Highlights
Aspirin did not prolong disability‑free survival in healthy older adults and produced no meaningful reduction in cardiovascular events. Major hemorrhage was significantly more frequent with aspirin (HR ~1.38 in-trial). An unexpected increase in all‑cause and cancer‑related mortality was observed during the randomized phase; extended follow‑up showed no long‑term cardiovascular benefit and persistently higher bleeding.
Background
Low‑dose aspirin has long been considered for primary prevention of atherosclerotic cardiovascular disease (ASCVD). In younger and middle‑aged populations, the balance between prevention of myocardial infarction and stroke versus bleeding has been debated; in older adults this balance is especially precarious because both cardiovascular risk and bleeding susceptibility increase with age. The ASPREE (Aspirin in Reducing Events in the Elderly) program was designed to answer whether daily low‑dose aspirin confers net clinical benefit in apparently healthy older adults without prior cardiovascular disease, dementia, or disability.
Study design and population
ASPREE encompassed a randomized, double‑blind, placebo‑controlled trial conducted in Australia and the United States (2010–2017) with extended post‑trial follow‑up (to 2022). Key design features were:
- Population: Community‑dwelling adults aged ≥70 years (or ≥65 for U.S. blacks and Hispanics), free of prior cardiovascular disease, dementia, or disability.
- Randomization: Daily enteric‑coated aspirin 100 mg versus matching placebo.
- Planned follow‑up: Median 4.7 years in‑trial; a subset provided consent for post‑trial follow‑up (median post‑trial ≈4.3 years in extended analysis).
- Key endpoints: Primary in the parent trial was disability‑free survival (a composite of death, dementia, or persistent physical disability). Prespecified secondary endpoints included major cardiovascular events (MACE), all‑cause mortality, cancer‑related death, and major hemorrhage. Deaths were adjudicated blinded to treatment assignment.
- Sample size: 19,114 randomized (9525 aspirin, 9589 placebo).
Key results — summary across the four ASPREE reports
The ASPREE publications of interest include the primary disability‑free survival report, focused cardiovascular and bleeding outcomes, the analysis of all‑cause mortality and cancer‑related death, and an extended follow‑up analysis of MACE and bleeding. The principal findings are summarized below and compared in the table that follows.
Primary disability‑free survival (NEJM, 2018)
Over a median of 4.7 years the composite primary endpoint (death, dementia, or persistent physical disability) occurred at nearly identical rates in the aspirin and placebo groups: 21.5 vs 21.2 events per 1000 person‑years (HR 1.01; 95% CI 0.92–1.11; P=0.79). The trial was stopped early for futility.
Cardiovascular events and bleeding (NEJM, 2018)
For in‑trial cardiovascular disease (a composite of myocardial infarction, stroke, or hospitalization for heart failure and other cardiovascular causes), rates were 10.7 events per 1000 person‑years (aspirin) versus 11.3 (placebo) yielding HR 0.95 (95% CI 0.83–1.08) — not statistically significant. Major hemorrhage was significantly increased with aspirin: 8.6 vs 6.2 events per 1000 person‑years (HR 1.38; 95% CI 1.18–1.62; P<0.001).
All‑cause and cancer mortality (NEJM, 2018)
All‑cause mortality was higher in the aspirin group: 12.7 vs 11.1 events per 1000 person‑years (HR 1.14; 95% CI 1.01–1.29). Cancer was the principal contributor to excess mortality (cancer death: 3.1% aspirin versus 2.3% placebo; HR 1.31; 95% CI 1.10–1.56) accounting for ≈1.6 excess deaths per 1000 person‑years. These findings were unexpected given prior evidence suggesting long‑term aspirin might reduce certain cancer mortalities (notably colorectal cancer).
Extended follow‑up: MACE and hemorrhage (Eur Heart J, 2025)
In participants without in‑trial MACE who consented to post‑trial follow‑up, the combined in‑trial and post‑trial period showed no long‑term benefit of randomization to aspirin for MACE (HR 1.04; 95% CI 0.94–1.15). Notably, during the post‑trial period alone there was an increased rate of MACE in participants randomized to aspirin (HR 1.17; 95% CI 1.01–1.36). Across the entire observation period, major hemorrhage remained higher in the aspirin group (HR 1.24; 95% CI 1.10–1.39).
Comparative results table (key metrics)
The following compact comparison highlights the most relevant metrics from the four reports.
Study population and follow‑up: 19,114 randomized (median age 74), median in‑trial follow‑up 4.7 years; extended post‑trial follow‑up median ≈4.3 years in subset.
Key outcomes (aspirin vs placebo):
- Disability‑free survival (primary): HR 1.01 (95% CI 0.92–1.11) — no benefit.
