OBJECTIVES:Ageism remains a pervasive barrier to delivering high-quality health care to older adults. The objective of this scoping review is to describe studies on educational interventions aimed at improving the empathy and attitudes of student pharmacists toward aging and older adults. FINDINGS:Of the 723 studies retrieved, 9 studies were eligible for inclusion. Studies were conducted in the United States (5), Malaysia (1), Brazil (1), Australia (1), and Singapore (1). Most studies (n = 8) used a single-group pre/post-test design, whereas 1 study employed a randomized, parallel-group, open-label design. Six studies employed direct interventions (ie, simulation-based, direct interaction with older adults, or technology-based), and 3 studies employed curriculum-based interventions (ie, geriatrics elective or Advanced Pharmacy Practice Experience). Seven studies utilized validated tools to measure empathy and attitudes, including the Geriatric Attitude Scale (n = 3), the Jefferson Scale of Empathy-Health Professions Students (n = 3), and the Kiersma-Chen Empathy Scale (n = 3). The 8 studies that used a pre/post-test design reported improvements in empathy or attitudes on at least 1 tool. The randomized study assessing an aging simulation suit found no significant differences between the intervention and control groups immediately following the intervention or at 12 weeks. SUMMARY:Although studies using quasi-experimental designs reported that interventions improved student pharmacists' empathy or attitudes toward aging or older adults, the randomized study did not support these findings. This review highlights the need for more rigorous research to evaluate interventions to improve empathy and attitudes in student pharmacists.

BACKGROUND:Little is known about substitution of alternative medications in the context of deprescribing. The objectives were to: (1) determine the frequency of medication substitutions among those who discontinued a central nervous system (CNS)-active medication, and (2) characterize substitutions as potentially inappropriate (as per the 2023 Beers Criteria) versus not. METHODS:We conducted a secondary analysis that combined data from the intervention and usual care arms from the STOP-FALLS deprescribing trial that tested a health-system-embedded intervention designed to reduce prescription of CNS-active medications. This analysis focused on participants followed for 360 days following baseline with chronic use of opioids, benzodiazepines, tricyclic antidepressants, skeletal muscle relaxants, or Z-drugs. Discontinuation was defined as the first date when there was no evidence of a prescription fill for 90 days, thus only participants with a discontinuation that occurred in the first 270 days were included. A list of likely alternative treatments was developed for each target medication. A substitution was operationalized as a new alternative medication prescribed during the 30 days prior to or 60 days after discontinuation of a target medication. RESULTS:The study sample included 2182 individuals (average age 70.5 years, 63.1% female). At baseline, a total of 2415 target medications were prescribed, of which 442 (18.3%) were discontinued. Discontinuation rates varied from 122 (8.0%) for users of opioids to 86 (49.7%) for users of skeletal muscle relaxants. Substitutions were made for 42 (9.5%) drug discontinuations. Of these substitutions, 11 of 42 (26.2%) were to a potentially inappropriate medication: tricyclic antidepressants (n = 5), benzodiazepines (n = 3) and hydroxyzine (n = 3). Other common substitutions included gabapentin, selective serotonin norepinephrine reuptake inhibitors, and trazodone. DISCUSSION:Of medication discontinuations with a substitution, one-quarter were to at least one potentially inappropriate medication. This finding highlights the need for additional guidance for prescribers to ensure safe deprescribing of CNS-active medications.

