Background: Several observational and randomized studies have found an association between aspirin use and lower risk of colorectal cancer (CRC) incidence and mortality. This association is thought to be mediated by COX-2 inhibition in epithelial cells, although platelet inhibition via COX-1 inhibition may also contribute. We aimed to investigate whether use of P2Y12 inhibitors was associated with CRC incidence and related mortality among individuals diagnosed with atherosclerotic cardiovascular disease (ASCVD), the major clinical indication for use of these agents.
Methods: We prospectively studied 334,882 individuals diagnosed with ASCVD (coronary artery disease/ cerebrovascular disease/ peripheral arterial disease) between 2006 and 2021 without a history of cancer or inflammatory bowel disease in ESPRESSO, a nationwide cohort in Sweden. We considered P2Y12 inhibitor (clopidogrel/ ticagrelor/ prasugrel) use as a time-varying exposure. To implement a new-user design, we excluded individuals with a cumulative Defined Daily Dose (cDDD) ≥ 12 weeks of P2Y12 inhibitor prescription prior to cohort entry. For analyses of CRC incidence, end of follow-up was defined as CRC diagnosis, death, emigration, or December 31^st, 2021, whichever came first. For analyses of survival after CRC diagnosis, end of follow-up was defined as CRC-specific death, ASCVD-specific death, or death from any cause, emigration, or December 31^st, 2021, whichever came first. We used cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs).
Results: Among 107,459 P2Y12 inhibitor users and 227,423 non-users, we documented 4,015 incident CRC cases and 2,610 CRC-related deaths during a median follow-up of 5.1 years (IQR, 2.1-9.0). No association was observed between P2Y12 inhibitor use and CRC incidence. In contrast, longer duration of P2Y12 inhibitor use was associated with improved CRC mortality, which persisted after adjusting for aspirin use. Compared to non-users, the adjusted HRs for CRC mortality was 0.74 (95% CI, 0.62-0.88) for individuals with 336-671 cDDDs and 0.82 (95% CI, 0.70-0.96) for individuals with ≥ 672 cDDDs (Table 1). Among 2948 individuals diagnosed with CRC, individuals who initiated a P2Y12 inhibitor after diagnosis had an adjusted HR for CRC mortality of 0.48 (95% CI, 0.35-0.65) compared to non-users (Table 2).
Conclusion: P2Y12 inhibitor use was not associated with CRC incidence but significantly associated with improved CRC mortality. Mortality benefits appeared to be due to improved survival after CRC diagnosis. Our results suggest that inhibition of platelets may improve survival in patients diagnosed with CRC. In addition, our results suggest that the mechanisms that underlie the effect of aspirin on CRC incidence may differ from those that underlie its effect on metastatic spread and survival.

Matteo Bottai

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