Polypharmacy in Older Heart Failure Patients: a Multidisciplinary Approach.

PURPOSE OF REVIEW: We provide a review of considerations when applying principles of optimal pharmacotherapy to older adults with heart failure (HF), an analysis on the pivotal clinical trials focusing on applicability to older adults, and multi-disciplinary strategies to optimize the health of HF patients with polypharmacy. RECENT FINDINGS: Polypharmacy is very common among patients with HF, due to medications for both HF and non-HF comorbidities. Definitions of polypharmacy were not developed specifically for older adults with HF and may need to be modified in order to meaningfully describe medication burden and promote appropriate medical therapy. This is because clinical practice guidelines for multi-drug HF regimens have unique considerations, given that they improve outcomes and symptoms of HF. Adults older than 65 years are well represented in contemporary clinical trials for HF with preserved ejection fraction (HFpEF) and guideline directed medical therapy (GDMT) for HF with reduced ejection fraction (HFrEF). While these trials did not have significant heterogeneity in safety or efficacy across a broad age spectrum, some may have limited representation of adults ≥ 80 years old, the sickest older adults, or those with decreased functional status. There is also a lack of data on the safety and efficacy of deprescribing HF medications, and deprescription in otherwise stable patients may lead to clinical destabilization or disease progression. There is therefore innate tension between the well-studied benefits of optimized HF therapy for older adults that must be weighed against the risks of polypharmacy and many unknowns that still exist. Given the strong evidence that optimized HF therapies confer symptomatic and mortality benefits for older adults, it is clear that polypharmacy in this context can be appropriate. A shift in paradigm is therefore needed when evaluating polypharmacy in patients with HF. Instead of assuming all polypharmacy is "good" or "bad," we propose a concerted move, using a multidisciplinary approach, to focus on the "appropriateness" of specific medications, in order to optimize HF medical therapy. Clinicians of all specialties caring for complex older adults with HF must consider goals of care, functional status, and new evidence-based therapies, in order to optimize this polypharmacy for older adults.

Deficient neurotrophic factors of CSPG4-type neural cell exosomes in Alzheimer 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 (AD2) and at their preclinical stage 3 to 8 yr earlier (AD1), with no differences between values at stages AD1 and AD2. 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.

High complement levels in astrocyte-derived exosomes of 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 < 0.0001). ADE normalized levels of interleukin (IL)-6, tumor necrosis factor-α, and IL-1ß 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. INTERPRETATION: 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.

Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease.

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.

Altered cargo proteins of human plasma endothelial cell-derived exosomes in atherosclerotic cerebrovascular 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.

Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease.

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 ß-peptide (Aß)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 ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), γ-secretase, soluble Aß42, soluble amyloid precursor protein (sAPP)ß, 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 sAPPß 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 Aß42 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.

Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.

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 ß-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.

Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease.

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.

Total 25(OH) vitamin D, free 25(OH) vitamin D and markers of bone turnover in cirrhotics with and without synthetic dysfunction.

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 < 0.01 for each]. iPTH was similar in low and normal albumin groups (33 vs. 28 pg/ml; P = 0.38), although serum CTX(0.46vs.0.28 ng/ml) and BSAP(31.7 vs. 24.8 µg/L) were increased (P < 0.01). An inverse relationship was observed between total 25(OH)D and iPTH in normal (r = -0.47, P = 0.01) but not low albumin cirrhotics (r = 0.07, P = 0.62). Similar associations were seen between free 25(OH)D and iPTH(Normal: r = -0.46, P = 0.01; Low: r = -0.03, P = 0.84). BSAP, osteocalcin and P1NP were elevated above the normal range in all cirrhotics but not consistently associated with total or free 25(OH)D. CONCLUSIONS: Cirrhotics with low vs. normal albumin have lower levels of DBP, total and free 25(OH)D. The expected relationship between total or free 25(OH)D with iPTH was observed in normal but not in low albumin cirrhotics, demonstrating that total 25(OH)D is not an accurate marker of bioactive vitamin D status in cirrhotics with synthetic dysfunction. Additional investigation into the role of vitamin D supplementation and its impact on bone mineral homoeostasis in this population is needed.

Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study.