Importance:Antihypertensive medications that stimulate angiotensin II type 2 or 4 receptors (angiotensin II-stimulating medications) may be associated with lower risk of dementia. Objective:To examine associations between cumulative exposure to angiotensin II-stimulating vs angiotensin II-inhibiting antihypertensive medications and neuropathology, accounting for blood pressure. Design, Setting, and Participants:This community-based autopsy cohort study from the Adult Changes in Thought cohort was conducted at Kaiser Permanente Washington between February 24, 1994, and November 25, 2022, among 756 participants who had blood pressure measurements and at least 1 person-year (PY) of angiotensin II-stimulating or -inhibiting antihypertensive medication exposure prior to death. Statistical analysis was performed between September 2024 and August 2025. Exposure:Angiotensin II-stimulating antihypertensive medications (angiotensin II receptor blockers, dihydropyridine calcium channel blockers, thiazides) and angiotensin II-inhibiting antihypertensive medications (angiotensin-converting enzyme inhibitors, β-blockers, nondihydropyridine calcium channel blockers) were ascertained from paper-based medical records (before 1977) and electronic prescription fill data (after 1977). The primary exposure was cumulative angiotensin II PYs, and the secondary exposure was long-term use (≥15 years). Main Outcomes and Measures:Neuropathology outcomes were classified as Alzheimer disease related, vascular brain injury, or other. Exploratory outcomes included quantitative measures of Aβ42 and phosphorylated tau. Data were analyzed using multivariable modified Poisson, proportional odds, and linear regression models and accounted for potential selection bias. Results:The sample included 756 participants (mean [SD] age at death, 89.2 [6.4] years; 440 women [58.2%]; mean [SD] follow-up, 22.2 [13.5] years). Compared with exposure to 5 additional PYs of angiotensin II-inhibiting antihypertensive medications, exposure to 5 additional PYs of angiotensin II-stimulating antihypertensive medications was associated with a 6% lower risk for arteriolosclerosis (relative risk [RR], 0.94; 95% CI, 0.89-0.99), with long-term use associated with a 24% lower risk (RR, 0.76; 95% CI, 0.63-0.91). For exploratory outcomes, PYs of angiotensin II-stimulating antihypertensive medications were associated with less quantitative phosphorylated tau burden in several brain regions (temporal lobe [adjusted ratio of geometric means, 0.79; 95% CI, 0.62-1.00], hippocampus [adjusted ratio of geometric means, 0.83; 95% CI, 0.71-0.97], cornu ammonis subfield 1 [adjusted ratio of geometric means, 0.86; 95% CI, 0.74-0.99], and transentorhinal cortex [adjusted ratio of geometric means, 0.83; 95% CI, 0.70-0.98]) but not with Aβ42 quantitative measures. Conclusions and Relevance:In this community-based autopsy cohort study, angiotensin II-stimulating antihypertensive medications were associated with lower risk of neuropathological burden, supporting findings from epidemiologic dementia studies. Additional mechanistic research examining the effects of individual antihypertensive classes on Alzheimer disease-related biomarkers is warranted.

INTRODUCTION:Falls are common among older people, and medications, in particular central nervous system-active medications, increase fall risk. The Centers for Disease Control and Prevention funded a pragmatic trial to test a deprescribing intervention (STOP-FALLS) for its effect on falls, while simultaneously collecting implementation process data. This article describes prospective modifications to the STOP-FALLS intervention and offers a summary of the strategies deployed per reporting recommendations from implementation science. METHODS:In a preimplementation phase for this pragmatic trial, the multidisciplinary research team collaborated with delivery system leaders to modify the intervention for this new context, held focus groups with end users representative of the new population to optimize patient educational brochures, and pilot-tested the intervention in a single clinic. This study took place in the Kaiser Permanente Washington integrated health care delivery system, primary care settings. Preimplementation activities were systematically tracked using 2 established implementation frameworks for: 1) intervention adaptation and 2) strategy deployment. RESULTS:Twenty-seven adaptations were made to STOP-FALLS, and 13 discrete implementation strategies were deployed across the 3 preimplementation phases of the study. CONCLUSION:Adaptation tracking revealed several changes to the intervention context and content that reflected different guidelines for this trial (eg, include opioid medications) and idiosyncrasies of Kaiser Permanente Washington delivery system operations, in addition to refinements to optimize the intervention according to patient and primary care practitioner preferences. Implementation strategies were not specific to the focus of the trial and may reflect best practices for health system-embedded pragmatic effectiveness trials moving forward.

Introduction: Proton pump inhibitors (PPI) could impact blood pressure regulation by suppressing gastric acid required for the conversion of oral nitrite into nitric oxide. Whether PPI use is associated with incident hypertension remains unknown. Methods: We included 64,720 postmenopausal women who were free from cardiovascular disease and hypertension at enrollment into the Women’s Health Initiative Observational Study (1993-1998). Baseline PPI use and duration was ascertained from medication inventories. The outcome was physician diagnosed-treated hypertension, assessed by self-report on annual questionnaires. Kaplan-Meier curves were used to visualize unadjusted annualized incident hypertension according to baseline PPI use. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazard models for incident hypertension according to baseline PPI use (no/yes) and duration (< 1 year, 1-3 years, >3 years). Propensity score adjustment was used to account for residual confounding by indication. Results: A total of 28,951 cases of incident hypertension were accrued after a mean follow up of 8.7 years. PPI users had significantly higher annualized hypertension incidence compared to non-users over the follow-up time (Figure). PPI use was associated with 15% higher risk of hypertension compared to non-use in the fully adjusted model (HR: 1.15, 95%CI: 1.06-1.25) and the association remained significant after propensity score adjustment (HR: 1.17, 95%CI: 1.14-1.19). Longer PPI use durations were associated with higher risk of hypertension (HR: 1.11, 1.16, 1.28, respectively) and showed a significant trend (P <.001). Conclusions: PPI use was associated with higher risk of diagnosed hypertension in postmenopausal women after adjusting for relevant confounders. The association showed a significant trend according to PPI duration of use. More research is needed to confirm such results.

