In healthy older adults, aspirin did not affect disability-free survival or CVD but increased death and bleeding

Abstract

Question In healthy, community-dwelling, older adults, what is the effect of aspirin for primary prevention compared with placebo? Methods Design Randomized placebo-controlled trial (Aspirin in Reducing Events in the Elderly [ASPREE] trial). ClinicalTrials.gov NCT01038583. The trial was stopped early for lack of benefit. Allocation Concealed.* Blinding Blinded* (patients, physicians, and outcome adjudicators). Follow-up period Median 4.7 years. Setting 34 sites in the USA and 16 sites in Australia. Participants 19114 community-dwelling adults 70 years of age or 65 years of age for black and Hispanic participants living in the USA (median age 74 y, 56% women, 8.7% nonwhite), who had no chronic illness that could limit survival to <5 years and no cardiovascular disease (CVD) or cerebrovascular disease. Exclusion criteria included dementia, physical disability, high risk for bleeding, or contraindication to aspirin. Intervention Enteric-coated aspirin, 100 mg/d (n =9525), or placebo (n =9589). Outcomes Primary outcome was disability-free survival (composite of mortality, dementia, or persistent physical disability). Secondary outcomes included components of the primary outcome, all-cause mortality, CVD, and major hemorrhage. 19000 participants were needed to detect a 10% reduction in the primary outcome with 90% power ( =0.05) Patient follow-up 97% (intention-to-treat analysis). Main results The main results are in the Table. Conclusion In healthy, older, community-dwelling adults, daily aspirin did not affect disability-free survival or cardiovascular disease but increased all-cause mortality and major hemorrhage. Aspirin vs placebo in healthy, community-dwelling, older adults Outcomes Event rates/1000 person-y At 4.7 y Aspirin Placebo Hazard ratio (95% CI) Disability-free survival 21.5 21.2 1.01 (0.92 to 1.11) All-cause mortality 12.7 11.1 1.14 (1.01 to 1.29) Dementia 6.7 6.9 0.98 (0.83 to 1.15) Physical disability 4.9 5.8 0.85 (0.70 to 1.03) Cardiovascular disease** 10.7 11.3 0.95 (0.83 to 1.08) Major hemorrhage 8.6 6.2 1.38 (1.18 to 1.62) Abbreviations defined in Glossary. Confidence intervals for the hazard ratios have not been adjusted for multiple comparisons. Survival free from dementia or persistent physical disability. **Fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure. Hemorrhagic stroke, symptomatic intracranial bleeding, or clinically significant extracranial bleeding. Commentary In the ASPREE trial, aspirin did not differ from placebo for primary prevention of CVD over 5 years. This apparent lack of benefit may have been due to underdosing. A previous individual patient meta-analysis showed that low-dose aspirin in adults who were 70 years of age and weighed <70 kg reduced risk for CVD (76% women, hazard ratio [HR] 0.70, 95% CI 0.55 to 0.88), whereas no benefit was seen in adults weighing 70 kg (57% men; HR 1.16, CI 0.91 to 1.49) (1). Risk for aspirin-associated major bleeding increases with each decade over age 65 years (2), starting early after initiation of aspirin. In ASPREE, bleeding occurred early and was associated with 2.4 more events per 1000 person-years than placebo. The ASPREE trial did not show any difference between aspirin and placebo in the primary outcome (a composite of mortality, disability, or dementia); however, cancer-related mortality, mostly colorectal cancer (CRC), was higher in the aspirin group beginning in the third year. Because de novo CRC takes 8 to 10 years to develop, the appearance of CRC and other adenomas within the time frame of ASPREE suggests that aspirin affects mortality from metastatic cancer. In younger adults, aspirin seems to be protective against CRC due to the probable reduction of metastases (1). These apparently contrary findings could result from lack of adjustment for multiple comparisons in ASPREE or may reflect cancer biology differences in adults 70 years of age. More research is needed to understand the role of aspirin in the primary prevention of cancer mortality. Low-dose aspirin does not increase disability-free survival or reduce CVD mortality but increases the risk for major hemorrhage; it should not be used for primary prevention of CVD in older adults.