BACKGROUND: Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. METHODS: Blood exosomes obtained at one time-point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time-points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by enzyme-linked immunosorbent assays. RESULTS: Mean exosomal levels of total tau, P-T181-tau, P-S396-tau, and amyloid ß 1-42 (Aß1-42) for AD and levels of P-T181-tau and Aß1-42 for FTD were significantly higher than for case-controls. Step-wise discriminant modeling incorporated P-T181-tau, P-S396-tau, and Aß1-42 in AD, but only P-T181-tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P-S396-tau, P-T181-tau, and Aß1-42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. CONCLUSIONS: Levels of P-S396-tau, P-T181-tau, and Aß1-42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.

Prescribing quality in older veterans: a multifocal approach.

BACKGROUND AND OBJECTIVE: 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. DESIGN AND PARTICIPANTS: Cross-sectional observational study of veterans age 65 years and older who received medications from Department of Veterans Affairs (VA) pharmacies in 2007. MAIN MEASURES: Using VA pharmacy data linked with encounter, laboratory and other data, we assessed five types of prescribing problems. KEY RESULTS: 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 risk < 1.3 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). CONCLUSIONS: 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.

Distinct energy requirements for human memory CD4 T-cell homeostatic functions.

Differentiation and activation of CD4 memory T cells (T(mem) cells) require energy from different sources, but little is known about energy sources for maintenance and surveillance activities of unactivated T(mem) cells. Mitochondrial fatty acid oxidation (FAO) in human unactivated CD4 T(mem) cells was significantly enhanced by inhibition of glycolysis, with respective means of 1.7- and 4.5-fold for subjects <45 yr and >65 yr, and by stimulation of AMP-activated protein kinase, with respective means of 1.3- and 5.2-fold. However, CCL19 and sphingosine 1-phosphate (S1P), which control homeostatic lymphoid trafficking of unactivated T(mem) cells, altered FAO and glycolysis only minimally or not at all. Inhibition of CD4 T(mem)-cell basal FAO, but not basal glycolysis, significantly suppressed CCL19- and S1P-mediated adherence to collagen by >50 and 20%, respectively, and chemotaxis by >20 and 50%. Apoptosis of unactivated T(mem) cells induced by IL-2 deprivation or CCL19 was increased significantly by >150 and 70%, respectively, with inhibition of FAO and by >110 and 30% with inhibition of glycolysis. Anti-TCR antibody activation of T(mem) cells increased their chemotaxis to CCL5, which was dependent predominantly on glycolysis rather than FAO. The sources supplying energy for diverse functions of unactivated T(mem) cells differ from that required for function after immune activation.

Aging enhances release of exosomal cytokine mRNAs by Aß1-42-stimulated macrophages.

Amyloid-ß1-42 (Aß) peptide effects on human models of central nervous system (CNS)-patrolling macrophages (Ms) and CD4 memory T-cells (CD4-Tms) were investigated to examine immune responses to Aß in Alzheimer's disease. Aß and lipopolysaccharide (LPS) elicited similar M cytokine and exosomal mRNA (ex-mRNA) responses. Aß- and LPS-stimulated Ms from 20 ≥65-yr-old subjects generated significantly more IL-1, TNF-α, and IL-6, but not IL-8 or IL-12, and significantly more ex-mRNAs for IL-6, TNF-α, and IL-12, but not for IL-8 or IL-1, than Ms from 20 matched 21- to 45-yr-old subjects. CD4-Tm generation of IL-2, IL-4, and IFN-γ and, for young subjects, IL-10, but not IL-6, evoked by Aß was significantly lower than with anti-T-cell antigen receptor antibodies (Abs). Abs significantly increased all CD4-Tm ex-mRNAs, but only IL-2 and IL-6 ex-mRNAs were increased by Aß. There were no significant differences between cytokine and ex-mRNA responses of CD4-Tms from the old compared to the young subjects. M-derived serum exosomes from the old subjects had significantly higher IL-6 and IL-12 ex-mRNA levels than those from the young subjects, whereas there were no differences for CD4-Tm-derived serum exosomes. An Aß level relevant to neurodegeneration elicited broad M cytokine and ex-mRNA responses that were significantly greater in the old subjects, but only narrow and age-independent CD4-Tm responses.

Current status of inclusion of older groups in evaluations of new medications: Gaps and implementation needs to fill them.