Abstract BACKGROUND Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including increased risk in dementia. Pharmacoepidemiology studies from various populations report associations between specific anticholinergic classes – antidepressants and bladder antimuscarinics – and increased dementia incidence. However, it is difficult to determine whether these associations are directly caused by the neurotoxic effects of anticholinergic drugs or by the underlying health conditions which the medications are taken for, known as confounding by indication. Here, we leverage human induced pluripotent stem cells‐derived‐neurons (hiPSC‐Ns) to complement the pharmacoepidemiology studies by directly examining the effects of various anticholinergic classes on dementia‐related cellular phenotypes. METHODS We treated human induced pluripotent stem cell (hiPSC)–derived neurons with eight drugs representing different AC medication classes, including antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics. We analyzed these neurons for cytotoxicity, amyloid beta (Aβ) peptide levels in the conditioned medium, and the level of intracellular phosphorylated tau from these cultures. RESULTS We observed that antidepressants and bladder antimuscarinics were consistently cytotoxic, whereas antihistamines and antispasmodics did not show overt cytotoxicity at the times and concentrations that we tested. Some of the cytotoxic medications altered the amounts of Aβ1‐42 peptides, but there were no significant differences in the intracellular ratio of phosphorylated tau/total tau between AC drug treatments. CONCLUSIONS These results corroborate population‐based studies and suggest a molecular basis for the differences in dementia risk observed according to AC class. This warrants future work examining the effect of AC medications on hiPSC‐derived cells from multiple subjects and examining other molecular outcomes including synaptic function and neuroinflammation in hiPSC‐based models. Highlights Certain classes of anticholinergic (AC) medications are linked to dementia. Human‐induced pluripotent stem cell (hiPSC) models are used to directly test the cytotoxicity of AC medications. AC classes that are associated with dementia are more neurotoxic.

Background Proton pump inhibitors (PPIs) could affect blood pressure regulation by suppressing gastric acid required for the conversion of oral nitrite into nitric oxide. Whether PPI use is associated with incident hypertension remains unknown. Methods We included 64 720 menopausal women who were free from cardiovascular disease and hypertension at enrollment in the Women's Health Initiative Observational Study (1993-1998). Baseline PPI use and duration were determined using medication inventories. The outcome was physician diagnosed/treated incident hypertension, assessed by self-report on annual questionnaires. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazard models for incident hypertension according to baseline PPI use (no/yes) and duration (<1 year, 1-3 years, >3 years). The association between PPI use and 3-year changes in measured blood pressure was examined using linear regression. Results There were 28 951 cases of incident hypertension after a mean follow-up of 8.7 years. PPI use was associated with 17% higher risk of hypertension compared with nonuse in the fully adjusted model (HR, 1.17 [95% CI, 1.08-1.27]). Longer PPI use durations were significantly associated with incrementally higher risk of hypertension (HR, 1.13, 1.17, 1.28, respectively; trend P<0.001). The 3-year change in multivariable-adjusted mean systolic blood pressure increased significantly for PPI new users (+3.39 mm Hg, P=0.049) compared with never users. Conclusions PPI use was associated with higher risk of diagnosed hypertension in menopausal women, and the risk showed a significant trend according to longer duration of use. Further studies are needed to confirm these findings.

