Aspirins legacy on cancer and overall benefit: risk balance over a 15-year horizon

/ ABSTRACT The overarching goal of Project 2 is to address significant evidence gaps, including a need for more evidence on low dose aspirin (LDA)’s role in cancer prevention, outlined by the US Preventive Services Task Force (USPSTF) in its 2022 updated recommendations on LDA use for primary cardiovascular disease (CVD) prevention. Additionally, we aim to update risk models to be applicable to the oldest-old. Our proposed 5-year extension of the ASPREE-XT study would be uniquely poised to address three key knowledge gaps identified by the USPSTF 2022: 1) Evaluate the effects of LDA use on colorectal cancer (CRC) incidence and mortality over the longterm (10 to 20 years and longer) in primary prevention populations and in the context of current screening practices. 2) Improve the accuracy of CVD risk prediction in all racial and ethnic and socioeconomic groups. 3) Quantify the gastrointestinal bleeding (GIB) risk associated with aspirin use in populations representative of the US primary CVD prevention population. Our overarching hypotheses are: 1) for primary prevention, a 5-year course of LDA in older adults has a favorable overall health benefit:risk balance in certain high-risk individuals when considering legacy effects on cancer, CVD, Alzheimer’s disease and related dementias (ADRD) and GIB over a 15-year horizon; and 2) incorporation of novel predictive factors can improve risk stratification, thereby optimizing personalized preventive aspirin therapy. To test these hypotheses, we propose to extend follow-up of the ASPREE cohort to a mean 15 years post-randomization, while collecting data on ongoing use of aspirin and other non-steroidal anti-inflammatory drugs and accounting for such intake in our analyses. Five years of extended follow-up will provide an unmatched opportunity to understand the 15-year legacy effect of initiating LDA in older adults on incident cancer and cancer-related mortality, as well as other diseases of aging such as ADRD and CVD. This comprehensive evaluation is essential to determine LDA’s long-term benefit:risk profile, particularly in the context of existing screening practices. This project will also establish this benefit:risk balance in specific subgroups defined by clinical, lifestyle, and molecular risk factors over a 15-year horizon. Ultimately, this work will provide definitive guidance for future clinical recommendations regarding LDA use in primary prevention, and in high-risk subgroups of older adults.