly robust approach was applied, including inverse probability of treatment weighting (IPTW) to balance covariates and Cox proportional hazards models adjusted for calendar year. A two‐stage residual inclusion (2‐SRI) model estimated the impact of the policy on bevacizumab duration and subsequent survival outcomes. Results: After IPTW adjustment, baseline characteristics were well‐balanced. The 36‐week PTDL policy was associated with improved PFS (adjusted hazard ratio: 0.814 [95% confidence interval: 0.691–0.959]) and ToT (0.821 [0.703–0.959]), but not OS (0.926 [0.751–1.142]). The 2‐SRI analysis showed the policy extended bevacizumab treatment by approximately 8 weeks and was associated with improvements in OS (0.912 [0.89–0.934]), PFS (0.941 [0.923–0.959]) and ToT (0.966 [0.95–0.984]). Conclusions: Relaxing the PTDL can extend bevacizumab treatment exposure, improving PFS and ToT.

Objective: Angiotensin‐II Receptor Blockers (ARBs) are commonly prescribed; however, their adverse events may prompt new drug prescriptions, known as prescribing cascade (PC). We aimed to identify potential ARB‐induced PCs using high‐throughput sequence symmetry analysis. Methods: Using claims data from a national sample of Medicare beneficiaries (2011–2020), we identified new ARB users aged ≥ 66 years with continuous enrollment ≥ 360 days before and ≥ 180 days after ARB initiation. We screened for initiation of 446 other (non‐antihypertensive) “marker” drug classes within ±90 days of ARB initiation. Sequence ratios (SRs) with 95% confidence intervals (CIs) were calculated as the ratio of the number of ARB users initiating the marker class after versus before ARB initiation. Adjusted SRs (aSRs) accounted for prescribing trends over time, and for significant aSRs, we calculated the naturalistic number needed to harm (NNTH); significant signals were reviewed by clinical experts for plausibility. Results: We identified 320,663 ARB initiators, age (mean ± standard deviation) 76.0 ± 7.2 years; 62.5% female; and 91.5% with hypertension. Of the 446 marker classes evaluated, 17 signals were significant, and three (18%) were classified as potential PCs after clinical review. The strongest signals ranked by the lowest NNTH included benzodiazepine derivatives (NNTH 2130, 95% CI 1437–4525), adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (NNTH 2656, 95% CI 1585–10,074), and other antianemic preparations (NNTH 9416, 95% CI 6606–23,784). The strongest signals ranked by highest aSR included other antianemic preparations (aSR 1.7, 95% CI 1.19–2.41), benzodiazepine derivatives (aSR 1.18, 95% CI 1.08–1.3), and adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (aSR 1.12, 95% CI 1.03–1.22). Conclusion: The identified PC signals reflected known and possibly under‐recognized ARB adverse events in this Medicare cohort. These hypothesis‐generating findings require further investigation to determine the extent and impact of these PCs on patient outcomes.

Background: Loop diuretic (LD) use may lead to a prescribing cascade whereby urinary symptoms are ascribed to genitourinary syndromes and treated with urinary symptom medications (USMs). We investigated if LDs lead to increased USM use among older adults and whether this potential prescribing cascade varies across key characteristics. Methods: This was a prescription sequence symmetry analysis of Veterans Administration data, involving veterans ≥66 years who initiated treatment with LD (2010-2019). USMs were antimuscarinics, beta-3 adrenergic agonists, peripheral alpha-1 blockers, and 5-alpha reductase inhibitors. We calculated the adjusted sequence ratio (aSR), assessing the cascade signal while adjusting for secular trends, and stratified by key variables. Results: There were 17 735 veterans who initiated USM within 6 months after LD and 25 190 who initiated USM within 6 months before LD; 99% were male. Unexpectedly, the aSR was 0.74 (95% CI, 0.73-0.76), meaning patients were 26% less likely to initiate USM within 6 months after initiating LD versus 6 months before. This inverse relationship held in men (aSR, 0.74, 95% CI, 0.72-0.76) but was null in women (aSR, 1.00, 95% CI, 0.80-1.26). In men without baseline urinary symptoms, we observed the LD–USM cascade in patients with heart failure (aSR 1.52, 95% CI, 1.41-1.63) and multimorbidity (eg, Charlson fourth quartile, aSR 1.24, 95% CI, 1.10-1.39). Conclusions: We did not find evidence for an LD–USM cascade among predominantly male older adults overall. Clinicians may underprescribe USMs in patients receiving LDs, perhaps due to strong attribution of urinary symptoms to LD use.

