Low-Dose Aspirin and Cancer Mortality in Older Adults: Long-Term ASPREE Results Challenge Previous Paradigms

Highlights

The 10-year follow-up of the ASPREE trial indicates that 100 mg of daily aspirin does not reduce the incidence of cancer in adults aged 70 years or older. Most significantly, aspirin was associated with a 15% increase in cancer-related mortality (HR 1.15). Unlike findings in middle-aged populations, no protective effect against colorectal cancer was observed. Furthermore, the study found no evidence of a ‘legacy effect’ after treatment was discontinued, as cancer incidence and mortality rates normalized in the post-trial observation period.

Background

For decades, low-dose aspirin (LDA) has been scrutinized not only as a cardiovascular prophylactic but as a potential chemopreventive agent. Meta-analyses of earlier trials, predominantly involving middle-aged participants, suggested that long-term aspirin use could reduce the risk of several cancers, most notably colorectal cancer (CRC). These findings influenced global guidelines, including previous recommendations from the US Preventive Services Task Force (USPSTF). However, the geriatric population (aged 70 and older) remained underrepresented in these foundational studies. The Aspirin in Reducing Events in the Elderly (ASPREE) trial was launched to address this evidence gap. While initial results at 4.7 years suggested an unexpected increase in late-stage cancer diagnoses and deaths in the aspirin group, clinicians hoped that a longer follow-up might reveal the delayed chemopreventive benefits observed in younger cohorts. This 10-year follow-up, incorporating the ASPREE-XT (Extension) data, provides a definitive look at the long-term impact of aspirin on cancer in the elderly.

Study Design and Population

The study was a community-based, binational (Australia and the United States) cohort study. It integrated data from the original ASPREE randomized clinical trial (2010–2017) and its observational extension, ASPREE-XT (2018–2024). The cohort included 19,114 community-dwelling older adults, defined as ≥70 years for Australian participants and ≥65 years for US minority participants. All participants were free from overt cardiovascular disease, dementia, or physical disability at baseline. The intervention consisted of a daily 100-mg dose of enteric-coated aspirin or a matching placebo. Following the cessation of the randomized phase, participants were followed observationally. The primary outcomes for this analysis were physician-adjudicated incident cancer, cancer type, stage at diagnosis, and cancer-related mortality. The median follow-up period reached 8.6 years, with some participants followed for up to 12 years.

Key Findings: Incidence and Mortality

The 10-year data present a complex and sobering picture of aspirin’s role in geriatric oncology. Over the full follow-up period, 3,448 incident cancers and 1,173 cancer-related deaths were recorded.

Overall Cancer Incidence

There was no statistically significant difference in the overall incidence of cancer between the aspirin and placebo groups. The hazard ratio (HR) was 0.98 (95% CI, 0.92-1.05). This lack of benefit extended across various cancer types, including those previously thought to be aspirin-sensitive.

Colorectal Cancer (CRC)

A key disappointment was the lack of protection against CRC. Previous studies in younger populations suggested a 10-year latency period before aspirin’s benefits became apparent. However, in this elderly cohort, the HR for CRC was 1.01 (95% CI, 0.84-1.21), suggesting no preventive effect even after a decade.

Cancer-Related Mortality

The most critical finding was the sustained increase in cancer-related mortality in the aspirin group. The hazard ratio for cancer death was 1.15 (95% CI, 1.03-1.29). This mortality signal was consistent with the findings from the initial 4.7-year report, indicating that the increased risk of death from cancer was not a transient statistical anomaly but a persistent trend during the active treatment phase.

The Absence of a Legacy Effect

One of the primary objectives of the ASPREE-XT extension was to determine if aspirin exposure left a ‘legacy effect’—a protective or harmful impact that persists after the drug is stopped. The researchers analyzed 14,907 participants who entered the extension phase without a prior cancer diagnosis. In this post-RCT period, the original aspirin assignment was not associated with differences in cancer incidence (HR 0.91; 95% CI, 0.82-1.01) or mortality (HR 1.02; 95% CI, 0.83-1.25). This suggests that the increased mortality risk observed during the trial was likely tied to the period of active drug exposure rather than permanent physiological changes, and conversely, no delayed benefits emerged after the drug was discontinued.

Clinical Interpretation and Mechanistic Insights

The discrepancy between the ASPREE results and earlier trials in middle-aged adults (such as the Women’s Health Study or the Physicians’ Health Study) highlights the unique physiology of the aging body. Several biological hypotheses may explain why aspirin appears to be harmful rather than helpful in older adults regarding cancer. One theory involves the role of the immune system. Aspirin’s anti-inflammatory properties and its effect on platelets might interfere with the body’s natural immunosurveillance of nascent tumors. In older adults, whose immune systems are already undergoing senescence, this interference might allow micro-metastases to progress more rapidly. Another possibility is that aspirin may alter the tumor microenvironment in a way that promotes progression in older tissues, even if it prevents initiation in younger tissues. The lack of a legacy effect further suggests that aspirin’s impact on cancer in the elderly is more likely related to the progression of existing, undiagnosed lesions rather than the initiation of new ones.

Expert Commentary and Practical Implications

These findings reinforce the shift in clinical guidelines regarding aspirin for primary prevention. The USPSTF and other major bodies have already moved toward recommending against the routine initiation of LDA in adults over 60 for cardiovascular prevention. The ASPREE 10-year data provide compelling evidence that cancer prevention should also not be a reason to start LDA in this age group. Clinicians should be particularly cautious. While aspirin is a staple of secondary prevention for those with established cardiovascular disease, its use as a primary preventive agent in the elderly lacks a favorable risk-benefit ratio, especially given the increased risk of major bleeding and, as shown here, the potential for increased cancer mortality. Limitations of the study include the fact that it was not powered to detect small effects in rare cancer subtypes and that the observational nature of the extension phase introduces the possibility of confounding, although the randomized nature of the initial exposure remains a strong methodological foundation.

Conclusion

The 10-year follow-up of the ASPREE trial serves as a landmark study in geriatric medicine. It effectively closes the door on the hope that low-dose aspirin might serve as a long-term chemopreventive agent for individuals initiating therapy after age 70. Instead, the data suggest a concerning association with increased cancer mortality that does not provide a delayed benefit over time. For the elderly, the message is clear: the risks of primary prevention with aspirin likely outweigh the benefits, and personalized clinical judgment must prioritize safety and the avoidance of harm.

Funding and ClinicalTrials.gov

The ASPREE trial was funded by the National Institute on Aging and the National Cancer Institute (National Institutes of Health, USA), the National Health and Medical Research Council (Australia), Monash University, and the Victorian Cancer Agency. The trial is registered at ClinicalTrials.gov (NCT01038583).