Search

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient-centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real-world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults.

Background: Despite emphasis on efforts to prevent cardiovascular disease (CVD), 13% to 34% of people never fill a prescribed statin (primary nonadherence). This study determined perceptions of adults with primary nonadherence to statins. Methods: Ten focus groups were conducted with 61 adults reporting primary nonadherence to statins (93% without known CVD). Participants were recruited from an academic medical center and nationwide Internet advertisements. Results: Major themes related to primary nonadherence were 1) desire to pursue alternatives before starting a statin (eg, diet and/or exercise, dietary supplements), 2) worry about risks and adverse effects of statins, 3) perceptions of good personal health (suggesting that a statin was not needed), and 4) doubt about the benefits of statins in the absence of disease. Additional themes included mistrust of the pharmaceutical industry, mistrust of prescribing providers, inadequate provider communication about statins, and negative prior experiences with medication. Although rare, a few patients said that high cholesterol does not require treatment if it is genetic. One third noted during focus group discussions that they did not communicate their decision not to take a statin to providers. Conclusions: Adults with primary nonadherence to statins describe seeking alternatives, avoiding perceived risks of statins, poor acceptance/understanding of CVD risk estimates, and doubts about the benefits of statins. Many do not disclose their decisions to providers, thus highlighting the need for provider awareness of the potential for primary nonadherence at the point of prescribing, and the need for future work to develop strategies to identify patients with potential primary nonadherence.

ImportanceOlder age may be accompanied by changes in the pharmacokinetics or pharmacodynamics or both of medications that can result in altered safety and efficacy profiles.ObjectiveTo assess representation of older adults in clinical trials of new drug applications (NDAs) and biologics license applications (BLAs).Design, Setting, and ParticipantsThis cross-sectional study analyzed US Food and Drug Administration (FDA) data for NDAs and BLAs approved from 2010 through 2019. Age distribution of clinical trial participants was compared with age distribution of the US population with the disease or disorder (prevalent population). Data were from adults enrolled in registration trials for depression, heart failure, insomnia, non–small cell lung cancer (NSCLC), nonvalvular atrial fibrillation (NVAF) stroke prevention, osteoporosis, and type 2 diabetes or adults sampled from US prevalent population in community-dwelling health data. Data were analyzed from November 2020 to February 2021.ExposuresTrial enrollment.Main Outcomes and MeasuresRepresentativeness of trial populations was assessed by the participation to prevalence ratio (PPR) defined as the percentage of patients by age group among clinical trial participants to the percentage of patients by age group among US prevalent population.ResultsData from 166 clinical trials (229 558 participants) for 44 NDAs and BLAs were analyzed. The most consistent finding was the limited enrollment of the oldest age groups, namely those 75 years and above for type 2 diabetes and NSCLC, and 80 years and above for NVAF stroke prevention, insomnia, heart failure, and osteoporosis. Adults aged 60 to 74 years were enrolled in equal or greater proportion than the US prevalent population.Conclusions and RelevanceIn this cross-sectional study, underrepresentation of the oldest adults existed during evaluation of new drugs and biologics, yet the older adults may represent significant proportions of the treatment population. Closing the representation gap between clinical trial enrollment and potential treatment populations is essential for safe and effective use of new drugs and biologics.

Author(s): Sukumar, Smrithi; Gulilat, Markus; Linton, Bradley; Gryn, Steven E; Dresser, George K; Alfonsi, Jeffrey E; Schwarz, Ute I; Kim, Richard B; Schwartz, Janice B | Abstract: ObjectivesLower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF.DesignConvenience sample of patients receiving anticoagulation during 2017.SettingAcademic medical center.ParticipantsStable adults older than 65 years with NVAF receiving apixaban on a chronic basis.MeasurementsPatient age, weight, creatinine, co-medications, and apixaban concentrations.ResultsA total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations.ConclusionsApixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902-1906, 2019.

