Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People: Secondary Analysis of a Randomized Clinical Trial.

Importance: Low-dose aspirin has been widely used for primary and secondary prevention of stroke. The balance between potential reduction of ischemic stroke events and increased intracranial bleeding has not been established in older individuals. Objective: To establish the risks of ischemic stroke and intracranial bleeding among healthy older people receiving daily low-dose aspirin. Design, Setting, and Participants: This secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, double-blind, placebo-controlled trial of daily low-dose aspirin was conducted among community-dwelling people living in Australia or the US. Participants were older adults free of symptomatic cardiovascular disease. Recruitment took place between 2010 and 2014, and participants were followed up for a median (IQR) of 4.7 (3.6-5.7) years. This analysis was completed from August 2021 to March 2023. Interventions: Daily 100-mg enteric-coated aspirin or matching placebo. Main Outcomes and Measures: Stroke and stroke etiology were predetermined secondary outcomes and are presented with a focus on prevention of initial stroke or intracranial bleeding event. Outcomes were assessed by review of medical records. Results: Among 19 114 older adults (10 782 females [56.4%]; median [IQR] age, 74 [71.6-77.7] years), 9525 individuals received aspirin and 9589 individuals received placebo. Aspirin did not produce a statistically significant reduction in the incidence of ischemic stroke (hazard ratio [HR], 0.89; 95% CI, 0.71-1.11). However, a statistically significant increase in intracranial bleeding was observed among individuals assigned to aspirin (108 individuals [1.1%]) compared with those receiving placebo (79 individuals [0.8%]; HR, 1.38; 95% CI, 1.03-1.84). This occurred by an increase in a combination of subdural, extradural, and subarachnoid bleeding with aspirin compared with placebo (59 individuals [0.6%] vs 41 individuals [0.4%]; HR, 1.45; 95% CI, 0.98-2.16). Hemorrhagic stroke was recorded in 49 individuals (0.5%) assigned to aspirin compared with 37 individuals (0.4%) in the placebo group (HR, 1.33; 95% CI, 0.87-2.04). Conclusions and Relevance: This study found a significant increase in intracranial bleeding with daily low-dose aspirin but no significant reduction of ischemic stroke. These findings may have particular relevance to older individuals prone to developing intracranial bleeding after head trauma. Trial Registration: ISRCTN.org Identifier: ISRCTN83772183.

Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study.

BACKGROUND & AIMS: Prior studies have suggested that proton pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline. METHODS: We conducted a post hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults ≥65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria. Secondary endpoints include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models. RESULTS: Baseline PPI use vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72-1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92-1.09), or with changes in overall cognitive test scores over time (multivariable B, -0.002; standard error, 0.01; P = .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints. CONCLUSIONS: In adults ≥65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly : A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial.

BACKGROUND: Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia. OBJECTIVE: To investigate the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations. DESIGN: Post hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial. (ClinicalTrials.gov: NCT01038583). SETTING: Primary/community care in Australia and the United States. PARTICIPANTS: Community-dwelling persons aged 70 years or older (≥65 years for Black persons and Hispanic persons). INTERVENTION: 100 mg of aspirin daily or placebo. MEASUREMENTS: Hemoglobin concentration was measured annually in all participants. Ferritin was measured at baseline and 3 years after random assignment in a large subset. RESULTS: 19 114 persons were randomly assigned. Anemia incidence in the aspirin and placebo groups was 51.2 events and 42.9 events per 1000 person-years, respectively (hazard ratio, 1.20 [95% CI, 1.12 to 1.29]). Hemoglobin concentrations declined by 3.6 g/L per 5 years in the placebo group and the aspirin group experienced a steeper decline by 0.6 g/L per 5 years (CI, 0.3 to 1.0 g/L). In 7139 participants with ferritin measures at baseline and year 3, the aspirin group had greater prevalence than placebo of ferritin levels less than 45 µg/L at year 3 (465 [13%] vs. 350 [9.8%]) and greater overall decline in ferritin by 11.5% (CI, 9.3% to 13.7%) compared with placebo. A sensitivity analysis quantifying the effect of aspirin in the absence of major bleeding produced similar results. LIMITATIONS: Hemoglobin was measured annually. No data were available on causes of anemia. CONCLUSION: Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding. Periodic monitoring of hemoglobin should be considered in older persons on aspirin. PRIMARY FUNDING SOURCE: National Institutes of Health and Australian National Health and Medical Research Council.

