Expanded statistical analysis plan for legacy and long-term effects of aspirin in the ASPREE-XT observational follow-up study of participants in the ASPREE randomized trial.

The ASPREE randomized controlled trial (2010-2017) of 19,114 community-dwelling older adults without cardiovascular disease and significant disability compared daily 100mg aspirin to placebo. A total of 16,317 (93%) of 17,546 surviving and non-withdrawn participants agreed to continue regular study follow-up visits in the post-trial phase, named ASPREE-XT (2017-2024). We present a statistical analysis plan to underpin three main papers to report aspirin effects through to the fourth post-trial ASPREE-XT study visit with focus areas of: (1) death, dementia, and disability, (2) CVD events and bleeding, and (3) cancer. The focus of the plan is to estimate long-term (entire timespan of RCT plus post-trial) and legacy (post-trial period only) effects of aspirin in the setting of primary prevention for older individuals. Preliminary insights to these effects are presented that are based on data that has been reported to the study's observational study monitoring board however formal data lock is not expected until October 2023.

Health Characteristics and Aspirin Use in Participants at the Baseline of the ASPirin in Reducing Events in the Elderly - eXTension (ASPREE-XT) Observational Study.

BACKGROUND: Aspirin as a primary preventative in healthy older adults did not prolong disability-free survival in the ASPREE randomized trial. Observational studies following randomized trials allow assessment of benefits and harms which may not appear during the trial. We describe health characteristics, physical function, and aspirin use in the ASPREE-eXTension (ASPREE-XT) observational study cohort. METHODS: Descriptive statistics compared health characteristics of those consented to ASPREE-XT at their first post-trial baseline (XT01) to corresponding ASPREE baseline values, and to those not consented. Likelihood of an indication for aspirin was assessed in participants reporting aspirin use at XT01. RESULTS: 16,317 (93%) of the remaining and eligible 17,546 ASPREE participants were consented into ASPREE-XT; 14,894 completed XT01. Mean participant age had increased from 74.9 to 80.6 years. Overall health and physical function declined from the original ASPREE baseline; more participants were living alone, there was higher prevalence of chronic kidney disease, diabetes, and frailty, grip strength was lower and gait speed slower. Those not consented into ASPREE-XT were slightly older, and had lower cognitive scores and higher prevalence of age-related conditions than those who continued. 1015/11,717 (8.7%) participants without an apparent indication for aspirin reported using aspirin at XT01. CONCLUSIONS: The ASPREE-XT cohort was slightly less healthy at the XT01 visit than at ASPREE trial initiation, and rates of aspirin use without indication were similar to ASPREE baseline. Participants will be followed long-term to investigate aspirin's potential legacy towards dementia and cancer prevention and explore determinants of healthy aging.

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.

An exploration of the trajectory of psychological distress associated with exposure to smoke during the 2014 Hazelwood coal mine fire.

Due to climate change, catastrophic events such as landscape fires are increasing in frequency and severity. However, relatively little is known about the longer-term mental health outcomes of such events. Follow-up was conducted of 709 adults exposed to smoke from the 2014 Hazelwood mine fire in Morwell, Victoria, Australia. Participants completed two surveys evaluating posttraumatic distress, measured using the Impact of Events Scale-Revised (IES-R), three and six years after the mine fire. Mixed-effects regression models were used to evaluate longitudinal changes in distress. IES-R total scores increased on average by 2.6 points (95%CI: 1.2 to 3.9 points) between the two survey rounds, with increases across all three posttraumatic distress symptom clusters, particularly intrusive symptoms. This increase in distress was evident across all levels of fine particulate matter (PM2.5) exposure to the mine fire smoke. Age was an effect modifier between mine fire PM2.5 exposure and posttraumatic distress, with younger adults impacted more by exposure to the mine fire. Greater exposure to PM2.5 from the mine fire was still associated with increased psychological distress some six years later, with the overall level of distress increasing between the two survey rounds. The follow-up survey coincided with the Black Summer bushfire season in south-eastern Australia and exposure to this new smoke event may have triggered distress sensitivities stemming from exposure to the earlier mine fire. Public health responses to disaster events should take into consideration prior exposures and vulnerable groups, particularly younger adults.