Improving the quality of medication use and medication safety are important priorities for healthcare providers who care for older adults. The objective of this article was to identify four exemplary articles with this focus in 2023. We selected high-quality studies that advanced this field of research. The chosen articles cover domains related to deprescribing/discontinuation, optimizing medication use, medication safety/adverse drug events, and other. The first study was a randomized clinical trial evaluating the efficacy of the patient-centered Shed-MEDS deprescribing intervention among older adults transitioning from the hospital to postacute care facilities (domain: deprescribing/discontinuation). The second study, a retrospective cohort study among Medicare beneficiaries, described the phenomenon of a prescribing cascade relic and evaluated continued potassium use after discontinuation of a loop diuretic (domain: optimizing medication use). The third study was a systematic review and meta-analysis describing the prevalence of drug-drug interactions among community-dwelling older adults (domain: other). Lastly, the fourth study was a retrospective cohort study among Medicare beneficiaries that evaluated concurrent gabapentin and opioid use and risk of mortality (domain: medication safety). Collectively, this review succinctly highlights pertinent topics related to promoting safe use of medications and promotes awareness of optimizing older adults' medication regimens.

Anticholinergic medication use has been found to be associated with higher dementia risk and cognitive decline in older adults. The presence of a biologic pathway through changes to white matter hyperintensities (WMH) remains unclear. We used the first clinically indicated magnetic resonance imaging (MRI) scan from each participant in the Adult Changes in Thought (ACT) Study—a prospective cohort study within Kaiser Permanente Washington (KPWA)—collected between January 2003 and March 2020 from participants ≥65 years old and with ≥10 years of continuous KPWA enrollment prior to the scan. Our primary cumulative exposure was total standardized daily dose (TSDD) of anticholinergic medications in the 10 years prior to the scan, grouped as non-use, 1-90 TSDD, 91-365 TSDD, 366-1095 TSDD, and ≥1096 TSDD. Neuroimaging outcomes were common data elements (CDEs) for WMH on MRI scans (Fazekas, Scheltens, Age-Related White Matter Changes [ARWMC]). We used separate linear regression models for each outcome to estimate adjusted mean values of CDEs in each exposure group and test for differences in mean values. Of the 1,043 individuals included in analyses, 28% had no use, 33% had 1-90 TSDD, 15% had 91-365 TSDD, 7% had 366-1095 TSDD, and 17% had ≥1096 TSDD. The mean age at the time of the scan was 81 years among a group that was majority female (58%) and White (88%). While most individuals were exposed to antihistamines (38%) among all anticholinergic classes, 65% of TSDD were accrued from antidepressants. Compared to no use, the ≥1096 TSDD group had a higher (worse) adjusted mean Fazekas (4.0 vs. 3.4; p: <0.001), Scheltens (14.3 vs. 12.2; p: <0.001), and ARWMC (5.6 vs. 4.8; p = 0.001). A dose-response relationship was not found, but adjusted mean outcomes values were observed to be higher (worse) in the 1-90 TSDD group relative to the no use group. The highest anticholinergic burden was associated with greater WMH burden among older individuals who received an MRI due to clinical indications. The lack of a demonstrated dose-response relationship warrants further research into biological mechanisms underlying the link between anticholinergic use and WMH burden.

Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including dementia risk. Evidence from population studies suggests that dementia risk may vary by AC class. This variation might be explained by confounding by indication. In vitro models, using human neural cells where cells are directly experimentally exposed to a drug and phenotypic outcomes are measured, may address this issue. We identified classes of AC medications with and without an association with dementia based on population studies. We treated human induced pluripotent stem cell-derived neurons (hiPSC-Ns) with each AC medication and performed cellular assays to examine the effects on AD phenotypes. We have generated hiPSC lines from participants in the Adult Changes in Thought Study (ACT), a longitudinal study in Seattle, WA. We differentiated hiPSC-Ns from ACT cell lines using protocols in our laboratory. We treated neurons with different classes of AC medications: antidepressants (amitriptyline, doxepin, paroxetine), antihistamines (diphenhydramine, chlorpheniramine), bladder antimuscarinics (oxybutynin, tolterodine), and antispasmodics (atropine). As a control, we treated cells with the classic cholinergic compound carbachol. Cells were treated with two drug doses (10 uM, 50 uM) at two time points (24 hours, 48 hours). We used molecular assays to test AD-associated cellular outcomes (neurotoxicity, synaptic gene expression and Amyloid beta [Aβ]). We document differential effects of medications on cytotoxicity, secreted Aβ levels, and synaptic gene expression. Several drugs demonstrated dose-dependent (doxepin, oxybutynin, paroxetine, amitriptyline) and/or time dependent (oxybutynin, paroxetine) neurotoxicity. We also observed differential effects on Aβ secretion. Oxybutynin, a bladder antimuscarinic, consistently induced an increase in the Aβ42/40 ratio, largely driven by increased secreted Aβ42. Further, all antidepressants and bladder antimuscarinics tested increased the secreted Aβ42/40 ratio at 50 uM. These findings are consistent across lines of different genetic backgrounds. Stem cell-derived neuronal models provide a useful strategy to complement pharmacoepidemiological studies to help distinguish molecular pathways versus confounding by indication of drugs associated with dementia risk. Preliminary results suggest that different AC medications have differential effects on AD-associated cellular outcomes that are consistent across hiPSC-Ns derived from individuals with various genetic backgrounds, indicating a molecular effect of the drug.