Potentially inappropriate medication use is associated with increased risk of incident disability in healthy older adults.

BACKGROUND: Efforts to minimize medication risks among older adults include avoidance of potentially inappropriate medications (PIMs). However, most PIMs research has focused on older people in aged or inpatient care, creating an evidence gap for community-dwelling older adults. To address this gap, we investigated the impact of PIMs use in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial cohort. METHODS: Analysis included 19,114 community-dwelling ASPREE participants aged 70+ years (65+ if US minorities) without major cardiovascular disease, cognitive impairment, or significant physical disability. PIMs were defined according to a modified 2019 AGS Beers Criteria. Cox proportional-hazards regression models were used to estimate the association between baseline PIMs exposure and disability-free survival, death, incident dementia, disability, and hospitalization, with adjustment for sex, age, country, years of education, frailty, average gait speed, and comorbidities. RESULTS: At baseline, 7396 (39% of the total) participants were prescribed at least one PIM. Compared with those unexposed, participants on a PIM at baseline were at an increased risk of persistent physical disability (adjusted hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.21, 1.80) and hospitalization (adjusted HR 1.26, 95% CI 1.20, 1.32), but had similar rates of disability-free survival (adjusted HR 1.02; 95% CI 0.93, 1.13) and death (adjusted HR 0.92, 95% CI 0.81, 1.05). These effects did not vary by polypharmacy status in interaction analyses. PIMs exposure was associated with higher risk of disability followed by hospitalization (adjusted HR 1.92, 95% CI 1.25, 2.96) as well as vice versa (adjusted HR 1.54, 95% CI 1.15, 2.05). PPIs, anti-psychotics and benzodiazepines, were associated with increased risk of disability. CONCLUSIONS: PIMs exposure is associated with subsequent increased risk of both incident disability and hospitalization. Increased risk of disability prior to hospitalization suggests that PIMs use may start the disability cascade in healthy older adults. Our findings emphasize the importance of caution when prescribing PIMs to older adults in otherwise good health.

Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes.

BACKGROUND: Metformin and aspirin are commonly co-prescribed to people with diabetes. Metformin may prevent cancer, but in older people (over 70 years), aspirin has been found to increase cancer mortality. This study examined whether metformin reduces cancer mortality and incidence in older people with diabetes; it used randomization to 100 mg aspirin or placebo in the ASPirin in Reducing Events in the Elderly (ASPREE) trial to quantify aspirin's impact on metformin users. METHODS: Analysis included community-dwelling ASPREE participants (aged ≥70 years, or ≥65 years for members of US minority populations) with diabetes. Diabetes was defined as a fasting blood glucose level greater than 125 mg/dL, self-report of diabetes, or antidiabetic medication use. Cox proportional hazards regression models were used to analyze the association of metformin and a metformin-aspirin interaction with cancer incidence and mortality, with adjustment for confounders. RESULTS: Of 2045 participants with diabetes at enrollment, 965 were concurrently using metformin. Metformin was associated with a reduced cancer incidence risk (adjusted hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.51 to 0.90), but no conclusive benefit for cancer mortality (adjusted HR = 0.72, 95% CI = 0.43 to 1.19). Metformin users randomized to aspirin had greater risk of cancer mortality compared with placebo (HR = 2.53, 95% CI = 1.18 to 5.43), but no effect was seen for cancer incidence (HR = 1.11, 95% CI = 0.75 to 1.64). The possible effect modification of aspirin on cancer mortality, however, was not statistically significant (interaction P = .11). CONCLUSIONS: In community-dwelling older adults with diabetes, metformin use was associated with reduced cancer incidence. Increased cancer mortality risk in metformin users randomized to aspirin warrants further investigation. ASPREE TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01038583.

