Fingerstick glucose monitoring by cognitive impairment status in Veterans Affairs nursing home residents with diabetes.

BACKGROUND: Guidelines recommend nursing home (NH) residents with cognitive impairment receive less intensive glycemic treatment and less frequent fingerstick monitoring. Our objective was to determine whether current practice aligns with guideline recommendations by examining fingerstick frequency in Veterans Affairs (VA) NH residents with diabetes across cognitive impairment levels. METHODS: We identified VA NH residents with diabetes aged ≥65 residing in VA NHs for >30 days between 2016 and 2019. Residents were grouped by cognitive impairment status based on the Cognitive Function Scale: cognitively intact, mild impairment, moderate impairment, and severe impairment. We also categorized residents into mutually exclusive glucose-lowering medication (GLM) categories: (1) no GLMs, (2) metformin only, (3) sulfonylureas/other GLMs (+/- metformin but no insulin), (4) long-acting insulin (+/- oral/other GLMs but no short-acting insulin), and (5) any short-acting insulin. Our outcome was mean daily fingersticks on day 31 of NH admission. RESULTS: Among 13,637 NH residents, mean age was 75 years and mean hemoglobin A1c was 7.0%. The percentage of NH residents on short-acting insulin varied by cognitive status from 22.7% in residents with severe cognitive impairment to 33.9% in residents who were cognitively intact. Mean daily fingersticks overall on day 31 was 1.50 (standard deviation = 1.73). There was a greater range in mean fingersticks across GLM categories compared to cognitive status. Fingersticks ranged widely across GLM categories from 0.39 per day (no GLMs) to 3.08 (short-acting insulin), while fingersticks ranged slightly across levels of cognitive impairment from 1.11 (severe cognitive impairment) to 1.59 (cognitively intact). CONCLUSION: NH residents receive frequent fingersticks regardless of level of cognitive impairment, suggesting that cognitive status is a minor consideration in monitoring decisions. Future studies should determine whether decreasing fingersticks in NH residents with moderate/severe cognitive impairment can reduce burdens without compromising safety.

Do functional status and Medicare claims data improve the predictive accuracy of an electronic health record mortality index? Findings from a national Veterans Affairs cohort.

BACKGROUND: Electronic health record (EHR) prediction models may be easier to use in busy clinical settings since EHR data can be auto-populated into models. This study assessed whether adding functional status and/or Medicare claims data (which are often not available in EHRs) improves the accuracy of a previously developed Veterans Affairs (VA) EHR-based mortality index. METHODS: This was a retrospective cohort study of veterans aged 75 years and older enrolled in VA primary care clinics followed from January 2014 to April 2020 (n = 62,014). We randomly split participants into development (n = 49,612) and validation (n = 12,402) cohorts. The primary outcome was all-cause mortality. We performed logistic regression with backward stepwise selection to develop a 100-predictor base model using 854 EHR candidate variables, including demographics, laboratory values, medications, healthcare utilization, diagnosis codes, and vitals. We incorporated functional measures in a base + function model by adding activities of daily living (range 0-5) and instrumental activities of daily living (range 0-7) scores. Medicare data, including healthcare utilization (e.g., emergency department visits, hospitalizations) and diagnosis codes, were incorporated in a base + Medicare model. A base + function + Medicare model included all data elements. We assessed model performance with the c-statistic, reclassification metrics, fraction of new information provided, and calibration plots. RESULTS: In the overall cohort, mean age was 82.6 years and 98.6% were male. At the end of follow-up, 30,263 participants (48.8%) had died. The base model c-statistic was 0.809 (95% CI 0.805-0.812) in the development cohort and 0.804 (95% CI 0.796-0.812) in the validation cohort. Validation cohort c-statistics for the base + function, base + Medicare, and base + function + Medicare models were 0.809 (95% CI 0.801-0.816), 0.811 (95% CI 0.803-0.818), and 0.814 (95% CI 0.807-0.822), respectively. Adding functional status and Medicare data resulted in similarly small improvements among other model performance measures. All models showed excellent calibration. CONCLUSIONS: Incorporation of functional status and Medicare data into a VA EHR-based mortality index led to small but likely clinically insignificant improvements in model performance.