Highlights • Patients strongly wanted to pursue alternative treatments before starting a statin. • Attitudes about taking statins based on risk differ from scientific recommendations. • 52% of patients did not tell their prescriber that they might not take the statin. • The existing literature likely underestimates rates of primary nonadherence., Statin medications reduce cardiovascular events, but many patients never start taking their prescribed statin (primary nonadherence). Limited knowledge exists about the attitudes and beliefs of those with primary nonadherence. In this study, patients with primary nonadherence to statin medications (n = 173) completed a self-administered cross-sectional survey that assessed their attitudes and beliefs related to primary nonadherence and to potential motivators for statin use. Patients were recruited in 2019 from two academic health systems and nationwide internet advertisements. Only 49 of 173 (28.3%) patients with primary nonadherence reported having cardiovascular disease (CVD). Ninety-nine patients (57.2%) never filled their prescription, and 74 (42.8%) filled but never took any statin. Over half failed to initially inform their prescriber they might not take the statin. Patients strongly or somewhat agreed that they desired alternate treatment plans such as diet and/or exercise (n = 134; 77.4%) or natural remedies/dietary supplements (n = 125; 72.3%). Ninety-eight (56.6%) stronglyor somewhat worried about the possibility of statin dependence or addiction. Twenty-seven (15.6%) patients noted that they would not take a statin based solely on CVD risk estimates; 50 (28.9%) selected a CVD risk threshold of >20%; and 23 (13.3%) a threshold of >50% as motivating factors to take statins. Patients with primary nonadherence have attitudes about taking statins based on CVD risk that differ from scientific recommendations, may not tell providers about their hesitation to take statins, and likely prefer alternative initial approaches to cholesterol lowering. Early shared decision-making and assessment of patient attitudes about statins could potentially better align initial approaches for CVD risk reduction.

Background/objectivesDespite lower major bleeding rates associated with direct oral anticoagulants (DOACs) as compared to conventional warfarin therapy, bleeding rates remain higher in older patients compared to younger patients suggesting a potential role for DOAC measurements. The objective of this study is to examine the effect of age on the relationship between apixaban concentrations and anti-Factor Xa activity in patients with non-valvular atrial fibrillation (NVAF).MethodsThis is a retrospective analysis based on a database created using data from the ARISTOTLE study. Outpatient, stable adult patients with NVAF receiving apixaban were included in this study. Data collection consisted of apixaban concentration, anti-Factor Xa activity, age, weight, creatinine, and co-medications.ResultsThe database composed of 2058 patients receiving apixaban. Distribution of race, NVAF subtype, and aspirin use was fairly similar across each age quantile. Older patients received a higher number of co-medications and received the 2.5mg apixaban dose more often as compared to younger patients (22% vs. < 1%). Linear regression demonstrated that the unadjusted slope for apixaban concentration effect on anti-Factor Xa activity was similar across each age quantile. Although, the overall adjusted linear regression analysis demonstrated that the age by concentration interaction was statistically significant, relative differences in anti-Factor Xa activity (< 8%) were not clinically meaningful.ConclusionData on apixaban concentrations and anti-Factor Xa activity from a pivotal randomized double-blind study of apixaban for the prevention of stroke in NVAF patients have confirmed that the chromogenic anti-Factor Xa activity assay can accurately assess apixaban concentrations in patients regardless of age. Age was not associated with a clinically relevant change in the apixaban vs. anti-Factor Xa activity response relationship and target ranges are unchanged.

Introduction Levels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI). Methods Participants (n = 20 per group) had either MCI converting to dementia within 3 years (MCIC), MCI remaining stable over 3 years (MCIS), Alzheimer's disease, or were controls. CPs of ADEs isolated from plasmas by anti-human glutamine aspartate transporter antibody absorption were quantified by ELISAs. Results ADE levels of C1q and C4b of the classical pathway, factor D and fragment Bb of the alternative pathway, and C5b, C3b, and C5b-C9 of both pathways were significantly higher in patients with MCIC than those with MCIS. ADE levels of inhibitory CPs decay-accelerating factor, CD46, CD59, and type 1 complement receptor were significantly lower in patients with MCIC than those with MCIS. Discussion ADE CPs are components of neurotoxic neuroinflammation that may be predictive biomarkers of MCI conversion to Alzheimer's disease.

Exosomes derived from chondroitin sulfate proteoglycan (CSPG) 4 type neural precursor cells (CSPG4Es) were purified from human plasma by sequential immunoabsorption with anti-CSPG4 and anti–platelet growth factor receptor α mAb to characterize the potential in vivo roles of CSPG4 cells in neuronal repair. Hepatocyte growth factor, fibroblast growth factors (FGFs)-2 and -13, and type 1 insulin-like growth factor (IGF-1), which enhance neuronal survival and functions, were quantified in CSPG4E extracts. For CSPG4Es of 24 healthy control subjects, mean levels of hepatocyte growth factor, FGF-13, and IGF-1, but not FGF-2, were significantly higher by up to 7-fold than in their neuronal-derived exosomes, and mean levels of all 4 growth factors were significantly higher by up to 8-fold than in their astrocyte-derived exosomes. Mean CSPG4E levels of all growth factors were significantly lower in patients with mild Alzheimer disease (AD) (n = 24) than in age- and sex-matched cognitively normal control subjects (n = 24). Mean CSPG4E levels of all growth factors were also significantly lower in 15 patients at the stage of moderate dementia from AD (AD(2)) and at their preclinical stage 3 to 8 yr earlier (AD(1)), with no differences between values at stages AD(1) and AD(2). Current findings suggest that CSPG4 cells export in exosomes higher levels of neurotrophic factors than neurons or astrocytes and that CSPG4E neurotrophic factors are diminished early in AD, with no significant progression of decreases later in the course.—Goetzl, E. J., Nogueras-Ortiz, C., Mustapic, M., Mullins, R. J., Abner, E. L., Schwartz, J. B., Kapogiannis, D. Deficient neurotrophic factors of CSPG4-type neural cell exosomes in Alzheimer disease.