- All‑cause mortality (in‑trial): HR 1.14 (95% CI 1.01–1.29); absolute rates 12.7 vs 11.1 events/1000 person‑years.
- Cancer‑related death (in‑trial): HR 1.31 (95% CI 1.10–1.56); 3.1% vs 2.3% cumulative.
- Cardiovascular disease / MACE (in‑trial): HR 0.95 (95% CI 0.83–1.08) — neutral.
- Major hemorrhage (in‑trial): HR 1.38 (95% CI 1.18–1.62); rates 8.6 vs 6.2 events/1000 person‑years.
- Extended follow‑up MACE: overall HR 1.04 (95% CI 0.94–1.15); post‑trial period HR 1.17 (95% CI 1.01–1.36) in favor of placebo.
- Extended follow‑up hemorrhage: overall HR 1.24 (95% CI 1.10–1.39) — higher with prior randomization to aspirin.
Interpretation and expert commentary
ASPREE provides high‑quality randomized evidence that initiating low‑dose aspirin in healthy older adults for primary prevention does not improve disability‑free survival or reduce cardiovascular events within ~5 years, and carries a clear increase in major bleeding. The unexpected increase in all‑cause and cancer mortality during the randomized period warrants cautious interpretation: it was a prespecified adjudicated outcome but represented a post‑hoc exploratory finding for cause‑specific mortality and contrasts with prior observational and some randomized data suggesting long‑term reductions in colorectal cancer incidence and mortality with chronic aspirin use.
Possible explanations for the cancer signal include chance (multiple comparisons), differential detection or diagnosis, late effects of prior aspirin exposure, or age‑dependent biological interactions. ASPREE participants were older at randomization (median 74 years); it is biologically plausible that effects of aspirin on tumor biology differ when started at older ages versus earlier in life. The trial’s adherence (~62% aspirin in final year) and the limited median in‑trial follow‑up reduce power to detect long‑term chemopreventive effects that may accrue over a decade.
Importantly, the extended follow‑up reinforces the absence of cardiovascular benefit and confirms a persistently higher bleeding risk among those randomized to aspirin. The post‑trial increase in MACE among those previously randomized to aspirin (HR 1.17 post‑trial) is intriguing but complex to interpret: it may reflect chance, differential post‑trial behaviors, or biological rebound effects after aspirin cessation; further mechanistic study is needed.
Strengths of ASPREE include its large sample size, randomized double‑blind design, adjudicated endpoints, and extended follow‑up. Limitations include the relatively short median in‑trial follow‑up for evaluating cancer prevention hypotheses, incomplete adherence, and generalizability limited to relatively healthy elderly community‑dwelling adults without prior cardiovascular disease.
Clinical implications
For clinicians advising older adults without established cardiovascular disease, ASPREE supports the position that routine initiation of low‑dose aspirin should not be recommended for primary prevention. Decision making should be individualized: patients at very high ASCVD risk who are not at excess bleeding risk might still be considered for aspirin in exceptional circumstances, but such use would represent deviation from the ASPREE‑informed balance of risk and benefit. For patients already taking aspirin for primary prevention, clinicians should reassess the indication, review bleeding risk, and consider deprescribing if primary prevention is the only indication.
Conclusions
ASPREE’s evidence is clear for the enrolled population: low‑dose aspirin initiated in healthy older adults provided no net benefit for disability‑free survival or cardiovascular prevention, increased major bleeding, and revealed an unexpected signal for higher cancer‑related and all‑cause mortality. Extended follow‑up confirmed no long‑term cardiovascular benefit and a continued excess risk of hemorrhage. These results should inform guideline updates and routine clinical practice: do not start aspirin for primary prevention in healthy older adults without a compelling, individualized reason.
Funding and trial registration
Funded by the National Institute on Aging and other sources. ClinicalTrials.gov NCT01038583.
References
1. McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability‑free survival in the healthy elderly. N Engl J Med 2018;379:1499–508. doi:10.1056/NEJMoa1800722 IF: 78.5 Q1
2. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509–18. doi:10.1056/NEJMoa1805819 IF: 78.5 Q1
3. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all‑cause mortality in the healthy elderly. N Engl J Med 2018;379:1519–28. doi:10.1056/NEJMoa1803955 IF: 78.5 Q1
4. Wolfe R, Broder JC, Zhou Z, et al. Aspirin, cardiovascular events, and major bleeding in older adults: extended follow‑up of the ASPREE trial. Eur Heart J. 2025 Nov 7;46(42):4410–4422. doi:10.1093/eurheartj/ehaf514 IF: 35.6 Q1 . PMID: 40796244 IF: 35.6 Q1 ; PMCID: PMC12596486 IF: 35.6 Q1 .、