Combination of gait speed and grip strength to predict cognitive decline and dementia.

Introduction: To determine whether slowed gait and weakened grip strength independently, or together, better identify risk of cognitive decline or dementia. Methods: Time to walk 3 meters and grip strength were measured in a randomized placebo-controlled clinical trial involving community-dwelling, initially cognitively healthy older adults (N = 19,114). Results: Over a median 4.7 years follow-up, slow gait and weak grip strength at baseline were independently associated with risk of incident dementia (hazard ratio [HR] = 1.44, 95% confidence interval [CI]: 1.19-1.73; and 1.24, 95% CI: 1.04-1.50, respectively) and cognitive decline (HR = 1.38, 95% CI: 1.26-1.51; and 1.04, 95% CI: 0.95-1.14, respectively) and when combined, were associated with 79% and 43% increase in risk of dementia and cognitive decline, respectively. Annual declines in gait and in grip over time showed similar results. Discussion: Gait speed and grip strength are low-cost markers that may be useful in the clinical setting to help identify and manage individuals at greater risk, or with early signs, of dementia, particularly when measured together. Highlights: Grip strength and gait speed are effective predictors and markers of dementia.Dementia risk is greater than cognitive decline risk with declines in gait or grip.Decline in gait speed, more so than in grip strength, predicts greater dementia risk.Greater risk prediction results from combining grip strength and gait speed.

The association between polypharmacy, frailty and disability-free survival in community-dwelling healthy older individuals.

OBJECTIVES: Polypharmacy and frailty are two common geriatric conditions. In community-dwelling healthy older adults, we examined whether polypharmacy is associated with frailty and affects disability-free survival (DFS), assessed as a composite of death, dementia, or persistent physical disability. METHODS: We included 19,114 participants (median age 74.0 years, IQR: 6.1 years) from ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. Frailty was assessed by a modified Fried phenotype and a deficit accumulation Frailty Index (FI). Polypharmacy was defined as concomitant use of five or more prescription medications. Multinomial logistic regression was used to examine the cross-sectional association between polypharmacy and frailty at base line, and Cox regression to determine the effect of polypharmacy and frailty on DFS over five years. RESULTS: Individuals with polypharmacy (vs. <5 medications) were 55% more likely to be pre-frail (Relative Risk Ratio or RRR: 1.55; 95%Confidence Interval or CI:1.44, 1.68) and three times more likely to be frail (RRR: 3.34; 95%CI:2.64, 4.22) according to Fried phenotype. Frailty alone was associated with double risk of the composite outcome (Hazard ratio or HR: 2.16; 95%CI: 1.56, 2.99), but frail individuals using polypharmacy had a four-fold risk (HR: 4.24; 95%CI: 3.28, 5.47). Effect sizes were larger when frailty was assessed using the FI. CONCLUSION: Polypharmacy was significantly associated with pre-frailty and frailty at baseline. Polypharmacy-exposed frailty increased the risk of reducing disability-free survival among older adults. Addressing polypharmacy in older people could ameliorate the impact of frailty on individuals' functional status, cognition and survival.

The Effect of Low-Dose Aspirin on Frailty Phenotype and Frailty Index in Community-Dwelling Older Adults in the ASPirin in Reducing Events in the Elderly Study.