OBJECTIVE Astrocytes fulfill neuronal trophic roles normally, but are transformed in Alzheimer disease (AD) into A1-type reactive astrocytes that may destroy neurons through unknown mechanisms. METHODS To investigate astrocyte inflammatory mechanisms, astrocyte-derived exosomes (ADEs) were isolated immunochemically from plasma samples of AD patients and matched controls for enzyme-linked immunosorbent assay quantification of complement proteins. RESULTS ADE levels of C1q, C4b, C3d, factor B, factor D, Bb, C3b, and C5b-C9 terminal complement complex, but not mannose-binding lectin, normalized by the CD81 exosome marker were significantly higher for AD patients (n = 28) than age- and gender-matched controls (all p

Interactions of the presynaptic proteins, neuronal pentraxin 2 (NPTX2) and neurexin 2α (NRXN2α), with their respective postsynaptic functional partners, GluA4-containing glutamate (AMPA4) receptor and neuroligin 1 (NLGN1), enhance excitatory synaptic activity in some areas of the hippocampus and cerebral cortex. As early damage of such excitatory circuits in the brain tissues of participants with Alzheimer's disease (AD) correlates with cognitive losses, plasma neuron-derived exosome (NDE) levels of these 2 pairs of specialized synaptic proteins were quantified to assess their biomarker characteristics. The NDE contents of all 4 proteins were decreased significantly in AD dementia ( n = 46), and diminished levels of AMPA4 and NLGN1 correlated with the extent of cognitive loss. In a preclinical period, 6-11 yr before the onset of dementia, the NDE levels of all but NPTX2 were significantly lower than those of matched controls, and levels of all proteins declined significantly with the development of dementia. Reductions in NDE levels of these specialized excitatory synaptic proteins may therefore be indicative of the extent of cognitive loss and may reflect progression of the severity of AD.-Goetzl, E. J., Abner, E. L., Jicha, G. A., Kapogiannis, D., Schwartz, J. B. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease.

Plasma endothelial cell-derived exosomes (EDEs) and platelet-derived exosomes (PDEs) were precipitated and enriched separately by immunospecific absorption procedures for analyses of cargo proteins relevant to atherosclerosis. EDEs had usual exosome size and marker protein content, and significantly higher levels than PDEs of the endothelial proteins vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase, whereas PDEs had significantly higher levels of platelet glycoprotein VI. EDE levels of VCAM-1, von Willebrand factor, platelet-derived growth factor (PDGF)-BB, angiopoietin-1, and lysyl oxidase-2 and the cerebrovascular-selective proteins glucose transporter 1, permeability-glycoprotein, and large neutral amino acid transporter 1 were significantly higher for 18 patients with cerebrovascular disease (CeVD) than for 18 age- and gender-matched control subjects. PDE levels of PDGF-AA, platelet glycoprotein VI, integrin-linked kinase-1, high mobility group box-1 protein, chemokine CXCL4, and thrombospondin-1 were significantly higher in patients with CeVD than in control subjects, but differences were less with greater overlaps than for EDE proteins. EDE levels of Yes-associated protein (YAP) were higher and of P(S127)-YAP lower in patients with CeVD than in control subjects, consistent with heightened activity of this mechanical force-sensitive system in atherosclerosis. Elevated EDE and PDE levels of atherosclerosis-promoting proteins in CeVD justify clinical studies of their potential value as biomarkers.-Goetzl, E. J., Schwartz, J. B., Mustapic, M., Lobach, I. V., Daneman, R., Abner, E. L., Jicha, G. A. Altered cargo proteins of human plasma endothelial cell-derived exosomes in atherosclerotic cerebrovascular disease.

