ASPREE - ASPirin in Reducing Events in the Elderly

Background

Low dose aspirin therapy has been shown to reduce the risk of vascular events in a wide range of primary and secondary care settings, mainly in middle-aged people. There was some evidence of its potential to reduce the rate of certain malignancies and the rate of cognitive decline in older individuals. However, part of the benefit of aspirin could be offset by a variety of adverse effects, particularly those related to increased bleeding risk.

The ASPREE (ASPirin in Reducing Events in the Elderly) randomized, placebo-controlled clinical trial was needed to resolve uncertainty regarding the effects of aspirin used for primary prevention amongst older persons. Operationally, ASPREE is divided into three key phases of follow-up (Figure 1): 

the ASPREE Clinical Trial (2010 – 12 June 2017), 

the Bridge period (13 June 2017 to 31 January 2018) and 

the ASPREE-XT cohort study (1 February 2018 onward).

The ASPREE Clinical Trial assessed the effects of low dose (100mg) daily aspirin versus placebo (randomized 50:50) on the primary endpoint of disability-free survival, the corollary of which was measured as the first event of incident dementia or persistent physical disability or death from any cause or (1). Other clinically important outcomes relevant to aspirin’s efficacy and safety, including the prevention of cardiovascular disease events, cancer, cognitive decline, depression and clinically significant bleeding, were also assessed. ASPREE-XT is an observational study that extends follow-up of the ASPREE participants, primarily to study legacy effects of randomization to aspirin versus placebo. The Bridge period was a short administrative intervening phase between the end of the intervention phase and the beginning of ASPREE-XT. 

Study Design

The ASPREE Clinical Trial screened and randomized 19,114 volunteers (2,411 in the US and 16,703 in Australia) between the commencement of recruitment in March 2010 and the closure of recruitment in December 2014 (2). All participants were 70+ years of age, except US Minorities who were 65+ years. The screening process included two baseline visits (Visit 1 and Visit 2). The first visit involved initial lifestyle questions, cognitive screening and physical function screening followed by laboratory investigations and a medication compliance evaluation. The second visit included further assessments and confirmation of eligibility. In Australia, confirmation of eligibility required a clinical sign off by the participant’s usual General Practitioner (GP). Key exclusion criteria included a history of a diagnosed cardiovascular disease (CVD) event, current use of aspirin for secondary prevention, serious intercurrent illness likely to cause death within the next five years, dementia or Modified Mini-Mental State (3MS) examination score of <78/100, independence-limiting physical disability, anemia or a condition with a high bleeding risk. The full list of exclusion criteria is provided in references 1, 2.

Following completion of both baseline visits, participants who satisfied all study entry criteria were randomly allocated to one of the two treatment groups and commenced the ‘follow-up’ phase of the trial during which they were sent annual supplies of study medication. During the ASPREE Clinical Trial, participants were followed up for a median of 4.7 years and phone contact with participants was attempted at three monthly intervals. The intervention phase ceased in June 2017 and participants were advised to stop taking study medication and study drug supplies ceased. Subsequently, during ASPREE-XT, phone contact was attempted at six months following each annual visit.

During each of the follow-up phases, participants were asked to attend the clinic for annual visits that included the following: collection of physical measurements (blood pressure, weight, waist circumference and height at select visits), health behaviors, lifestyle questions including basic activities of daily living, quality of life, wellbeing and recent medical history updates, hospital visitations and collection of concomitant medications. Mood was evaluated annually with the Center for Epidemiologic Studies—Depression 10 question assessment (CES-D 10) tool. Laboratory measures for hemoglobin, CVD risk (lipids and triglyceride), renal function and fasting blood glucose were collected annually. During the ASPREE Clinical Trial, physical function assessments were carried out during even years of follow-up and cognitive screening alternately during odd years. Physical function measures included a 3m gait speed assessment, at usual walking pace, and grip strength (2). Cognitive measures included the 3MS, Controlled Oral Word Association Test (COWAT), Symbol-Digit Modalities Test (SDMT), Hopkins Verbal Learning Test—Revised (HVLT-R). An exception to this alternate year timing was that all measures were collected at participants’ close-out visits at the end of the trial; these ‘Milestone’ visits were scheduled to occur in 2017 (the trial was originally anticipated to finish in December 2017, but a decision was made to cease in June 2017, due to futility). 

During ASPREE-XT, the annual data collected during the ASPREE Clinical Trial continued, with annual measures of physical function and all cognitive measures (with Color Trails added) from the second ASPREE-XT annual visit (XT02). Laboratory measures were extended to include Full Blood Examination (FBE) and Complete Blood Count (CBC) annually from XT02, with plasma HbA1c replacing fasting blood glucose. References 1, 2 and 3, and the ASPREE Protocol (www.aspree.org) contain a detailed description of the data collection schedule of each phase of the study.

Outcomes

During 2017, participants completed Milestone visits that included all study assessments and an additional questionnaire about study medication, aspirin and over-the-counter medication use. Following cessation of study medication on 12 June 2017, these Milestone visits continued until 31 January 2018. This period is referred to as the ‘Bridge’ and was immediately followed with the beginning of the ASPREE-XT cohort study from 1 February 2018. ASPREE-XT is a longitudinal observational cohort study of ASPREE participants who agreed to be followed up for an additional five years.

Results/Conclusions

Throughout ASPREE and ASPREE-XT, study endpoints and major events were identified and recorded; usually triggered by participant self-report or from medical records obtained at the primary care practice. Documentation supporting clinical events was sought from medical practices, hospitals, specialists, pathology providers and other sources. Cases were prepared by the Endpoint team, de-identified and uploaded for review by specialist clinical Endpoint adjudication committees. These committees determined whether an endpoint had been reached according to strict pre-specified criteria (1). 

References:

1. McNeil JJ, Woods RL, Nelson MR, Reid CM, Kirpach B, Wolfe R, et al. Effect of aspirin on disability-free survival in the healthy elderly. The New England Journal of Medicine. 2018;379(16):1499-508.
2. McNeil JJ, Woods RL, Nelson MR, Murray AM, Reid CM, Kirpach B, et al. Baseline characteristics of participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study. The Journals of Gerontology: Series A. 2017;72(11):1586-93.
3. Ernst ME, Broder JC, Wolfe R, Woods RL, Nelson MR, Ryan J, et al. Health Characteristics and Aspirin Use in Participants at the Baseline of the ASPirin in Reducing Events in the Elderly - eXTension (ASPREE-XT) Observational Study. Contemp Clin Trials. 2023;130:107231.