BACKGROUND: Frailty is associated with chronic inflammation, which may be modified by aspirin. The purpose of this study was to determine whether low-dose aspirin reduces incident frailty in healthy older adult participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. METHODS: In the United States and Australia, 19 114 community-dwelling individuals aged ≥70 and older (U.S. minorities ≥65 years) and free of overt cardiovascular disease, persistent physical disability, and dementia were enrolled in ASPREE, a double-blind, placebo-controlled trial of 100-mg daily aspirin versus placebo. Frailty, a prespecified study end point, was defined according to a modified Fried frailty definition (Fried frailty) and the frailty index based on the deficit accumulation model (frailty index). Competing risk Cox proportional hazard models were used to compare time to incident frailty by aspirin versus placebo. Sensitivity analysis was conducted to include frailty data with and without imputation of missing data. RESULTS: Over a median 4.7 years, 2 252 participants developed incident Fried frailty, and 4 451 had incident frailty according to the frailty index. Compared with placebo, aspirin treatment did not alter the risk of incident frailty (Fried frailty hazard ratio [HR]: 1.04, 95% confidence interval [CI] 0.96-1.13; frailty index HR: 1.03, 95% CI 0.97-1.09). The proportion of individuals classified as frail, and the trajectory in continuous frailty scores over time, were not different between the aspirin and placebo treatment groups. The results were consistent across a series of subgroups. CONCLUSIONS: Low-dose aspirin use in healthy older adults when initiated in older ages does not reduce risk of incident frailty or the trajectory of frailty.

Anticholinergic medication burden and cognitive function in participants of the ASPREE study.

STUDY OBJECTIVE: What is the association between anticholinergic burden and specific domains of cognitive function in older adults who are initially without major cognitive impairment? DESIGN: Post-hoc analysis of longitudinal observational data from the ASPirin in Reducing Events in the Elderly (ASPREE) study. PATIENTS: 19,114 participants from Australia and the United States aged 70 years and older (65 years and older for US minorities) were recruited and followed for a median of 4.7 years. At enrollment, participants were free of known cardiovascular disease, major physical disability, or dementia. MEASUREMENTS: Cognitive assessments administered at baseline and biennially at follow-up visits included the Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall, Controlled Oral Word Association Test (COWAT), and Symbol Digit Modalities Test (SDMT). Anticholinergic burden was calculated at baseline using the Anticholinergic Cognitive Burden (ACB) scale and grouped as scores of 0 (no burden), 1-2 (low to moderate), or 3+ (high). MAIN RESULTS: Linear mixed effects models were used to assess the relationship between ACB score and cognition over time. After adjusting for sex, age, education, minority status, smoking status, hypertension, diabetes, depression, chronic kidney disease, country, and frailty, participants with a high ACB score had worse performance over time for 3MS (Adjusted [Adj] B=-0.092, P=0.034), HVLT-R delayed recall (Adj B=-0.104, P<0.001), COWAT (Adj B=-0.151, P<0.001), and SDMT (Adj B=-0.129, P=0.026), than participants with an ACB score of 0. A low to moderate ACB score was also associated with worse performance over time for HVLT-R delayed recall (Adj B=-0.037, P=0.007) and COWAT (Adj B=-0.065, P=0.003), compared to those with no ACB. CONCLUSIONS: Anticholinergic burden predicts worse cognitive function over time in initially dementia-free older adults, particularly for executive function (COWAT) and episodic memory (HVLT-R).

Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population.

Few studies have measured the effect of genetic factors on dementia and cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of dementia and cognitive decline, stratified by APOE genotypes and polygenic risk score (PRS) tertiles, in 12,978 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed dementia, cardiovascular disease, physical disability or cognitive impairment. Dementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence for all-cause dementia and cognitive decline was calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants. During a median 4.5 years of follow-up, 324 participants developed dementia, 503 died. Cumulative incidence of dementia to age 85 years was 7.4% in all participants, 12.6% in APOE ε3/ε4 and 26.6% in ε4/ε4. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased dementia risk and 1.4/1.8-fold cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4-fold dementia risk versus low (CI 1.04-1.76, p = 0.02), but was not associated with cognitive decline (CI 0.96-1.22, p = 0.18). Incidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults.

