OP-JNCI200119 221..222

The Aspirin in Reducing Events in the Elderly (ASPREE) trial, a large (n1⁄4 19 114) multi-center, randomized, double-blind, placebo-controlled study examining the effects of low-dose aspirin (100 mg/d) on disability-free survival, cardiovascular disease (CVD), and major hemorrhage in the elderly (1), originally reported its results in 3 separate articles published in 2018 (2-4). In this aged population, aspirin use did not prolong disabilityfree survival over 5 years (2), nor did it confer cardiovascular protection, but it statistically significantly increased the rate of major hemorrhage (3). These results are in line with results from both the Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) and A Study of Cardiovascular Events in Diabetes (ASCEND) trials, conducted and reported concomitantly with ASPREE (5,6). But unlike ARRIVE, ASCEND, and nearly all prior primary prevention CVD trials of aspirin (7), ASPREE surprisingly demonstrated increased all-cause mortality in the aspirin group, which appeared to be driven largely by an increase in cancer-related deaths (4). These findings have raised important concerns regarding the use of aspirin among the elderly. In this issue of the Journal, McNeil et al. (8) now follow up with a more in-depth analysis of cancer incidence and mortality by site and stage in ASPREE. In brief, overall and site-specific cancer incidence did not differ between the treatment groups; however, there were differences by stage. Aspirin increased the risk of metastatic cancer (hazard ratio [HR] 1⁄4 1.19, 95% confidence interval [CI] 1⁄4 1.00 to 1.43) and stage IV cancer at diagnosis (HR 1⁄4 1.22, 95% CI 1⁄4 1.02 to 1.45). Regarding mortality, aspirin conferred a statistically significant increased risk of death from all cancers (HR 1⁄4 1.35, 95% CI 1⁄4 1.13 to 1.61), both localized (HR 1⁄4 1.47, 95% CI 1⁄4 1.07 to 2.02) and metastatic cancers (HR 1⁄4 1.30, 95% CI 1⁄4 1.03 to 1.70), cancers presenting at stage III (HR 1⁄4 2.11, 95% CI 1⁄4 1.03 to 4.33) or stage IV (HR 1⁄4 1.31, 95% CI 1⁄4 1.04 to 1.64), and colorectal cancer (HR 1⁄4 1.77, 95% CI 1⁄4 1.02 to 3.06). Unfortunately, these new findings neither explain nor alleviate the concerns raised by the initial ASPREE report with regard to increased all-cause and cancer-related mortality. These results and their potential implications are in opposition to the large body of evidence from preclinical, observational, and clinical studies supporting the potential use of aspirin for cancer prevention (9). As the authors discuss in more detail, potential sources of bias in the ASPREE results, such as from multiple testing or in the ascertainment of outcomes, are unlikely to explain their findings. Nevertheless, such unexpected and contrary findings compel us to seek confirmation as well as potential biologically plausible explanations for why aspirin use would result in a cancer-promoting effect in the elderly compared with its cancer-protective or -inhibiting effects reported in earlier studies of more heterogeneous populations. Confirmation, however, may prove difficult, because it is unlikely that another such primary prevention trial will be conducted given the clinically significant harms (eg, bleeding) and lack of benefit from aspirin use that have been consistently documented across ASPREE, ASCEND, and ARRIVE. The ASCEND trial, with a longer follow-up period but younger cohort, did not detect a difference in cancer mortality between its treatment groups. The ARRIVE trial, which recruited men aged 55 years and older and women aged 60 years and older, has yet to report on cancer outcomes but may represent the best chance for confirmation. McNeil et al. (10) point towards several ongoing randomized controlled trials that are examining aspirin prescribed following a cancer diagnosis as potential sources of confirmation, but these trials are considerably smaller than ASPREE and do not focus on elderly patients (one, NCT02927249, specifically excludes them) so are therefore unlikely to either confirm or refute ASPREE’s unexpected findings. Long-term follow-up of ASPREE participants is ongoing and will be critical in assessing any delayed benefits or harms of aspirin in this population, particularly as they relate to cancer incidence and mortality. Until any of these data become available, we must consider ASPREE’s findings solely on their own merit. Potential biologically plausible explanations for the apparent differential effect of aspirin in aged vs younger populations ED IT O R IA L