Central nervous system (CNS)-active medications pose serious health risks for older adults with dementia but are nonetheless commonly used. Few deprescribing interventions have focused on people with dementia. We conducted a one-arm pilot study in six primary care practices of an integrated healthcare system between February and August 2023. The deprescribing intervention consisted of patient/care partner education and self-management materials and provider decision support. Participants were aged 60+ with diagnosed dementia and prescribed at least one CNS-active medication for three or more months of the six-month period prior to study start. We assessed feasibility and acceptability of the intervention and feasibility of ascertaining medication discontinuation and medically treated falls. The intervention was delivered to all (N = 114) eligible participants; their mean age was 80 ± 9 years; 72% were female and 13% non-White. Intervention acceptability, assessed by Weiner’s Acceptability of Intervention measure, was rated 3.5/5 (range 1–5; higher scores indicate higher acceptability). Among baseline antipsychotic users (N = 89), 39 (43.8%) had discontinued at follow-up. Among baseline tricyclic antidepressant users (N = 11), 6 (54.5%) had discontinued at follow-up. Among baseline skeletal muscle relaxant users (N = 3), 2 (66.7%) had discontinued at follow-up. Among baseline benzodiazepine users (N = 3), 1 (33.3%) had discontinued at follow-up. Among baseline opioid users (N = 13), 1 (7.7%) had discontinued at follow-up. Medically treated falls occurred among 22% at baseline vs. 21% at follow-up. The intervention is feasible and acceptable and may achieve meaningful reduction in CNS-active medication prescriptions. Findings support a controlled trial with sufficient power to assess effects on relevant clinical outcomes.

Importance:Anticholinergics have been associated with functional decline in older adults. Past studies have assumed constant effects over time and have not considered the etiologically relevant exposure window. Objective:To examine the association of anticholinergic exposure with gait speed and grip strength assuming constant and time-varying effects of daily exposure. Design, Setting, and Participants:This cohort study used data collected from February 1994 to March 2020 in the Adult Changes in Thought study at Kaiser Permanente Washington, an integrated health care delivery organization. Participants with at least 2 study visits and at least 10 years of enrollment prior to index were included. Data were analyzed from January 2023 to December 2024. Exposure:Conventional anticholinergic exposures (10-year total standardized daily dose [TSDD] and 2-year mean SDD [mSDD]) assumed constant daily exposure effects. Weighted cumulative exposures (WCE) explored different exposure windows (T = 2, 4, 6, 8, or 10 years) and were quantified as T-year weighted mSDD to allow for time-varying effects of daily exposure. Main Outcomes and Measures:Adjusted linear models with generalized estimating equations estimated mean differences (MDs) in change rates in gait speed or grip strength between anticholinergic TSDD and mSDD categories and per unit increase in weighted mSDD. Model fits were assessed by quasi-information criterion (QIC). Results:The total sample included 4283 participants, with 4210 participants (2468 women [58.6%]; mean [SD] age,74.3 [6.1] years) with 8.2 (5.4) years of follow-up in the gait speed sample, and 4200 participants (2458 [58.5%] women, mean [SD] age 74.5 [6.1]) in the grip strength sample. Compared with nonusers, a greater decline rate in gait speed was found for those with 10-year TSDD 1096 or greater (MD per year, -0.0132 [95% CI, -0.0193 to -0.0070] m/s) and for 2-year mSDD 0.5 or greater (MD per year, -0.0101 [95% CI, -0.0174 to -0.0029] m/s). The 4-year WCE model had the lowest QIC and showed a significantly greater decline rate per 1-unit increase in weighted mSDD (MD per year, -0.0034 [95% CI -0.0048 to -0.0019] m/s). There were no significant associations between conventional exposures and grip strength, but the 6-year WCE model had the lowest QIC (MD per year, -0.0329 [95% CI -0.0612 to -0.0046] kg). Conclusions and Relevance:Is this cohort study, higher anticholinergic exposure was associated with accelerated decline in physical performance, consistent with clinically meaningful decline. These findings suggest that minimizing anticholinergic medications is important for healthy aging.