BACKGROUND: Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking. OBJECTIVE: Compare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people. DESIGN: Prospective cohort study. SETTING: Primary care (Australia and USA). PARTICIPANTS: 19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100. MEASUREMENTS: Baseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition. RESULTS: At baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1-2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications. LIMITATIONS: Residual confounding and reverse causality are possible. Assessment of dose or duration was not possible. CONCLUSIONS: High anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.

Effects of aspirin on the long-term management of depression in older people: a double-blind randomised placebo-controlled trial.

Late-life depression is common and often inadequately managed using existing therapies. Depression is also associated with increased markers of inflammation, suggesting a potential role for anti-inflammatory agents. ASPREE-D is a sub-study of ASPREE, a large multi-centre, population-based, double-blind, placebo-controlled trial of aspirin vs placebo in older Australian and American adults (median follow-up: 4.7 years) of whom 1879 were depressed at baseline. Participants were given 100 mg daily dose of aspirin or placebo. Depressive symptoms were assessed annually using the validated, self-rated short version of the Center for Epidemiological Studies Depression scale. There was a significant increase in depressive scores (0.6; 95% CI 0.2 to 0.9; χ2 (1) = 10.37; p = 0.001) and a decreased score in the mental health component of a quality of life scale (-0.7; 95% CI -1.4 to -0.1; χ2 (1) = 4.74; p = 0.029) in the aspirin group compared to the placebo group. These effects were greater in the first year of follow-up and persisted throughout the study, albeit with small to very small effect sizes. This study failed to demonstrate any benefit of aspirin in the long-term course of depression in this community-dwelling sample of older adults over a 5-year period, and identified an adverse effect of aspirin in the course of depression in those with pre-existing depressive symptoms.

Musculoskeletal Pain Experienced on Most Days is a Common Accompaniment of Ageing amongst Community-Dwelling Older Australians: A Questionnaire-Based Study.

Objective: To describe the prevalence, location and impact of moderate to severe pain experienced on most days in community-dwelling older (≥70 years) adults who were ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial participants. Methods: Cross-sectional ASPREE Longitudinal Study of Older Persons (ALSOP) data were collected from self-reported questionnaires administered to 16,439 ASPREE participants. Results: Of 14,155 respondents, 41% of males (n = 2651/6475) and 50% of females (n = 3803/7680) reported experiencing pain on most days. One quarter of respondents reported experiencing pain on most days that was moderate or severe in intensity (n = 3560/14,155), commonly located in the lower back, knees and upper back. Of those reporting moderate or severe pain, 51% reported taking analgesic medication on most days (n = 1812/3560), almost one-third also reported regular interference with sleep (29%, n = 1024/3560), walking (35%, n = 1239/3560) and daily activities (41%, n = 1467/3560). Discussion: Lower back, knee or upper back pain is a common accompaniment of ageing.

Effect of Aspirin on Activities of Daily Living Disability in Community-Dwelling Older Adults.

BACKGROUND: Cerebrovascular events, dementia, and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults. METHODS: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100 mg aspirin versus placebo recruited 19 114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the United States. Six basic ADLs were assessed every 6 months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after 6 months. Proportional hazards modeling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk. RESULTS: Over a median of 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing, and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 vs 5.3 events/1000 py; hazard ratio [HR] = 0.81, 95% confidence interval [CI]: 0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability, there were more deaths in the aspirin group (24 vs 12). DISCUSSION: Low-dose aspirin in initially healthy older people did not reduce the risk of incident ADL disability, although there was evidence of reduced persistent ADL disability.

Normative performance of older individuals on the Hopkins Verbal Learning Test-Revised (HVLT-R) according to ethno-racial group, gender, age and education level.

