Overcoming challenges to data quality in the ASPREE clinical trial

© 2019 The Author(s). Background: Large-scale studies risk generating inaccurate and missing data due to the complexity of data collection. Technology has the potential to improve data quality by providing operational support to data collectors. However, this potential is under-explored in community-based trials. The Aspirin in reducing events in the elderly (ASPREE) trial developed a data suite that was specifically designed to support data collectors: the ASPREE Web Accessible Relational Database (AWARD). This paper describes AWARD and the impact of system design on data quality. Methods: AWARD's operational requirements, conceptual design, key challenges and design solutions for data quality are presented. Impact of design features is assessed through comparison of baseline data collected prior to implementation of key functionality (n = 1000) with data collected post implementation (n = 18,114). Overall data quality is assessed according to data category. Results: At baseline, implementation of user-driven functionality reduced staff error (from 0.3% to 0.01%), out-of-range data entry (from 0.14% to 0.04%) and protocol deviations (from 0.4% to 0.08%). In the longitudinal data set, which contained more than 39 million data values collected within AWARD, 96.6% of data values were entered within specified query range or found to be accurate upon querying. The remaining data were missing (3.4%). Participant non-attendance at scheduled study activity was the most common cause of missing data. Costs associated with cleaning data in ASPREE were lower than expected compared with reports from other trials. Conclusions: Clinical trials undertake complex operational activity in order to collect data, but technology rarely provides sufficient support. We find the AWARD suite provides proof of principle that designing technology to support data collectors can mitigate known causes of poor data quality and produce higher-quality data. Health information technology (IT) products that support the conduct of scheduled activity in addition to traditional data entry will enhance community-based clinical trials. A standardised framework for reporting data quality would aid comparisons across clinical trials

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

OnlinePublBACKGROUND: 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.Jessica E. Lockery, Taya A. Collyer, Robyn L. Woods, Suzanne G. Orchard, Anne Murray, Mark R. Nelson, Nigel P. Stocks, Rory Wolfe, Chris Moran, Michael E. Ernst, on behalf of the ASPREE Investigator Grou

Prescription medication use in older adults without major cardiovascular disease enrolled in the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial

Background: Efforts to minimize medication risks among older adults include avoidance of potentially inappropriate medications. Contemporary analysis of medication use in community-dwelling older people compared with the general population is lacking. Participants: A total of 19,114 community-dwelling adults in Australia and the United States aged 70 years or older (65 years or older for U.S. minorities) without histories of major cardiovascular disease, cognitive impairment, or disability participated in a randomized, placebo-controlled trial of aspirin: ASPirin in Reducing Events in the Elderly study. Measurements: Prescribed baseline medications obtained by self-report and medical record review were grouped by World Health Organization Anatomic and Therapeutic Chemical category. Potentially inappropriate medications were defined using a modified American Geriatrics Society Beers Criteria. Polypharmacy was defined as 5 or more medications, and hyperpolypharmacy defined as 10 or more medications. Cross-sectional descriptive statistics and adjusted odds ratios were computed. Results: The median number of prescription medications per participant was three, regardless of age. Women had a higher medication prevalence. Cardiovascular drugs (primarily antihypertensives) were the most commonly reported (64%). Overall, 39% of the cohort reported taking at least one potentially inappropriate medication, with proton-pump inhibitors being the most commonly reported (21.2% of cohort). Of the cohort, 27% had polypharmacy, and 2% hyperpolypharmacy. Age 75 years or older, less than 12 years of education, hypertension, diabetes mellitus, chronic kidney disease, frailty, gastrointestinal complaint, and depressive symptoms were associated with an increased likelihood of potentially inappropriate medications and polypharmacy. For almost all medication classes, prevalence was equivalent or lower than the general older population. Conclusion: Overall medication burden and polypharmacy are low in older adults free of major cardiovascular disease, disability, and cognitive impairment. The prevalence of potentially inappropriate medications is higher than previously reported and similar to more vulnerable populations as a result of the introduction of proton-pump inhibitors to the American Geriatrics Society Beers Criteria. Longitudinal follow-up is required to further understand the balance of benefits and risks for potentially inappropriate medications and polypharmacy in community-dwelling older people.Jessica E. Lockery, Michael E. Ernst, Jonathan C. Broder, Suzanne G. Orchard, Anne Murray, Mark R. Nelson, Nigel P. Stocks, Rory Wolfe, Christopher M. Reid, Danny Liew, Robyn L. Woods, and the ASPREE Investigator Grou

