Daily aspirin results in little to no reduction in colorectal cancer incidence during the first 15 years of follow-up and may increase colorectal cancer mortality in the first 5 to 10 years, according to a review published in the Cochrane Database of Systematic Reviews. Researchers also found high-certainty evidence that aspirin increases the risk of serious extracranial hemorrhage.
CRC ranks as the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related mortality, with approximately 1.9 million new cases and more than 900,000 deaths in 2022. Whether aspirin—an irreversible inhibitor of cyclooxygenase enzymes—reduces that burden has remained uncertain despite decades of randomized trial data.
Study Design
Researchers searched major medical databases through March 3, 2025, for randomized controlled trials comparing aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) with inactive control or alternative treatment for primary prevention of CRC or colorectal adenoma (CRA) in the general population.
The review included 10 randomized controlled trials enrolling 124,837 participants: ARRIVE, ASPREE, BDAT, JPAD, JPPP, PHS, SALT, TPT, UK-TIA, and WHS. Most participants were older adults in the United States and United Kingdom; two Japanese trials contributed approximately 30% of participants.
Seven trials evaluated low-dose aspirin (75 to 100 mg daily), and 3 evaluated higher doses. Intervention durations ranged from about 3 to 10 years, with 7 trials reporting extended observational follow-up of up to 23 years.
Primary outcomes were CRC incidence and serious adverse events. Secondary outcomes included CRC mortality, CRA incidence, serious extracranial hemorrhage, and hemorrhagic stroke.
No Clear Reduction in Cancer Incidence
At 5 to less than 10 years of follow-up, aspirin showed little to no difference in CRC incidence compared with inactive control with similar findings at 10 to less than 15 years.
At 15 years or longer, pooled estimates suggested a possible reduction in CRC incidence. However, the certainty of evidence was rated very low because these findings were derived from posttrial observational follow-up periods, during which blinding had ended.
Mortality Findings
In one large trial of older adults, aspirin was associated with increased CRC mortality at 5 to less than 10 years. Investigators from that trial hypothesized that aspirin may accelerate progression of preexisting, undetected cancers in older patients, potentially through suppression of antitumor inflammatory or immune responses.
At longer follow-up intervals, individual trials showed no statistically significant differences in CRC mortality. Pooled long-term data suggested a possible mortality reduction beyond 15 years, but the certainty of evidence was very low.
Data on CRA incidence were limited and inconclusive.
Bleeding Risk Confirmed
Aspirin did not significantly affect overall serious adverse events but increased the risk of serious extracranial hemorrhage.
Across 8 trials, serious bleeding events increased from approximately 8 per 1,000 patients in control groups to 12 per 1,000 patients receiving aspirin.
Hemorrhagic stroke risk was also increased. Higher aspirin doses were associated with greater bleeding risk compared with low-dose regimens.
Subgroup and Sensitivity Analyses
Subgroup analyses by aspirin dose, age group, and race or ethnicity showed no statistically significant differences in CRC incidence or mortality.
Sensitivity analyses excluding trials at higher risk of bias did not materially change the results.
Limitations
Several limitations affected certainty of evidence. Many included trials were originally designed to evaluate cardiovascular outcomes rather than cancer endpoints, potentially influencing cancer detection and reporting.
Long-term findings were based on observational follow-up after randomized treatment ended, introducing risk of bias from treatment crossover and loss of blinding.
Participants were predominantly White, older adults in high-income countries, limiting generalizability.
No eligible randomized trials evaluated nonaspirin NSAIDs for primary CRC prevention in the general population.
The interaction between aspirin chemoprevention and widespread endoscopic screening remains unclear.
Clinical Implications
The researchers stated that current evidence is insufficient to draw definitive conclusions about the routine use of aspirin for primary prevention of CRC in the general population.
They noted that the US Preventive Services Task Force reversed its 2016 recommendation supporting aspirin for CRC prevention in 2022, citing conflicting evidence.
“The uncertain and delayed potential for benefit must be weighed against a definite harm,” the researchers wrote. “While aspirin probably has little to no effect on overall serious adverse events, it increases the risk of serious extracranial hemorrhage and probably increases the risk of serious extracranial hemorrhage.”
Clinical decisions should focus on individualized assessment and shared decision-making, weighing potential cardiovascular benefits against bleeding risk.
Future Research
The researchers identified several priorities for future study, including:
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Randomized trials evaluating nonaspirin NSAIDs
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Extended follow-up of existing trials
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Analytical methods to address postrandomization confounding
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Studies assessing aspirin in the context of widespread colorectal screening
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Molecular pathological epidemiology approaches to identify patient subgroups most likely to benefit
The authors declared having no competing interests.