Purpose Comorbid insomnia and sleep apnea (COMISA) is a prevalent clinical syndrome. We characterized differences in characteristics and medication use patterns between participants with COMISA and those with sleep apnea alone. Methods Data used came from 2018 Health and Retirement Study, a nationally representative cohort study of U.S. middle-aged and older adults. Participants were asked if “a doctor had ever told them they have a sleep disorder” and which disorder. They also reported frequency of insomnia symptoms (i.e., “falling asleep,” “waking during the night,” “waking too early,”) and how often they “felt rested in the morning.” We tested differences in demographic and clinical characteristics as well as medication use between participants with COMISA vs. those with sleep apnea alone by using logistic regression. Results Out of N = 1,776 with sleep apnea, 47% had COMISA. Compared to those with sleep apnea alone, participants with COMISA were more likely to be female (p = 0.032), have lower education (p < 0.001), and report lung disease, stroke, psychiatric problems, and dementia/cognitive impairment (all p’s < 0.001). They reported difficulty in functioning (i.e., activities of daily living), and greater depressive symptomatology (all p’s < 0.001). Finally, they were more likely to report the use of opioids (p = 0.037), stomach (p = 0.028), and sleep medications (p < 0.001). Conclusions Compared to those with sleep apnea alone, COMISA participants had a more medically complex health profile and medication use that may exacerbate sleep apnea (e.g., opioids and sleep medications). Future research should focus on managing COMISA in medically complex patients for improved health outcomes.

Purpose: Angiotensin‐converting enzyme inhibitors (ACEIs) are commonly prescribed, but their adverse effects may prompt new drug prescription(s), known as prescribing cascades (PCs). We aimed to identify potential ACEI‐induced PCs using high‐throughput sequence symmetry analysis.Methods: Using claims data from a national sample of Medicare beneficiaries (2011–2020), we identified new ACEI users aged ≥ 66 years with continuous enrollment ≥ 360 days before and ≥ 180 days after ACEI initiation. We screened for initiation of 446 other (non‐antihypertensive) “marker” drug classes within ±90 days of ACEI initiation, generating sequence ratios (SRs) reflecting proportions of ACEI users starting the marker class after versus before ACEI initiation. Adjusted SRs (aSRs) accounted for prescribing trends over time. For significant aSRs, we calculated the naturalistic number needed to harm (NNTH), and significant signals underwent clinical review for plausibility.Results: We identified 308 579 ACEI initiators (mean age 76.1 ± 7.5 years; 59.6% female; 88.6% with hypertension). Of 446 marker classes evaluated, 81 signals were significant, and 42 (52%) classified as potential PCs after clinical review. The strongest signals ranked by lowest NNTH included corticosteroids (NNTH 313; 95% CI, 262–392) and serotonin type 3 (5‐HT₃) antagonists (NNTH 496; 95% CI, 392–689); the strongest signals ranked by highest aSR included sympathomimetics (aSR, 1.97; 95% CI, 1.10–3.53) and other antianemic preparations (aSR, 1.87; 95% CI, 1.31–2.67).Conclusion: Identified prescribing cascade signals were indicative of known and possibly underrecognized ACEI adverse events in this Medicare cohort. The findings are hypothesis‐generating and require further investigation to determine the extent and impact of the identified PCs on health outcomes.

Purpose: Concomitant use of hormonal contraceptive agents (HCAs) and enzyme‐inducting antiepileptic drugs (EIAEDs) may lead to contraceptive failure and unintended pregnancy. This review identified and evaluated concordance and quality of clinical treatment guidelines related to the use of HCAs in women with epilepsy (WWE) receiving EIAEDs.Methods: Relevant clinical guidelines were identified across four databases and were independently evaluated for quality utilizing the AGREE‐II protocol instrument. Quality in this context is defined as the rigor and transparency of the methodologies used to develop the guideline. Guidelines were further assessed in terms of concordance and discordance with the latest body of knowledge concerning the use of hormonal contraception in the presence of EIAEDs.Results: A total of n = 5 guidelines were retrieved and evaluated. Overall guideline scores ranged from 17% to 92%, while individual domain scores ranged from 0% to 100%. Contraceptive guidelines consistently recommended the use of intrauterine systems and long‐acting injectables in the presence of EIAEDs, recommended against the use of oral, transdermal, and vaginal ring contraceptives, and differed regarding recommendations related to implants. Guidelines agreed regarding recommendations that women treated with EIAEDs should receive intrauterine systems and long‐acting injectables; however, the suggested frequency of administration of injectable contraceptives differed. The use of intrauterine systems in this population is supported by evidence, but there is uncertainty surrounding the use of long‐acting injectables and contraceptive implants.Conclusions: To mitigate the risk of unintended pregnancy and its consequences, recommendations related to implants and long‐acting injectable contraceptives should be evidence‐based.