Author(s): Schwartz, Janice; Merrill, Steve; de Leon, Noelle; Thompson, Ashley; Fang, Margaret | Abstract: Background/objectiveDirect-acting oral anticoagulants (DOACs) are increasingly used to prevent or treat thromboembolism. We conducted a study to compare how well initial DOAC prescribing for adult inpatients adhered to dosing recommendations approved by the US Food and Drug Administration (FDA).DesignRetrospective analysis.SettingSingle academic medical center, July 1, 2014 to June 30, 2015.Patients508 adult inpatients.MeasurementsDOAC prescriptions were evaluated to determine whether they met FDA-recommended dosing and administration according to patient age, weight, sex, race, kidney function, diagnoses, and concomitant medications.ResultsDOACs were prescribed in 635 admissions (247 apixaban, 97 dabigatran, 291 rivaroxaban). The indication was atrial fibrillation/flutter in 465 admissions (8% with bioprostheses or valve repair), chronic deep vein thrombosis (DVT) in 67, acute DVT in 32, chronic pulmonary embolism in 23, acute pulmonary embolism in 19, DVT prevention after hip or knee surgery in 19, and non-FDA-approved indications in 10. Sixteen percent of orders for venous thromboembolic disease were for patients with active malignancy. Dosages not concordant with recommendations were prescribed for apixaban in 18% of admissions, for rivaroxaban in 14%, and for dabigatran in 7% (? = 0.04). Lower than recommended dosing was more common than higher than recommended dosing (? l 0.05). Half the deviations were continuations of outpatient dosing. Atrial fibrillation/flutter and post-hip or -knee surgery dosing deviations were more common than venous thromboembolic disease deviations (? l 0.001) but were not related to prescriber specialty.ConclusionsDOAC prescribing recommendation deviations that can affect clinical efficacy were identified. Education and point-of-care decision support tools for improving dosing are needed, as are outcome data for patients who receive DOACs at lower than recommended dosing or for off-label indications.

Background Direct-acting oral anticoagulants (DOACs), such as apixaban, are the most commonly prescribed anticoagulants, with advantages in that they do not require routine monitoring. However, less frequent contact with healthcare professionals may contribute to poor patient knowledge about potential interactions between over-the-counter (OTC) products and DOACs. Objective Determine the prevalence of use of OTC products (OTC medications and dietary supplements) with potentially serious apixaban interactions and assess patient knowledge of potential interactions. Design Cross-sectional survey. Setting Academic-affiliated outpatient medical practices in northern and southern California. Participants A total of 791 English- or Spanish-speaking patients prescribed apixaban. Measurements Use and knowledge of OTC medications and dietary supplements with potentially serious apixaban interactions. Results Almost all respondents (n = 771; 97.5%) reported OTC product use. Of respondents, 33% (n = 266) took at least one OTC product with potentially serious apixaban interactions daily/most days and 53 (6.7%) took multiple products (mean = 2.6 [SD = 2.6]). Aspirin was taken daily by 116 (14.7%; of which 75 [64.7%] also consumed other potentially interacting OTC products), and some days/as needed by an additional 82 (10.4%). Ibuprofen and naproxen were taken daily/most days by 14 (1.8%) and occasionally by 225 (28.5%). Dietary supplements with potentially serious interactions were taken daily/most days by 160 (20.2%). Approximately 66% of respondents were either uncertain or incorrect about the potential for increased bleeding from combining nonsteroidal anti-inflammatory drugs and apixaban. Less knowledge about OTC products with potentially serious interactions was associated with greater OTC product use (odds ratio = 0.54; 95% confidence interval = 0.35-0.85). Conclusion Significant numbers of patients take OTC products (particularly dietary supplements) with potentially serious interactions with the DOAC apixaban and appear to lack knowledge about potentially harmful interactions. Interventions are needed to educate patients and healthcare providers about potential dangers of taking interacting OTC products in combination with apixaban, and data are needed on outcomes associated with concomitant apixaban-OTC product use. J Am Geriatr Soc 68:155-162, 2019.

OBJECTIVES To identify the top priority areas for research to optimize pharmacotherapy in older adults with cardiovascular disease (CVD). DESIGN Consensus meeting. SETTING Multidisciplinary workshop supported by the National Institute on Aging, the American College of Cardiology, and the American Geriatrics Society, February 6–7, 2017. PARTICIPANTS Leaders in the Cardiology and Geriatrics communities, (officers in professional societies, journal editors, clinical trialists, Division chiefs), representatives from the NIA; National Heart, Lung, and Blood Institute; Food and Drug Administration; Centers for Medicare and Medicaid Services, Alliance for Academic Internal Medicine, Patient‐Centered Outcomes Research Institute, Agency for Healthcare Research and Quality, pharmaceutical industry, and trainees and early career faculty with interests in geriatric cardiology. MEASUREMENTS Summary of workshop proceedings and recommendations. RESULTS To better align older adults’ healthcare preferences with their care, research is needed to improve skills in patient engagement and communication. Similarly, to coordinate and meet the needs of older adults with multiple comorbidities encountering multiple healthcare providers and systems, systems and disciplines must be integrated. The lack of data from efficacy trials of CVD medications relevant to the majority of older adults creates uncertainty in determining the risks and benefits of many CVD therapies; thus, developing evidence‐based guidelines for older adults with CVD is a top research priority. Polypharmacy and medication nonadherence lead to poor outcomes in older people, making research on appropriate prescribing and deprescribing to reduce polypharmacy and methods to improve adherence to beneficial therapies a priority. CONCLUSION The needs and circumstances of older adults with CVD differ from those that the current medical system has been designed to meet. Optimizing pharmacotherapy in older adults will require new data from traditional and pragmatic research to determine optimal CVD therapy, reduce polypharmacy, increase adherence, and meet person‐centered goals. Better integration of the multiple systems and disciplines involved in the care of older adults will be essential to implement and disseminate best practices. J Am Geriatr Soc 67:371–380, 2019.