OBJECTIVE: The Hopkins Verbal Learning Test-Revised (HVLT-R) provides a measure of verbal learning and memory. The aim of this study was to provide normative performance data on the HVLT-R for community-dwelling older individuals according to ethno-racial group, age, gender, and years of completed education, in Australia and the U.S. METHOD: The ASPirin in Reducing Events in the Elderly (ASPREE) study recruited 19,114 generally healthy community dwelling individuals aged 70 years and over (65 years and over for U.S minorities), who were without a diagnosis of dementia and scored above 77 on the modified Mini-Mental State (3MS) examination. Included in the analysis presented here were 16,251 white Australians, and in the U.S. 1,082 white, 894 African American and 314 Hispanic/Latino individuals at baseline. RESULTS: Performance on each of the components of the HVLT-R (trials 1-3, total, learning, delayed recall, delayed recognition, percentage retention and recognition discrimination index [RDI]) differed by demographic variables. In country and ethno-racial stratified analyses, female gender, younger age and higher education were significantly associated with better total recall, delayed recall and RDI. Among white Australians these characteristics were also associated with better retention. Age, education and gender-specific reference values across ethno-racial categories were determined. CONCLUSIONS: Ethno-racial, age, gender and education-stratified normative data from this large cohort of community-dwelling older individuals will serve as important reference standards in Australia and the U.S. to assess cognition in older individuals.

Subgroup analysis of the ASPirin in Reducing Events in the Elderly randomized clinical trial suggests aspirin did not improve outcomes in older adults with chronic kidney disease.

The role of aspirin for primary prevention in older adults with chronic kidney disease (CKD) is unclear. Therefore, post hoc analysis of the randomized controlled trial ASPirin in Reducing Events in the Elderly (ASPREE) was undertaken comparing 100 mg of enteric-coated aspirin daily against matching placebo. Participants were community dwelling adults aged 70 years and older in Australia, 65 years and older in the United States, all free of a history of dementia or cardiovascular disease and of any disease expected to lead to death within five years. CKD was defined as present at baseline if either eGFR under 60mL/min/1.73m2 or urine albumin to creatinine ratio 3 mg/mmol or more. In 4758 participants with and 13004 without CKD, the rates of a composite endpoint (dementia, persistent physical disability or death), major adverse cardiovascular events and clinically significant bleeding in the CKD participants were almost double those without CKD. Aspirin's effects as estimated by hazard ratios were generally similar between CKD and non-CKD groups for dementia, persistent physical disability or death, major adverse cardiovascular events and clinically significant bleeding. Thus, in our analysis aspirin did not improve outcomes in older people while increasing the risk of bleeding, with mostly consistent effects in participants with and without CKD.

Effect of aspirin on deaths associated with sepsis in healthy older people (ANTISEPSIS): a randomised, double-blind, placebo-controlled primary prevention trial.

BACKGROUND: Sepsis is a serious global health issue and a major cause of death and disability. The availability of a simple, community-based preventive strategy could substantially reduce the burden of sepsis. We aimed to establish whether low-dose aspirin reduced deaths or hospital admissions associated with sepsis in older people. METHODS: ANTISEPSIS was a substudy of ASPREE (a randomised controlled primary prevention trial of low-dose aspirin [100 mg per day] compared with placebo in community dwelling older adults conducted in Australia and the USA), with the Australian cohort included in the ANTISEPSIS substudy. Inclusion criteria were participants aged at least 70 years who did not have major illnesses. Participants were block randomised (1:1) via a centralised web portal and stratified by general practice and age. Participants, investigators, and staff were masked to the intervention. Teams of clinical specialist investigators assessed potential sepsis events to establish if they satisfied the primary endpoint of death associated with sepsis. The analyses were by intention-to-treat with univariate survival analysis methods, the log-rank test, and Cox proportional hazards regression. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000349741. RESULTS: Between March 10, 2010, and Dec 24, 2014, of 20 288 individuals assessed for eligibility, 16 703 participants aged 70 years and older at trial entry were enrolled and followed up for a median of 4·6 years (IQR 3·6-5·6). 8322 (49·8%) participants were assigned to receive aspirin and 8381 (50·2%) to placebo. 203 deaths were considered to be associated with sepsis. Univariate analysis showed similar rates of death associated with sepsis in the two study groups (hazard ratio for aspirin vs placebo 1·08, 95% CI 0·82-1·43; p=0·57). Adverse events were previously reported in the ASPREE trial. INTERPRETATION: Daily low-dose aspirin treatment did not reduce deaths associated with sepsis in community dwelling older adults. Our findings do not support the use of aspirin as a primary prevention strategy to reduce the burden of sepsis in this population. FUNDING: National Health and Medical Research Council of Australia, National Institutes of Health, Monash University.