In 2012, the Centers for Disease Control and Prevention (CDC) released STEADI (Stopping Elderly Accidents, Deaths and Injuries) toolkit which is based on the 2011 American Geriatrics Society/British Geriatrics Society (AGS/BGS) fall prevention guideline. In 2024, the National Network of Public Health Institutes (NNPHI), via a Cooperative Award with the CDC of the Department of Health and Human Services (HHS), invited AGS to recommend updates to STEADI with a focus on falls prevention in primary care. An AGS workgroup reviewed the 2022/2024 publications and held three outreach events with stakeholders (448 participants) to get feedback on current STEADI materials and draft recommendations focused on primary care. Recommendations for improving uptake of STEADI included reframing the why (alignment with ambulation goals) and the how (engage all available interdisciplinary team members) and addressing time limitations by prioritizing STEADI elements that can be done with available time and completing assessments across multiple visits. Screening recommendations included using the Three Key Questions first, and only if positive, asking the remaining Stay Independent questions. Assessment recommendations were to limit the scope of some activities (e.g., consider specifically fall risk-increasing drugs) while expanding others (e.g., incorporating hearing and bladder health assessments). Where the choice of intervention is obvious from screening (e.g., referral to a physical therapist if screening questions points to a strength, mobility, or gait problem), an in-office assessment may reasonably be skipped. These recommendations could improve effectiveness and ease of implementation of STEADI in primary care and help primary care teams reframe fall prevention as a chronic condition deserving ongoing engagement, assessment, intervention, and follow-up.

Purpose Anticholinergic medication use measured via the Anticholinergic Cognitive Burden (ACB) scale has been associated with an increased dementia incidence in older adults but has not been explored specifically for Parkinson disease dementia (PDD). We used adjusted Cox models to estimate the risk of incident PDD associated with demographic factors, clinical characteristics, and time-varying total ACB in a longitudinal, deeply-phenotyped prospective PD cohort. Major findings 56.5% of study participants were taking ACB-scale drugs at enrollment. Increasing age, motor symptom burden and psychosis were associated with PDD risk. Female sex and educational achievement were protective against PDD. ACB categories were not associated with PDD overall, but depression and impulse control disorder were strongly associated with PDD in a subsample with high baseline ACB. Conclusions Patient and clinical factors modify PDD risk. PD drug safety and drug-disease interaction studies may require considering multiple mechanisms and including dose-based, prospectively acquired medication exposure measures.

BACKGROUND:Anticholinergic exposure is associated with dementia risk; however, the mechanisms for this association remain unclear. The objective of this study was to examine the association between anticholinergic exposure and white matter hyperintensity (WMH) burden. METHODS:This was a retrospective analysis of data from the Adult Changes in Thought (ACT) study, a prospective cohort study among adults aged ≥65 years on dementia risk factors. We used data collected through March 2020 for this analysis. The sample included ACT participants who were referred for and had a clinical magnetic resonance imaging (MRI) scan and ≥10 years of continuous healthcare enrollment prior to the scan. Our primary exposure was total standardized daily dose (TSDD) of anticholinergics. Outcomes included three semi-quantitative ratings of WMH volume. We used separate linear regression models for each outcome to estimate and compare covariate-adjusted mean values of WMH ratings in each exposure group. RESULTS:Of the 1043 individuals included in the analyses, 28% had no use, 33% had 1-90 TSDD, 15% had 91-365 TSDD, 7% had 366-1095 TSDD, and 17% had ≥1096 TSDD. The mean age was 81 years, most were female (58%) and White race (88%). Compared to those with no use, the ≥1096 TSDD group had a higher (worse) adjusted mean [95% confidence intervals] Fazekas (4.0 [3.8, 4.2] vs. 3.4 [3.2, 3.5]; p: <0.001), Modified Scheltens (14.3 [13.4, 15.2] vs. 12.2 [11.5, 12.9]; p: <0.001), and Age-Related White Matter Changes (5.6 [5.3, 6.0] vs. 4.8 [4.5, 5.1]; p = 0.001). A dose-response relationship was not found. CONCLUSIONS:The highest anticholinergic exposure was associated with greater WMH burden. Future studies should focus on longitudinal changes of WMH burden to better understand the biological mechanisms underlying the link between anticholinergics and dementia risk.