Author(s): Sukumar, Smrithi; Cabero, Melissa; Tiu, Sharon; Fang, Margaret C; Kogan, Scott C; Schwartz, Janice B | Abstract: BackgroundDirect-acting oral anticoagulants (DOACs) are increasingly used to prevent and treat thromboembolism. Although measurement of DOAC concentrations is not currently recommended as part of routine patient care, measurement of DOAC concentrations with anti-factor Xa activity assays have recently become clinically available.ObjectivesOur goal was to determine the clinical conditions under which DOAC concentration measurements are requested.Materials and methodsRetrospective electronic medical record analysis of indications for DOAC concentration measurements by anti-factor Xa activity assay at a single academic medical center from July 2015 through April 2020.Results and conclusionsNinety-one DOAC concentration measurements were made in 69 patients: 28 received apixaban and 41 received rivaroxaban. The most frequent indication for concentration measurement was drug exposure assessment (38/69; 55%) in patients with potentially altered pharmacokinetics (altered absorption or clearance), recurrent thromboembolic events, or possible medication nonadherence. Fourteen of 69 patients had repeated measurements during preoperative evaluation before emergent surgery; one-third of those with detectable levels upon presentation had repeated measurements until concentrations were undetectable. Levels were undetectable in 4 of 4 patients scheduled for elective surgery. Eleven of 69 patients had DOAC measurements in the setting of major bleeding; 5 of these 11 received a specific DOAC reversal agent. While most of the observed indications appear in clinical guidelines, altered absorption does not. Overall, clinicians are requesting DOAC concentration measurements to evaluate drug exposure in patients with conditions that might alter the absorption or clearance of the DOAC, to evaluate surgical bleeding risk, and in the setting of major bleeding.

Objectives To determine the potential effect of substituting glomerular filtration rate (GFR) estimates for renal clearance estimated using the Cockcroft–Gault method (CrCL-CG) to calculate direct oral anticoagulant (DOAC) dosing. Design Simulation and retrospective data analysis. Setting Community, academic institution, nursing home. Participants Noninstitutionalized individuals aged 19 to 80 from the National Health and Nutrition Examination Survey (NHANES) (2011/12) (n = 4,687) and medically stable research participants aged 25 to 105 (n = 208). Measurements Age, height, weight, sex, race, serum creatinine, CrCL-CG, and GFR (according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations). Outcome measures were dosing errors if GFR were to be substituted for CrCL-CG. Results Renal clearance estimates according to all methods were highly correlated (P < .001), although at lower clearances, substitution of GFR estimates for CrCL-CG resulted in failure to recognize needs for dose reductions of rivaroxaban or edoxaban in 28% of NHANES subjects and 47% to 56% of research subjects. At a CrCL-CG of less than 30 mL/min, GFR estimates missed indicated dosage reductions for dabigatran in 18% to 21% of NHANES subjects and 57% to 86% of research subjects. Age and weight contributed to differences between renal clearance estimates (P < .001), but correction of GFR for body surface area (BSA) did not reduce dosing errors. At a CrCL-CG greater than 95 mL/min, edoxaban is not recommended, and GFR esimates misclassified 24% of NHANES and 39% of research subjects. Correction for BSA reduced misclassification to 7% for NHANES and 14% in research subjects. Conclusion Substitution of GFR estimates for estimated CrCl can lead to failure to recognize indications for reducing DOAC dose and potentially higher bleeding rates than in randomized trials.