Safety of ceasing aspirin used without a clinical indication after age 70 years: a subgroup analysis of the ASPREE randomized trial

Background: The ASPREE (ASPirin in Reducing Events inthe Elderly) trial was a randomized, double-blind, placebocontrolledprimary prevention trial of aspirin in 19114 communitydwellingpersons aged 70 years and older (≥65 years in U.S.racial minorities). The results of the trial demonstrated that aspirinhad no benefit for disability-free survival, prevention of cardiovasculardisease events, or prevention of incident cancer,and increased risk for major bleeding and all-cause mortality(1–3). These findings were interpreted by some as being relevantonly to aspirin initiation and not aspirin discontinuation (4).The availability of evidence to inform the risks (for example, forgonecardiovascular protection) and benefits (for example,decreased risk for major hemorrhage) from aspirin cessationamong older adults is timely, given updated guideline recommendationsregarding aspirin use and clinical uncertainty (5). Objective: To investigate the effect of aspirin cessation versuscontinuation on disability-free survival and other clinical outcomesin a post hoc analysis of ASPREE participants who wereregularly taking aspirin before trial enrollment

Patterns of Association between Depressive Symptoms and Chronic Medical Morbidities in Older Adults

© 2020 The American Geriatrics Society OBJECTIVES: To investigate the association between depressive symptoms and several medical morbidities, and their combination, in a large older population. DESIGN: Cross-sectional study of baseline data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. SETTING: Multicentric study conducted in Australia and the United States. PARTICIPANTS: A total of 19,110 older adults (mean age = 75 years [standard deviation = ±4.5]). MEASUREMENTS: Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES-D 10) scale. Medical morbidities were defined according to condition-specific methods. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to test associations before and after accounting for possible confounders. RESULTS: Depressive symptoms were significantly associated with obesity (OR = 1.19; 95% CI = 1.07-1.32), diabetes (OR = 1.22; 95% CI = 1.05-1.42), gastroesophageal reflux disease (GERD) (OR = 1.41; 95% CI = 1.28-1.57), metabolic syndrome (OR = 1.16; 95% CI = 1.03-1.29), osteoarthritis (OR = 1.41; 95% CI = 1.27-1.57), respiratory conditions (OR = 1.25; 95% CI = 1.10-1.42), history of cancer (OR = 1.19; 95% CI = 1.05-1.34), Parkinson’s disease (OR = 2.56; 95% CI = 1.83-3.56), polypharmacy (OR = 1.60; 95% CI = 1.44-1.79), and multimorbidity (OR = 1.29; 95% CI = 1.12-1.49). No significant association was observed between depressive symptoms and hypertension, chronic kidney disease, dyslipidemia, and gout (P >.05). A significant dose-response relationship was evident between the number of medical comorbidities and the prevalence of depression (OR = 1.18; 95% CI = 1.13-1.22). CONCLUSION: Late-life depressive symptoms are significantly associated with several medical morbidities, and there appears to be a cumulative effect of the number of somatic diseases on the prevalence of depression. These findings augment the evidence for a complex relationship between mental and physical health in an otherwise healthy older population and might guide clinicians toward early recognition of high-risk individuals

Antihypertensive medication use and blood pressure control among treated older adults