Under-representation of subgroups of the population in clinical trials has been and continues to be a problem despite goals of academia, industry, and government. Older adults are among the groups that are under-represented in trials of medications that they are likely to receive once marketing approval has been received. Recent legislation that mandates that clinical trial participants be representative of patient population has been passed and creates hope that greater numbers of older adults will be enrolled in clinical trials and that they will be representative of "typical" geriatric patients. However, there is the need for collection of current data on disease prevalences with granularity as to age, gender, and race as well as geriatric co-morbidities to assess the representativeness of clinical trial participants relative to patient populations. Consensus on definitions and collection of data relevant to geriatric patient populations are needed to evaluate effects of comorbidities, frailty, cognitive and physical function. There will also be a need for expansion of the geriatric research workforce, facilities for research both in academic centers but also in the community and long-term care facilities, and for engagement with and involvement of communities that have been traditionally under-represented to conduct clinical trials that enroll truly representative patient populations.

Attitudes on participation in clinical drug trials: A nationally representative survey of older adults with multimorbidity.

BACKGROUND: Older adults with multimorbidity are under-represented in clinical drug trials. Their inclusion will not increase unless they are willing and able to participate. Data on motivators and barriers to participation in trials of new medications of older adults with multimorbidity are needed. METHODS: Cross-sectional internet and telephone survey of a nationally representative sample of adults ≥65 years with ≥3 chronic conditions (NORC University of Chicago Amerispeak Panel) conducted from March-April, 2023 to determine motivators and barriers to drug trial participation, described graphically and using statistics. RESULTS: Surveyed 1318 (1142 Internet, 176 phone) with mean age 72.3 ± 6.3 (SD), 52% women; race: 83% White, 10% Black or African American, 5% Hispanic or Latino, 1.1% Asian; 4.4 ± 1.9 chronic conditions (of 16 queried), taking 7.5 ± 3.3 medications. Barriers included fear of side effects (48%), taking too many medications (44%), placebo (44%), mobility (33%), bathroom needs (25%), hearing (19%), eyesight (15%), video visits (33%; higher in women, Black or African-American respondents, and those ≥80 years). Sixty-five percent would join all in-person trials, 49% would join all-video trials. Travel >1 h was difficult for 66%, most difficult for women. Trust was a concern in 25% of Black respondents. Caregiving responsibilities or lack of time were not obstacles. Participants were most likely to consider a drug trial for a problem they have (63%) versus prevention (44%) and if invited by a physician (80%) or University healthcare system (58%). Getting better care was ranked very important (79%) followed by helping others (57%). CONCLUSIONS: Major concerns of older patients with multimorbidity about participation in drug trials are potential side effects, taking too many medicines, and video visits. Physicians have the greatest influence on decisions and in-person visits are preferred. Proposed changes in trial design to increase enrollment of under-represented older adults may not align with patient-reported preferences.

Distinctive immunoregulatory effects of adenosine on T cells of older humans.

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<0.0001) for older (145±47 nM, mean±sd) than younger (58±5.5 nM) subjects. Expression of the activation coreceptor CD28 was suppressed significantly by 0.1 to 1 µM exogenous adenosine, with greater effects of 1 µM (P<0.01) on T cells of younger (mean suppression of 67 and 65% for CD4 and CD8 T cells, respectively) than older (means of 42 and 46%) subjects. T-cell chemotaxis to CCL21 was suppressed significantly by 0.3 and 1 µM exogenous adenosine, with mean maximum decreases of 39 and 49%, respectively, for younger subjects and 28 and 31% for older subjects. Generation of IL-2 and IFN-γ by T cells of younger and older subjects was suppressed substantially only at adenosine levels of 3 µM or higher. Lower baseline expression of CD28 and chemotaxis to CCL21 and S1P for T cells from older subjects attributable to endogenous adenosine were reversed completely by two different A(2A) adenosine receptor antagonists without affecting T cells of younger subjects. Adenosine is an endogenous T-cell immunosuppressor in older humans, and A(2A) antagonists reverse adenosine-induced T-cell deficiencies of aging.

Reasons for Nonadherence to the Direct Oral Anticoagulant Apixaban: A Cross-Sectional Survey of Atrial Fibrillation Patients.