Efficient intercellular transfer of RNAs, proteins, and lipids as protected exosomal cargo has been demonstrated in the CNS, but distinct physiologic and pathologic roles have not been well defined for this pathway. The capacity to isolate immunochemically human plasma neuron-derived exosomes (NDEs), containing neuron-specific cargo, has permitted characterization of CNS-derived exosomes in living humans. Constituents of the amyloid β-peptide (Aβ)42-generating system now are examined in 2 distinct sets of human neural cells by quantification in astrocyte-derived exosomes (ADEs) and NDEs, enriched separately from plasmas of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD) and matched cognitively normal controls. ADE levels of β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), γ-secretase, soluble Aβ42, soluble amyloid precursor protein (sAPP)β, sAPPα, glial-derived neurotrophic factor (GDNF), P-T181-tau, and P-S396-tau were significantly (3- to 20-fold) higher than levels in NDEs for patients and controls. BACE-1 levels also were a mean of 7-fold higher in ADEs than in NDEs from cultured rat type-specific neural cells. Levels of BACE-1 and sAPPβ were significantly higher and of GDNF significantly lower in ADEs of patients with AD than in those of controls, but not significantly different in patients with FTD than in controls. Abundant proteins of the Aβ42 peptide-generating system in ADEs may sustain levels in neurons. ADE cargo proteins may be useful for studies of mechanisms of cellular interactions and effects of BACE-1 inhibitors in AD.-Goetzl, E. J., Mustapic, M., Kapogiannis, D., Eitan, E., Lobach, I. V., Goetzl, L., Schwartz, J. B., Miller, B. L. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease.

Objectives To determine the dose-response relationship between 25-hydroxyvitamin D (25(OH)D) and supplemental vitamin D3 in elderly nursing home residents. Design Randomized double-blind investigation. Setting Nursing home. Participants Of 81 women (n = 51) and men (n = 30) (mean age 87.4 ± 8) enrolled, 72 completed the study. Intervention Sixteen weeks of oral vitamin D3 at 800, 2,000, or 4,000 IU/d or 50,000 IU/wk. Measurements The main outcome was 25(OH)D concentrations (tandem mass spectrometry) after 16 weeks. Free 25(OH)D and intact parathyroid hormone (iPTH) were also analyzed. Safety monitoring of calcium and estimated glomerular filtration rate was performed, and adherence and clinical status were measured. Results 25(OH)D concentrations increased with dose (P

ContextThe optimal measure of vitamin D status is unknown.ObjectiveTo directly measure circulating free 25-hydroxyvitamin D[25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans.DesignCross-sectional analysis.SettingSeven academic sites.PatientsA total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79).InterventionsMerge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype.Main outcome measuresDistribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates).ResultsFree 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype.ConclusionsTotal 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.

Author(s): Moore, Kelly L; Patel, Kanan; Boscardin, W John; Steinman, Michael A; Ritchie, Christine; Schwartz, Janice B | Abstract: ObjectivePolypharmacy is common in older patients but relationships between polypharmacy and common co-morbid conditions have not been elucidated. Our goal was to determine relationships between daily oral medication use and common co-morbid disease dyads and triads using comprehensive medication and diagnostic data from a national sample of nursing homes (NH).DesignRetrospective, cross-sectional study.SettingNationally representative sample of U.S. Nursing Homes.ParticipantsNationally representative sample of long-term stay residents (n = 11734, 75% women) aged 65 years or older.MeasurementsDiagnosis and medication data were analyzed. Proportion of daily oral medication intake attributed to treatment of common two-(dyads) and three-disease (triad) combinations and "health maintenance" agents (vitamins, dietary supplements, stool softeners without related diagnoses) was determined.ResultsOlder NH residents received slightly g8 oral medications/day with the number related to number of medical diagnoses (p l .0001). One third of chronic oral medication intake/day (excluding health maintenance agents) could be attributed to dyad combinations and about half to triad combinations despite an average of 5 other diagnoses. Triads were comprised of hypertension +/- arthritis +/- vascular disease, +/-depression, +/- osteoporosis +/- gastroesophageal reflux disease and +/- diabetes. Health maintenance agents accounted for 15-17% of daily oral medication intake (1.4 medications) such that almost two-thirds of daily oral medications were attributable to disease triads plus health maintenance. Fewer medications were prescribed for NH residents over age 85 (decreased ACE inhibitor and HMG CoA reductase inhibitor USE (p l .001)) while use of Alzheimer medications was higher (p l .01).ConclusionsA large fraction of daily oral medications were attributed to management of common co-morbid disease dyads and triads. Efforts to reduce polypharmacy and unwanted medication interactions could focus on regimens for common co-morbid dyads and triads in varying populations.

Objective: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. Methods: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. Results: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies ( p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia ( p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD ( p ≤ 0.0003). Conclusions: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural-derived exosomes of Alzheimer's disease or frontotemporal dementia patients and matched controls. Exosomal levels of low-density lipoprotein receptor-related protein 6, heat-shock factor-1, and repressor element 1-silencing transcription factor all were significantly lower in Alzheimer's disease patients than controls (P&nbsp