Time to Benefit of Bisphosphonate Therapy for the Prevention of Fractures Among Postmenopausal Women With Osteoporosis: A Meta-analysis of Randomized Clinical Trials.

Importance: The clinical decision to initiate bisphosphonate therapy for the treatment of osteoporosis requires balancing shorter-term harms and burdens (eg, gastroesophageal irritation or severe musculoskeletal pain) with longer-term benefits in reducing potential fractures. Objective: To assess the time to benefit (TTB) of bisphosphonate therapy for the prevention of nonvertebral and other fractures among postmenopausal women with osteoporosis. Data Sources: Randomized clinical trials (RCTs) were identified from systematic reviews commissioned by the US Preventive Services Task Force (1 review), the Agency for Healthcare Research and Quality (1 review), the Cochrane Library (2 reviews), and the Endocrine Society (1 review). Study Selection: Studies selected were RCTs involving postmenopausal women with a diagnosis of osteoporosis based on existing vertebral fractures or bone mineral density T scores of -2.5 or lower. The selection process was focused on studies of alendronate, risedronate, and zoledronic acid because they are guideline-recommended first-line agents for reducing nonvertebral fractures. Studies were excluded if they did not focus on women with a primary diagnosis of osteoporosis, had no placebo arm, or had a lack of data on time to fracture. Data Extraction and Synthesis: Random-effects Weibull survival curves were fitted and Markov chain Monte Carlo methods were used to estimate the absolute risk reduction (ARR) and TTB for each study. These estimates were pooled using a random-effects meta-analysis model. Main Outcomes and Measures: The primary outcome was the time to 3 different ARR thresholds (0.002, 0.005, and 0.010) for the first nonvertebral fracture. Secondary outcomes included the time to 4 ARR thresholds (0.001, 0.002, 0.005, and 0.010) for hip fracture, any clinical fracture, and clinical vertebral fracture. Results: Of 67 full-text articles identified, 10 RCTs comprising 23 384 postmenopausal women with osteoporosis were included either as the original RCT or part of subsequently published pooled analyses. Among the studies, the number of participants ranged from 994 to 7765, with mean (SD) age ranging from 63 (7) years to 74 (3) years and follow-up duration ranging from 12 to 48 months. The pooled meta-analysis found that 12.4 months (95% CI, 6.3-18.4 months) were needed to avoid 1 nonvertebral fracture per 100 postmenopausal women receiving bisphosphonate therapy at an ARR of 0.010. To prevent 1 hip fracture, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 20.3 months (95% CI, 11.0-29.7 months) at an ARR of 0.005. In addition, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 12.1 months (95% CI, 6.4-17.8 months) to avoid 1 clinical vertebral fracture at an ARR of 0.005. Conclusions and Relevance: This meta-analysis found that the TTB of bisphosphonate therapy was 12.4 months to prevent 1 nonvertebral fracture per 100 postmenopausal women with osteoporosis. These results suggest that bisphosphonate therapy is most likely to benefit postmenopausal women with osteoporosis who have a life expectancy greater than 12.4 months.

Behavioral and psychological symptoms in Alzheimer's dementia and vascular dementia.

Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent and represent a significant burden for patients and their caregivers. Early recognition and management of these symptoms is crucial as they are associated with increased risk of institutionalization, impairments in daily functioning, reduced quality of life, and more rapid progression to severe dementia. This chapter will discuss the pathophysiology, proposed diagnostic criteria, clinical features, and management of BPSD, including apathy, depression, agitation/aggression, psychosis, and sleep disturbances. Apathy and depression are the most common overall, and apathy is associated with high symptom severity likely because of its greater persistence. Symptoms such as agitation, aggression, hallucinations, and delusions may be especially distressing and dangerous to patients and caregivers. Nonpharmacologic management should be considered first-line therapy in most cases due to the modest and inconsistent evidence base for pharmacologic agents and greater risk of harm. However, the judicious use of pharmacologic agents may be warranted when symptoms are dangerous and/or severely distressing.

