Study design of ASPirin in Reducing Events in the Elderly (ASPREE): A randomized, controlled trial

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Abstract

Cost-effective strategies to maintain healthy active lifestyle in aging populations are required to address the global burden of age-related diseases. ASPREE will examine whether the potential primary prevention benefits of low dose aspirin outweigh the risks in older healthy individuals. Our primary hypothesis is that daily oral 100 mg enteric-coated aspirin will extend a composite primary endpoint termed ‘disability-free life’ including onset of dementia, total mortality, or persistent disability in at least one of the Katz Activities of Daily Living in 19,000 healthy participants aged 65 years and above (‘US minorities’) and 70 years and above (non-‘US minorities’). ASPREE is a double-blind, randomized, placebo-controlled trial of oral 100 mg enteric-coated acetyl salicylic acid (ASA) or matching placebo being conducted in Australian and US community settings on individuals free of dementia, disability and cardiovascular disease (CVD) events. Secondary endpoints are all-cause and cause specific mortality, fatal and non-fatal cardiovascular events, fatal and non-fatal cancer (excluding non-melanoma skin cancer), dementia, mild cognitive impairment, depression, physical disability, and clinically significant bleeding. To 20 September 2013 14,383 participants have been recruited. Recruitment and study completion are anticipated in July 2014 and December 2018 respectively. In contrast to other aspirin trials that have largely focused on cardiovascular endpoints, ASPREE has a unique composite primary endpoint to better capture the overall risk and benefit of aspirin to extend healthy independent lifespan in older adults in the US and Australia.

Introduction

There is evidence that aspirin may be effective in primary prevention against a broad spectrum of diseases prevalent in the aged such as myocardial infarction, stroke, cancer and possibly dementia, yet there has been no study focused on older persons [1], [2], [3]. Aspirin also has well documented potential for harm, mainly due to bleeding into the brain, gastrointestinal tract and elsewhere, which are also more prevalent in the elderly [4]. In some diseases, such as stroke, there is the potential for both harm and benefit [1], [5]. The population 65 years of age and older have rarely been the focus of most clinical trials and have been conspicuously absent in primary prevention studies of aspirin constituting only 12% of the primary prevention study population [6], [7], [8], [9], [10], [11].

In contrast to other aspirin trials that have focused primarily on cardiovascular endpoints, ASPREE is examining whether the potential benefits of 100 mg daily aspirin for longevity and diseases associated with aging outweigh the risks associated with its use. ASPREE utilizes a unique composite primary endpoint with a trial design that examines the overall risk and benefit of aspirin in the elderly in promoting healthy independent lifespan. The secondary endpoints were selected based on the literature, raising hypotheses indicating potential benefits and/or harm associated with aspirin use.

The study was originally planned as a primary prevention cardiovascular disease (CVD) outcome study in the early 1990s to address the lack of aged participants in contemporary trials [6], [7], [12], [13]. The current iteration commenced in 2002 with the rationale still evident but expansion of the endpoints to include other prevalent diseases in the aged [8], [9], [10], [11], [14], [15]. The combination of aspirin's off-patent status and low cost limited industry participation to providing trial drug and matching placebo. Funding was obtained from the Australian National Health and Medical Research Council (NHMRC) and the National Institute on Aging (NIA). Randomization commenced in March 2010.

Section snippets

Design overview

ASPREE is a double-blind, randomized, placebo-controlled primary prevention trial with an average follow-up of 5 years, designed to assess whether daily active treatment of oral 100 mg enteric-coated aspirin will extend the duration of disability- and dementia-free life in healthy participants 65 years and older for the US minority groups of African Americans and Hispanics, with Caucasians and other minority groups 70 years and older. Participant visits occur at baseline (2 visits 1 month apart) and

Discussion

A large-scale clinical trial of aspirin in the aged is needed to capture risk and benefit in an aging population in whom life expectancy is truncated and multiple morbidity, polypharmacy, and disability are common. For example aspirin has well recognized protection against thromboembolic stroke but adverse risk for hemorrhagic stroke [1], [5]. It became obvious during the study development process that our primary endpoint needed to address these concerns and funder's requirements. The latter

Conclusion

Healthy aging is a global public health goal with the proportion of the population reaching the age of 65 years and older dramatically increasing in most developed and developing countries. Cost-effective strategies to maintain healthy active life in these populations are required to address the global burden of age-related diseases. Daily low dose aspirin has the potential to be such a strategy as a simple, readily available, cost-effective intervention to extend healthy lifespan around the

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    ASPREE is registered on the International Standard Randomized Controlled Trial Number Register (ISRCTN83772183). ASPREE has received project grants from the National Institute on Aging, the National Health and Medical Research Council (Australia), Heart Foundation (Australia), the National Cancer Institute and the Victorian Cancer Agency (Australia). Bayer Pharma AG provides blinded aspirin and placebo. ASPREE has multiple IRB approvals in the US and Australia.

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