Chronic Obstructive Pulmonary Disease in Adults Exposed to Fine Particles from a Coal Mine Fire.

Rationale: In 2014, the Hazelwood open-cut coal mine in southeastern Australia burned for 6 weeks, exposing nearby residents to high concentrations of fine particulate matter (PM2.5). The long-term health consequences are unknown and are being evaluated as part of the Hazelwood Health Study. Objectives: To explore the association between PM2.5 exposure and chronic obstructive pulmonary disease (COPD). Methods: A sample of 346 exposed and 173 unexposed adults participated in the longitudinal Respiratory Stream of the Hazelwood Health Study. Participants underwent spirometry and gas transfer measurements and answered validated respiratory questionnaires 3.5-4 years after the fire. Individual-level mine fire-related PM2.5 exposure was modeled. Multivariate linear regression and logistic models were fitted to analyze associations between mean and peak PM2.5 exposure and clinical outcomes, stratified by smoking status. Results: A 10 µg/m3 increase in mean PM2.5 exposure was associated with a 69% (95% confidence interval [CI], 11-158%) increase in odds of spirometry consistent with COPD among nonsmokers and increased odds of chest tightness (odds ratio [OR], 1.30; 95% CI, 1.03-1.64) and chronic cough (OR, 1.24; 95% CI, 1.02-1.51) in the previous 12 months in all participants. For current smokers, increments in mean PM2.5 exposure were associated with higher odds of chronic cough in the preceding 12 months (OR, 2.13; 95% CI, 1.24-3.65). Conclusions: Almost 4 years after a 6-week period of coal fire PM2.5 exposure, we identified a dose-response association between exposure and COPD in nonsmokers. With climate change a likely contributor to increased risk of landscape fires, the findings will inform policy decisions during future sustained smoke events.

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).

The association between neighbourhood walkability and after-school physical activity in Australian schoolchildren.

INTRODUCTION: Physical inactivity is a risk factor for many noncommunicable diseases. As reported by the World Health Organisation, 81% of children worldwide are physically inactive. Environmental factors, such as neighbourhood walkability, can shape people's physical activity (PA) behaviour. This study explored the association between neighbourhood walkability and after-school PA among Australian schoolchildren. METHODS: The Department for Education and Child Development (DECD) distributed the survey to 189 schools across South Australia to assess the health and well-being of schoolchildren aged between 8 and 14 years. Neighbourhood was defined as an area corresponding to a four digit postcode, and its walkability was measured using Walk Score® . The association between neighbourhood walkability and after-school PA was analysed using multinomial logistic regression adjusted for age, gender, SEIFA score, number of days of TV watching, number of times of eating junk food, neighbourhood safety and children's weight status. RESULTS: Children residing in highly walkable areas (walker's paradise) compared to car-dependent areas had higher odds (OR(95%CI)) of engaging in after-school PA three (1.216 (1.029, 1.436), P = .021), four (1.287 (1.064, 1.557), P = .009) and five times a week (1.230 (1.030, 1.133), P = .022) compared to children never participating in PA. CONCLUSION: Living in highly walkable areas (walker's paradise), compared to living in car-dependent areas was associated with higher levels of after-school PA. So what? Creating walkable neighbourhoods with greater access to amenities, services and public transportation may help increase after-school PA among schoolchildren.

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.

Near-fatal uterine hemorrhage during induction chemotherapy for acute myeloid leukemia: a case report of bilateral uterine artery embolization.

Severe transfusion-dependent uterine hemorrhage is a relatively uncommon complication of induction chemotherapy for acute myeloid leukemia (AML). Even less common is the failure of systemic conjugated estrogens in this setting. We report a case of life-threatening uterine hemorrhage in a 38-year-old woman in the setting of transfusion-refractory thrombocytopenia after completing induction chemotherapy for AML. She experienced dramatic breakthrough uterine hemorrhage despite multiple platelet transfusions, conjugated estrogens, recombinant factor VIIa, epsilon-aminocaproic acid, and intracavitary thrombin-soaked gauze tamponade. At the point of near-exsanguination in the setting of hypotension, hematocrit of 14%, and a platelet count of 3,000/microL, she underwent bilateral uterine artery embolization which proved immediately successful. We review the literature and indications for this procedure in the oncologic patient care setting.