Association of Sensory and Cognitive Impairment With Healthcare Utilization and Cost in Older Adults.

OBJECTIVES: To examine the association between self-reported vision impairment (VI), hearing impairment (HI), and dual-sensory impairment (DSI), stratified by dementia status, on hospital admissions, hospice use, and healthcare costs. DESIGN: Retrospective analysis. SETTING: Medicare Current Beneficiary Survey from 1999 to 2006. PARTICIPANTS: Rotating panel of community-dwelling Medicare beneficiaries, aged 65 years and older (N = 24 009). MEASUREMENTS: VI and HI were ascertained by self-report. Dementia status was determined by self-report or diagnosis codes in claims data. Primary outcomes included any inpatient admission over a 2-year period, hospice use over a 2-year period, annual Medicare fee-for-service costs, and total healthcare costs (which included information from Medicare claims data and other self-reported payments). RESULTS: Self-reported DSI was present in 30.2% (n = 263/871) of participants with dementia and 17.8% (n = 4112/23 138) of participants without dementia. In multivariable logistic regression models, HI, VI, or DSI was generally associated with increased odds of hospitalization and hospice use regardless of dementia status. In a generalized linear model adjusted for demographics, annual total healthcare costs were greater for those with DSI and dementia compared to those with DSI without dementia ($28 875 vs $3340, respectively). Presence of any sensory impairment was generally associated with higher healthcare costs. In a model adjusted for demographics, Medicaid status, and chronic medical conditions, DSI compared with no sensory impairment was associated with a small, but statistically significant, difference in total healthcare spending in those without dementia ($1151 vs $1056; P < .001) but not in those with dementia ($11 303 vs $10 466; P = .395). CONCLUSION: Older adults with sensory and cognitive impairments constitute a particularly prevalent and vulnerable population who are at increased risk of hospitalization and contribute to higher healthcare spending. J Am Geriatr Soc 67:1617-1624, 2019.

Targeting neuroinflammation in Alzheimer's disease: evidence for NSAIDs and novel therapeutics.

INTRODUCTION: There is an increasing recognition of the immune system as an important mediator in the pathogenesis of Alzheimer's disease (AD). As immune system modulators, non-steroidal anti-inflammatory drugs (NSAIDs) garnered initial enthusiasm from pre-clinical and epidemiologic studies as agents to reduce the risk of AD. Areas covered: This article will examine the evidence for the use of NSAIDs in AD by discussing the proposed mechanism of action, results from epidemiologic studies, and data from randomized controlled trials. In addition, a survey of several novel approaches to targeting inflammatory pathways currently in pre-clinical and clinical phases of development is presented. These agents primarily act to modulate microglial functioning, enhance amyloid-ß phagocytosis, suppress potentially harmful pro-inflammatory responses, or enhance systemic immunity. Expert commentary: While long-term use of NSAIDs is associated with a reduced incidence of AD in epidemiologic studies, randomized controlled trials have not replicated these findings. Thus, NSAID use cannot currently be recommended either for primary prevention or treatment of AD. However, the available evidence does suggest that cognitively normal patients taking long-term courses of NSAIDs for other indications likely have a decreased risk of AD, which represents an important finding given the high prevalence of NSAID use among older adults.

A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer's disease.

Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

Pharmacotherapeutic strategies in the treatment of severe Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease. Patients with severe AD often require assistance with daily functioning and have a substantially higher probability of admission to nursing homes compared to the general population. AREAS COVERED: Medications approved by the US Food and Drug Administration for the treatment of severe AD include the cholinesterase inhibitors (ChEIs), donepezil (10 and 23 mg/day) and rivastigmine (transdermal patch, 13.3 mg/24 hours), and the N-methyl-D-aspartate receptor antagonist memantine (immediate- and extended-release formulations). This article will review the efficacy, safety, and tolerability data of these agents in the treatment of severe AD. Issues related to combination therapy, neuropsychiatric symptoms, and treatment discontinuation are also discussed. EXPERT OPINION: AD therapeutics provide benefits on measures of cognition, functioning, behavior, and global status even in the severe stages of AD. Combination therapy with memantine and ChEIs may provide additive benefits compared with ChEI monotherapy. Decisions regarding discontinuation of these medications should be made on a case-by-case basis, with some evidence suggesting that discontinuation may worsen cognition and functional impairment. It is recommended that patients entering the terminal stages of AD discontinue all medications not necessary for comfort.

