Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) for preventing colorectal cancer and colorectal adenoma in the general population.

[RATIONALE] The role of nonsteroidal anti-inflammatory drugs, particularly aspirin, in the primary prevention of colorectal cancer remains controversial. The debate over aspirin use is driven by the challenge of balancing uncertain preventive benefits against the risks of adverse effects. Given the inconsistent findings from clinical trials and conflicting clinical guidelines, a rigorous and updated systematic review is necessary to clarify the evidence base.

[OBJECTIVES] To assess the benefits and harms of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, for preventing colorectal cancer (CRC) and colorectal adenoma (CRA) in the general population.

[SEARCH METHODS] We searched CENTRAL, MEDLINE, Embase, and two clinical trial registers (ClinicalTrials.gov and WHO ICTRP) on 3 March 2025.

[ELIGIBILITY CRITERIA] We included parallel-group or factorial-design randomized controlled trials (RCTs) comparing aspirin and other NSAIDs with either no treatment or a different treatment for preventing CRC or CRA in the general population.

[OUTCOMES] Our critical outcomes were CRC incidence and serious adverse events (SAE). Our important outcomes included CRC mortality, CRA incidence, serious extracranial hemorrhage, and hemorrhagic stroke. When data were available, we categorized findings into prespecified follow-up intervals: 5 to < 10 years, 10 to < 15 years, and ≥ 15 years.

[RISK OF BIAS] We assessed the risk of bias for study outcomes as high risk, some concerns, or low risk, using the Cochrane RoB 2 tool.

[SYNTHESIS METHODS] We synthesized data for each outcome using random-effects meta-analysis. For time-dependent outcomes, we prioritized time-to-event data, calculating hazard ratios (HRs) with 95% confidence intervals (CIs). When these were unavailable, we used dichotomous data to calculate risk ratios (RRs). For rare outcomes, we calculated Peto odds ratios (ORs) using a fixed-effect model. We used GRADE to assess the certainty of the evidence.

[INCLUDED STUDIES] We included 10 RCTs involving a total of 124,837 participants. These studies compared aspirin with either placebo or no treatment for the primary prevention of CRC. Low-dose aspirin (75 to 100 mg per day) was typically used, though three studies evaluated higher doses. The studies were mostly conducted in Europe and North America. One study had sites in Australia, and there were two large studies conducted in Japan. Seven studies reported long-term results with extended observational follow-up where blinding had ceased. We did not identify any RCTs that evaluated the use of non-aspirin NSAIDs by the general population for primary CRC prevention.

[SYNTHESIS OF RESULTS] For the comparison of aspirin versus inactive control in the general population, we rated the certainty of the evidence as very low to high. We downgraded the certainty level for several outcomes due primarily to risk of bias and imprecision. Regarding CRC incidence, aspirin probably results in little to no difference at follow-up ≥ 5 to < 10 years (HR 1.00, 95% CI 0.81 to 1.24; 3 studies, 26,702 participants; moderate-certainty evidence) and at ≥ 10 to < 15 years (HR 0.95, 95% CI 0.77 to 1.17; 2 studies, 42,412 participants; moderate-certainty evidence). Aspirin may reduce CRC incidence slightly at follow-up ≥ 15 years (HR 0.78, 95% CI 0.67 to 0.91; 3 studies, 47,464 participants; very low-certainty evidence), but the evidence is very uncertain. Regarding CRC mortality, aspirin may increase mortality at follow-up ≥ 5 to < 10 years (HR 1.77, 95% CI 1.02 to 3.07; 1 study, 19,114 participants; low-certainty evidence), may result in little to no difference in mortality at follow-up ≥ 10 years and < 15 years (Peto OR 1.14, 95% CI 0.73 to 1.78; 1 study, 39,876 participants; low-certainty evidence), but may reduce mortality at follow-up ≥ 15 years (Peto OR 0.74, 95% CI 0.60 to 0.90; 5 studies, 53,909 participants; very low certainty evidence), but the evidence is very uncertain. Regarding CRA incidence, aspirin may result in little to no difference in CRA incidence at ≥ 5 to < 10 years of follow-up (Peto OR 0.42, 95% CI 0.10 to 1.87; 1 study, 12,546 participants; very low certainty evidence), but the evidence is very uncertain. Regarding safety, although aspirin probably results in little to no difference in overall SAE (RR 1.06, 95% CI 0.84 to 1.34; 3 studies, 16,442 participants; moderate-certainty evidence), aspirin does increase the risk of serious extracranial hemorrhage (RR 1.59, 95% CI 1.30 to 1.95; 8 studies, 97,567 participants; high-certainty evidence) and probably increases the risk of hemorrhagic stroke (Peto OR 1.40, 95% CI 1.11 to 1.77; 8 studies, 105,037 participants; moderate-certainty evidence).

[AUTHORS' CONCLUSIONS] It is not possible to draw definitive conclusions or outline specific implications for the routine use of aspirin for CRC primary prevention based on the current evidence. Our findings reveal complex, time-dependent preventive effects and concerns about potential harms for clinicians and patients to consider. Evidence of very low to moderate certainty shows little to no benefit for CRC or CRA incidence in the first 15 years, and low-certainty evidence suggests a potential increase in CRC mortality in the first 5 to 10 years. Very low-certainty evidence suggests potential benefits for CRC incidence and mortality after long-term follow-up (≥ 15 years), but these potential long-term benefits are derived from findings in the observational follow-up phases of RCTs, where standard intention-to-treat analyses are not robust to post-randomization confounding from factors such as treatment contamination. The uncertain and delayed potential for benefit must be weighed against a definite harm. While aspirin probably has little to no effect on overall serious adverse events (moderate-certainty evidence), it increases the risk of serious extracranial hemorrhage (high-certainty evidence) and probably increases the risk of hemorrhagic stroke (moderate-certainty evidence). In light of the mixed evidence, clinical practice should continue to center on an individualized assessment and a shared decision-making process, carefully balancing a patient's established cardiovascular risk profile against their risk of bleeding.

[FUNDING] This Cochrane review was funded (in part) by the China Postdoctoral Science Foundation (2024M752248) and the Postdoctoral Fellowship Program (Grade A) of China Postdoctoral Science Foundation (BX20230244).

[REGISTRATION] Protocol available via doi.org/10.1002/14651858.CD015266.