© 2015 Elsevier Inc. Recent cardiovascular prevention guidelines place a greater emphasis on randomized placebo-controlled trial data as the basis for recommendations. While such trial data are sparse for people over the age of 75 or 80 years, data demonstrate altered risk-benefit relationships in these older patients. Primary prevention strategy decisions should consider estimated life expectancy and overall function as well as cardiovascular event risks, magnitude and time to benefit or harm, potentially altered adverse effect profiles, and informed patient preferences. Data support treatment of systolic hypertension to reduce stroke, cardiovascular events, and dementia in older patients with at least a 2-year estimated lifespan with modifications in systolic blood pressure goals and a need for greater attention to non-cardiovascular side effects such as falls in the very old. Lowering of elevated cholesterol levels with HMG-CoA reductase inhibitors for primary prevention in people over the age of 75 years requires greater individual considerations, as benefits may not accrue for 3-5 years and there is the potential impact of adverse effects. There is a rationale for lipid-lowering treatment in the more highly functional older patient with cardiovascular (especially stroke) risk higher than side effect risks in the near term and with an estimated lifespan longer than the time to benefit. Aspirin has higher side effect risks and requires a longer time to achieve benefit. Trial data are lacking on exercise interventions, but multi-system benefits have been shown in older patients such that exercise should be part of a preventive regimen. Preventive therapy in the very old means considering not only medical issues of co-morbidities, polypharmacy, and altered risk-benefit relationship of medications but also adjusting goals and approaches across the older agespan in keeping with informed patient preferences.

Astrocytes fulfill neuronal trophic roles normally, but are transformed in Alzheimer disease (AD) into A1-type reactive astrocytes that may destroy neurons through unknown mechanisms.To investigate astrocyte inflammatory mechanisms, astrocyte-derived exosomes (ADEs) were isolated immunochemically from plasma samples of AD patients and matched controls for enzyme-linked immunosorbent assay quantification of complement proteins.ADE levels of C1q, C4b, C3d, factor B, factor D, Bb, C3b, and C5b-C9 terminal complement complex, but not mannose-binding lectin, normalized by the CD81 exosome marker were significantly higher for AD patients (n = 28) than age- and gender-matched controls (all p 0.0001). ADE normalized levels of interleukin (IL)-6, tumor necrosis factor-α, and IL-1β were significantly higher for AD patients than controls, but there was greater overlap between the two groups than for complement proteins. Mean ADE levels of complement proteins for AD patients in a longitudinal study were significantly higher (n = 16, p 0.0001) at the AD2 stage of moderate dementia than at the AD1 preclinical stage 5 to 12 years earlier, which were the same as for controls. ADE levels of complement regulatory proteins CD59, CD46, decay-accelerating factor (DAF), and complement receptor type 1, but not factor I, were significantly lower for AD patients than controls (p 0.0001 for CD59 and DAF), were diminished by the AD1 stage, and were further decreased at the AD2 stage.ADE complement effector proteins in AD are produced by dysregulated systems, attain higher levels than in controls, and may potentially damage neurons in the late inflammatory phase of AD. Ann Neurol 2018;83:544-552.

Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (≥60years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer’s disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease.

Quality prescribing for older adults involves multiple considerations. We evaluated multiple aspects of prescribing quality in older veterans to develop an integrated view of prescribing problems and to understand how the prevalence of these problems varies across clinically important subgroups of older adults.Cross-sectional observational study of veterans age 65 years and older who received medications from Department of Veterans Affairs (VA) pharmacies in 2007.Using VA pharmacy data linked with encounter, laboratory and other data, we assessed five types of prescribing problems.Among 462,405 patients age 65 and older, mean age was 75 years, 98 % were male, and patients were prescribed a median of five medications. Half of patients (50 %) had one or more prescribing problems, including 12 % taking one or more medications at an inappropriately high dose, 30 % with drug-drug interactions, 3 % with drug-disease interactions, and 26 % taking one or more Beers criteria drugs. In addition, 16 % were taking a high-risk drug (warfarin, insulin, and/or digoxin). On multivariable analysis, age was not strongly associated with four of the five types of prescribing issues assessed (relative risk1.3 across age groups), and comorbid burden conferred substantially increased risk only for drug-disease interactions and use of high-risk drugs. In contrast, the number of drugs used was consistently the strongest predictor of prescribing problems. Patients in the highest quartile of medication use had 6.6-fold to12.5-fold greater risk of each type of prescribing problem compared to patients in the lowest quartile (P 0.001 for each).The number of medications used is by far the strongest risk factor for each of five types of prescribing problems. Efforts to improve prescribing should especially target patients taking multiple medications.

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia in patients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid β-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias.-Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., Jicha, G. A., Karydas, A. M., Boxer, A., Miller, B. L. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.