Introduction: Evidence from in-vitro and animal studies suggests that proton pump inhibitor (PPI) use is associated with incident cardiovascular disease (CVD). Observational studies in humans have shown conflicting results and didn’t account for relevant confounders such as diet and physical activity or confounding by indication. Methods: This study included 148,452 postmenopausal women without history of CVD at enrollment into the Women’s Health Initiative (WHI) observational study and clinical trials in 1993-1998. The primary exposure was PPI use (no, yes) determined by medication inventory conducted at baseline. The main outcome was incident primary CVD defined as a composite endpoint of physician-adjudicated myocardial infarction, coronary revascularization, stroke, and CVD mortality. Follow-up time was to September 2010. Cox proportional hazards regression was used to estimate hazards ratios (HR) and 95% confidence intervals (CI) for the association of PPI use and CVD. All models were adjusted for baseline age and stratified according to WHI study component. Additional models were further adjusted for demographics (education, income), lifestyle (smoking, alcohol, diet quality, physical activity, sleep duration), and major CVD risk factors (body mass index, family history of CVD, treated hypercholesterolemia, treated diabetes, treated hypertension). Results: Baseline prevalence of PPI use was 1.91%. After a mean follow-up of 11.3 years, there were 10,944 CVD events. PPI use was associated with a 28% higher risk of CVD compared to non-use in the age adjusted model (HR: 1.28, 95%CI: 1.13-1.45). The association was attenuated but remained significant after adjusting for potential confounders and was materially unchanged when using propensity score adjustment to better address confounding by indication (Table). Conclusions: PPI use was associated with higher risk of incident CVD in postmenopausal women. Further investigations are warranted to confirm this finding and identify potential mechanisms.

Importance High-risk medications that contribute to adverse health outcomes are frequently prescribed to older adults. Deprescribing interventions reduce their use, but studies are often not designed to examine effects on patient-relevant health outcomes. Objective To test the effect of a health system–embedded deprescribing intervention targeting older adults and their primary care clinicians for reducing the use of central nervous system–active drugs and preventing medically treated falls. Design, Setting, and Participants In this cluster randomized, parallel-group, clinical trial, 18 primary care practices from an integrated health care delivery system in Washington state were recruited from April 1, 2021, to June 16, 2022, to participate, along with their eligible patients. Randomization occurred at the clinic level. Patients were community-dwelling adults aged 60 years or older, prescribed at least 1 medication from any of 5 targeted medication classes (opioids, sedative-hypnotics, skeletal muscle relaxants, tricyclic antidepressants, and first-generation antihistamines) for at least 3 consecutive months. Intervention Patient education and clinician decision support. Control arm participants received usual care. Main Outcomes and Measures The primary outcome was medically treated falls. Secondary outcomes included medication discontinuation, sustained medication discontinuation, and dose reduction of any and each target medication. Serious adverse drug withdrawal events involving opioids or sedative-hypnotics were the main safety outcome. Analyses were conducted using intent-to-treat analysis. Results Among 2367 patient participants (mean [SD] age, 70.6 [7.6] years; 1488 women [63%]), the adjusted cumulative incidence rate of a first medically treated fall at 18 months was 0.33 (95% CI, 0.29-0.37) in the intervention group and 0.30 (95% CI, 0.27-0.34) in the usual care group (estimated adjusted hazard ratio, 1.11 (95% CI, 0.94-1.31) ( P = .11). There were significant differences favoring the intervention group in discontinuation, sustained discontinuation, and dose reduction of tricyclic antidepressants at 6 months (discontinuation adjusted rate: intervention group, 0.23 [95% CI, 0.18-0.28] vs usual care group, 0.13 [95% CI, 0.09-0.17]; adjusted relative risk, 1.79 [95% CI, 1.29-2.50]; P = .001) and secondary time points (9, 12, and 15 months). Conclusions and Relevance In this randomized clinical trial of a health system–embedded deprescribing intervention targeting community-dwelling older adults prescribed central nervous system–active medications and their primary care clinicians, the intervention was no more effective than usual care in reducing medically treated falls. For health systems that attend to deprescribing as part of routine clinical practice, additional interventions may confer modest benefits on prescribing without a measurable effect on clinical outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT05689554