Evaluation of the Pain Impact Index for Community-Dwelling Older Adults Through the Application of Rasch Modelling.

OBJECTIVE: Evaluate the Pain Impact Index, a simple, brief, easy-to-use, and novel tool to assess the impact of chronic pain in community-dwelling older adults. METHODS: A Rasch modelling analysis was undertaken in Stata using a partial credit model suited to the Likert-type items that comprised the Index. The Index was evaluated for ordering of category thresholds, unidimensionality, overall fit to the Rasch model, measurement bias (Differential Item Functioning, DIF), targeting, and construct validity. RESULTS: The four-item Pain Impact Index was self-completed by 6454 community-dwelling Australians who were aged at least 70 years and experienced pain on most days. Two items showed evidence of threshold disordering, and this was resolved by collapsing response categories (from 5 to 3) for all items. The rescored Index conformed to the unidimensionality assumption and had satisfactory fit with the Rasch model (analyses conducted on a reduced sample size to mitigate the potential for overpowering: n = 377, P > 0.0125, power > 77%). When considering uniform DIF, the most frequent sources of measurement bias were age, knee pain, and upper back pain. When considering nonuniform DIF, the most frequent source of measurement bias was knee pain. The Index had good ability to differentiate between respondents with different levels of pain impact and had highest measurement precision for respondents located around the average level of pain impact in the study sample. Both convergent and discriminant validity of the Index were supported. CONCLUSION: The Pain Impact Index showed evidence of unidimensionality, was able to successfully differentiate between levels of pain impact, and had good evidence of construct validity.

Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial.

OBJECTIVE: There is a lack of robust data on significant gastrointestinal bleeding in older people using aspirin. We calculated the incidence, risk factors and absolute risk using data from a large randomised, controlled trial. DESIGN: Data were extracted from an aspirin versus placebo primary prevention trial conducted throughout 2010-2017 ('ASPirin in Reducing Events in the Elderly (ASPREE)', n=19 114) in community-dwelling persons aged ≥70 years. Clinical characteristics were collected at baseline and annually. The endpoint was major GI bleeding that resulted in transfusion, hospitalisation, surgery or death, adjudicated independently by two physicians blinded to trial arm. RESULTS: Over a median follow-up of 4.7 years (88 389 person years), there were 137 upper GI bleeds (89 in aspirin arm and 48 in placebo arm, HR 1.87, 95% CI 1.32 to 2.66, p<0.01) and 127 lower GI bleeds (73 in aspirin and 54 in placebo arm, HR 1.36, 95% CI 0.96 to 1.94, p=0.08) reflecting a 60% increase in bleeding overall. There were two fatal bleeds in the placebo arm. Multivariable analyses indicated age, smoking, hypertension, chronic kidney disease and obesity increased bleeding risk. The absolute 5-year risk of bleeding was 0.25% (95% CI 0.16% to 0.37%) for a 70 year old not on aspirin and up to 5.03% (2.56% to 8.73%) for an 80 year old taking aspirin with additional risk factors. CONCLUSION: Aspirin increases overall GI bleeding risk by 60%; however, the 5-year absolute risk of serious bleeding is modest in younger, well individuals. These data may assist patients and their clinicians to make informed decisions about prophylactic use of aspirin. TRIAL REGISTRATION NUMBER: ASPREE. NCT01038583.