Background: Nonadherence to direct oral anticoagulants to prevent stroke occurs in up to 40% of atrial fibrillation patients. Underlying reasons are poorly understood. Objectives: This study quantified patient-reported reasons for nonadherence and identified strategies to improve adherence. Methods: This is a cross-sectional survey of atrial fibrillation patients in 2 academic health systems who reported apixaban nonadherence. We examined patient-reported reasons for nonadherence and level of nonadherence (assessed by a validated 3-item adherence measure) using a multivariable logistic regression model. Results: Of 419 study patients, 41.5% were women. The mean age was 71.1 ± 10 years and mean CHA2DS2VASc score was 3.2 ± 1.6. About two-thirds had adherence scores ≥80 (mild nonadherence) and one-third scores <80 (poor adherence). In all groups, forgetfulness contributed to nonadherence. Attitudes/beliefs associated with adherence score <80 included: not believing apixaban was needed (odds ratio [OR]: 12.24 [95% CI: 2.25-66.47]); medication cost (OR: 3.97 [95% CI: 1.67-9.42]); and fear of severe bleeding (OR: 3.28 [95% CI: 1.20-8.96]). Strategies that patients with adherence scores <80 selected as helping "a great deal/a lot" to increase adherence included bloodwork to evaluate efficacy (56%), physician counseling about adherence (55%), and having a reversal agent (39%). Almost one-half of all patients did not disclose nonadherence to their providers. Conclusions: Patients may not disclose their nonadherence to prescribers, and attitudes related to apixaban nonadherence differ among patients with mild nonadherence versus poor adherence. While all patients may benefit from strategies to address forgetfulness, concerns related to the purpose of apixaban, cost, and bleeding risk may require special attention in those with poor adherence.

Participation of Older Adults in Clinical Trials for New Drug Applications and Biologics License Applications From 2010 Through 2019.

Importance: Older age may be accompanied by changes in the pharmacokinetics or pharmacodynamics or both of medications that can result in altered safety and efficacy profiles. Objective: To assess representation of older adults in clinical trials of new drug applications (NDAs) and biologics license applications (BLAs). Design, Setting, and Participants: This 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. Exposures: Trial enrollment. Main Outcomes and Measures: Representativeness 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. Results: Data 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 Relevance: In 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.

Apixaban Concentrations in Routine Clinical Care of Older Adults With Nonvalvular Atrial Fibrillation.

BACKGROUND: Direct-acting oral anticoagulants are first-line agents for prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF), but data are limited for the oldest patients, and with reduced dosing. OBJECTIVES: To determine steady-state apixaban peak and trough concentrations during routine care of older adults with NVAF, compare concentrations to clinical trial concentrations, and explore factors associated with concentrations. METHODS: A cross-sectional study of medically stable older adults with NVAF (≥75 years or ≥70 years if Black) receiving apixaban. Peak (2-4.4 hours post-dose) and trough (before next dose) concentrations were determined by anti-Xa activity calibrated chromogenic assay. Patient characteristics associated with concentrations were determined by multivariate modeling. RESULTS: The median age of patients (n = 115) was 80 (interquartile range: 77-84) years. The cohort comprised 46 women and 69 men; of which 98 are White, 11 Black, and 6 Asian. With 5 mg twice daily per labelling (n = 88), peak concentrations were higher in women: 248 ± 105 vs 174 ± 67 ng/mL in men (P < 0.001) and exceeded expected 95% range in 6 of 30 vs 0 of 55 men (P = 0.002). With 2.5 mg twice daily per label (n = 11), concentrations were <5 mg twice daily (peak: 136 ± 87 vs 201 ± 90 ng/mL, P = 0.026; trough: 65 ± 28 vs 109 ± 56 ng/mL, P < 0.001), but not different than 2.5 mg twice daily without reduction criteria (n = 13; peak: 132 ± 88; trough: 65 ± 31 ng/mL). Covariates associated with concentrations included sex, number of daily medications, and creatinine clearance. CONCLUSIONS: Older women had higher than expected peak apixaban concentrations, and 2.5 mg twice daily produced lower concentrations than standard dosing. Factors not currently included in dosing recommendations affected concentrations. The impact of apixaban concentrations on outcomes needs evaluation.