Yao et al. [(1)][1] reported on novel anticoagulant (NOAC) dosing patterns in patients with atrial fibrillation and outcomes with underdosing and overdosing. A major concern is that, in a study that investigates correct or incorrect dosing and the consequences, the authors have not correctly

A role for adenosine in immunosenescence was investigated in T cells from older (≥65 yr) and younger (24–45 yr) healthy humans. Adenosine concentrations in cultures of activated T cells were significantly higher (P

Lenalidomide, an analog of thalidomide, modified responses of stimulated T cells from healthy young (ages 21-40 years) and old (≥ age 65 years) subjects. At 0.03 μM to 1 μM, lenalidomide enhanced generation of IL-2 and IFN-γ by T cell receptor-stimulated T cells of young subjects up to respective maximum increases of 17-fold and three-fold, but at 0.3 μM and 1 μM suppressed IL-17 generation. The same concentrations of lenalidomide enhanced IL-2 and IFN-γ generation by stimulated T cells of old subjects more, with greater respective maximal increases of up to 120-fold and six-fold, without suppressing IL-17 generation. Lenalidomide enhanced proliferation and suppressed apoptosis of stimulated T cells from old subjects, by IL-2-dependent mechanisms, and restored diminished T cell chemotactic responses to CCL21 and sphingosine 1-phosphate. The reversal of T cell abnormalities of immunosenescence by low concentrations of lenalidomide suggest a potential for improvement of immunity in the elderly.

Cytokine generation by T cells and monocytes was determined for 50 subjects aged 65 yr or older and concurrently studied young subjects individually matched to each old subject for sex, race, and national origin. Highly significant differences between cytokine levels of old and young subjects all were gender specific. For T cells stimulated with anti-CD3 plus anti-CD28 antibodies, mean ratios of IFN-γ generation for healthy old to young subjects were 0.22 for men (P

Background & Aims Current clinical assays for total 25-hydroxy (OH) vitamin D measure vitamin D bound to vitamin D-binding protein (DBP) and albumin plus unbound (‘free’) D. We investigated the relationship between total and free 25(OH)D with bone metabolism markers in normal (>3.5 g/dl) vs. low (≤3.5 g/dl) albumin cirrhotics. Methods Eighty-two cirrhotics underwent measurement of free and total 25(OH)D by immunoassay, DBP and markers of bone metabolism [intact parathyroid hormone (iPTH), C-telopeptide (CTX), bone-specific alkaline phosphatase (BSAP), osteocalcin, amino-terminal pro-peptide of type 1-collagen (P1NP)]. Pearson's coefficients assessed relevant associations. Results Cirrhotics with low (n = 54) vs. normal (n = 28) albumin had lower total 25(OH)D (12.1 vs. 21.7 ng/ml), free 25(OH)D (6.2vs.8.6 pg/ml) and DBP(91.4 vs. 140.3 μg/ml) [P

Background— Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS); their safe use in women, however, remains a concern. The contribution of dosing to the observed sex-related differences in bleeding is unknown. Methods and Results— We explored the relationship between patient sex, GP IIb/IIIa inhibitor use, dose, and bleeding in 32 601 patients with NSTE ACS across 400 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) hospitals, of whom 18 436 were treated. GP IIb/IIIa inhibitor dose was defined as excessive if not reduced when creatinine clearance was P P P Conclusions— Women experience more bleeding than men whether or not they are treated with GP IIb/IIIa inhibitors; however, because of frequent excessive dosing in women, up to one fourth of this sex-related risk difference in bleeding is avoidable. Appropriate dosing will improve care of all patients with NSTE ACS, with a particular benefit for women.

Objective To determine whether menopausal hormone therapy alters the QT interval in primarily healthy postmenopausal women. Background Despite well-known gender differences in myocardial repolarization that include a longer heart-rate-corrected QT interval (QT(C)) in women compared to men, the effects of menopausal hormone therapy on myocardial repolarization in women have not been well characterized. Methods We studied 34,378 postmenopausal women participating in the dietary intervention component of the Women's Health Initiative. Cross-sectional associations were examined to assess possible effects of estrogen + progesterone on myocardial repolarization. Women who reported that they were never treated with menopausal hormone therapy (n = 12,451) were compared to women with a past use of menopausal hormone therapy (n = 3891), currently taking unopposed estrogen therapy (n = 9987), or combined current estrogen and progesterone therapy (n = 8049). Results Using analysis of covariance, the mean (+/-SEM) QT(C) interval was 423.1 +/- 0.2 milliseconds (ms) in those never treated with menopausal hormone therapy, 423.9 +/- 0.3 ms in past menopausal hormone therapy users, 425.6 +/- 0.2 ms in those currently on estrogen alone, and 424.0 +/- 0.2 ms in women currently on combined estrogen-progesterone therapy. Differences in mean QT(C) between those on estrogen alone and the other three groups were statistically significant. Comparisons of JT intervals, QT intervals, and linear corrected QT intervals among the groups yielded similar results. Conclusion These results suggest that unopposed estrogen in menopausal women mildly prolongs myocardial repolarization, and the effect is reversed by progesterone. Whether these findings have clinical significance requires further study.