The association of different antihypertensive regimens with blood pressure (BP) control is not well-described among community-dwelling older adults with low comorbidity. We examined antihypertensive use and BP control in 10 062 treated hypertensives from Australia and the United States (US) using baseline data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Renin-angiotensin system (RAS) drugs were the most prevalently used antihypertensive in both countries (Australia: 81.7% of all regimens; US: 62.9% of all regimens; P P P P = .002; diuretic monotherapy: BP control = 45.2% vs 64.5%; P = .001; and RAS blocker/diuretic combo: BP control = 50.2% vs 65.6%; P = .001). Our findings highlight variation in antihypertensive use in older adults treated for hypertension, with implications for BP control. Differences in BP control that were observed may be influenced, in part, by reasons other than choice of specific regimens

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

Published online: 27 January 2021Late-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.Michael Berk, Bruno Agustini, Robyn L. Woods, Mark R. Nelson, Raj C. Shah, Christopher M. Reid ... et al

Effect of Aspirin vs Placebo on the Prevention of Depression in Older People: A Randomized Clinical Trial

© 2020 American Medical Association. All rights reserved. Importance: Depression is associated with increased inflammation, which may precede its onset, especially in older people. Some preclinical data suggest potential antidepressant effects of aspirin, supported by limited observational data suggesting lower rates of depression in individuals treated with aspirin. There currently appears to be no evidence-based pharmacotherapies for the primary prevention of depression. Objective: To determine whether low-dose aspirin (100 mg) reduces the risk of depression in healthy older adults. Design, Setting, and Participants: This double-blinded, placebo-controlled randomized clinical trial was a substudy of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, which examined if aspirin increased healthy life span, defined as survival free of dementia and disability. The prespecified secondary outcome was depression. Individuals of all races/ethnicities older than 70 years in Australia, as well as white individuals older than 70 years and black and Hispanic individuals older than 65 years in the United States, were included. Interventions: Participants were randomized to aspirin (100 mg daily) or placebo, with a median (interquartile range) follow-up of 4.7 (3.5-5.6) years. Main Outcomes and Measures: The primary outcome was a proxy measure of major depressive disorder defined as a score of 8 or more on the Center for Epidemiologic Studies Depression 10-item (CES-D-10) scale. Results: Of the 19114 participants enrolled in the trial, 9525 received aspirin and 9589 received a placebo. The mean (SD) age was 75.2 (4.0) years in the aspirin group and 75.1 (4.5) years in the placebo group; 9531 (56.4%) were women. Participants' demographics and clinical characteristics at baseline were similar between groups. A total of 79886 annual CES-D-10 measurements were taken, with a mean of 4.2 measurements per participant. There were no significant differences at annual visits in the proportions of CES-D-10 scores of 8 or more between the aspirin and placebo groups. The incidence rate of new CES-D-10 scores of 8 or more was 70.4 events per 1000 person-years in the aspirin group and 69.1 in the placebo group (hazard ratio, 1.02 [95% CI, 0.96-1.08]; P =.54). Conclusions and Relevance: Low-dose aspirin did not prevent depression in this large-scale study of otherwise healthy older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT01038583

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 100mg aspirin versus placebo recruited 19,114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the U.S. Six basic ADLs were assessed every six months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after six months. Proportional hazards modelling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk.Results: Over a median 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 versus 5.3 events/1000py; HR=0.81, 95% 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 versus 12).Discussion: Low-dose aspirin in initially healthy older people did not reduce risk of incident ADL disability, although there was evidence of reduced persistent ADL disability

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

Advance Access publication November 10, 2021BACKGROUND: 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 U.S and Australia, 19,114 community-dwelling individuals aged ≥70 years (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 100mg daily aspirin versus placebo. Frailty, a pre-specified study endpoint, 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 hazards 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, 2252 participants developed incident Fried frailty, and 4451 had incident frailty according to the frailty index. Compared with placebo, aspirin treatment did not alter the risk of incident frailty (Fried frailty HR: 1.04, 95% 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.Sara E Espinoza, Robyn L Woods, A R M Saifuddin Ekram, Michael E Ernst, Galina Polekhina, Rory Wolfe ... et al