Efficacy of rivastigmine tartrate, transdermal system, in Alzheimer's disease.

INTRODUCTION: As the most common major neurocognitive disorder, Alzheimer's disease (AD) will play an increasingly important role both socially and financially as the population ages. Approved treatments for AD are symptomatic in nature and show modest improvements in cognition and global functioning among patients with AD. AREAS COVERED: This article focuses on the pharmacokinetics, pharmacodynamics, efficacy, and safety of the transdermal patch form of the cholinesterase inhibitor rivastigmine. The rivastigmine transdermal system is approved for the treatment of patients with mild, moderate, and severe AD. Three randomized trials have shown the rivastigmine patch to be efficacious and tolerable across all stages of AD. EXPERT OPINION: The rivastigmine patch offers several advantages over the capsule form, including decreased peak to trough plasma fluctuations, reduced rates of nausea and vomiting, better treatment adherence, higher probability of reaching the target dose, ease of administration, and greater satisfaction among caregivers. These factors may be especially important in patients with severe AD, in which patients are more vulnerable to adverse side effects from higher doses. While the patch is more expensive than generic therapies, patient populations that may benefit from the patch include those that are particularly sensitive to GI side effects, have chronic gastrointestinal problems, have difficulty swallowing medications, or have failed to respond with high doses of other generic options.

The Use of Cholinesterase Inhibitors Across All Stages of Alzheimer's Disease.

Current pharmacological therapy for Alzheimer's disease (AD) includes the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine, and galantamine and the N-methyl D-aspartate receptor antagonist memantine. Based on the results of randomized controlled trials and several meta-analyses, ChEIs appear to show modest but statistically significant improvements on several measures, including cognition and global functioning. Given their modest effects, there is a lack of consensus among clinicians regarding issues related to initiation, optimal duration, and discontinuation of ChEI therapy across the spectrum of AD. There is evidence from long-term observational controlled studies that early initiation and persistent exposure to AD therapy lead to delays in nursing home admission and significantly slower rates of cognitive and functional impairment. In the moderate to severe stages of AD, therapeutic trials of higher dose ChEIs and the addition of memantine are recommended for patients who are no longer responding to lower doses. While side effects are generally mild and gastrointestinal in nature, these events can lead to significant morbidity in more susceptible patients with advanced disease. Patients should thus be regularly monitored for any potential serious side effects of ChEI therapy, which also may include syncope and bradycardia. At the terminal stages of AD, such as when patients become hospice eligible, attempts to cautiously discontinue all medications not necessary for quality of life, including AD drugs, should be made.

Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication.

Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.

A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine.

INTRODUCTION: As a leading cause of disability, major depressive disorder (MDD) is characterized by reduced quality of life and altered functioning. Current pharmaceutical treatment options are limited in their success by modest effects and adverse events that often lead to discontinuation. One current trend in antidepressant development is to combine inhibition of the serotonin transporter with other pharmacological targets, including the norepinephrine transporter or different serotonin receptors. AREAS COVERED: In a span of < 3 years, the FDA approved three new antidepressants for the treatment of MDD: vilazodone in January 2011, levomilnacipran in July 2013 and vortioxetine in September 2013. This article reviews the efficacy, safety and tolerability of these three drugs mainly from the Phase III trial data. EXPERT OPINION: All three drugs are effective in the treatment of MDD, but data comparing them to other antidepressants is currently lacking. Vilazodone was proposed to produce a more rapid onset and have fewer sexual side effects but neither effect has been conclusively shown. Levomilnacipran appears to be effective in improving functional impairment, including both social and work functioning. Vortioxetine is currently the only drug of the three with proven efficacy in elderly patients. It also appears to have cognitive enhancing properties which are largely independent of improved depressive symptoms. Overall, these drugs represent a promising step forward in antidepressant drug development.