In 6,732 NHANES 2011-2018 adults aged 40 or older without prior cardiovascular events, regular aspirin use (15 or more days a month) showed opposite associations with atherosclerotic cardiovascular mortality depending on smoking exposure. Current smokers had a fully adjusted hazard ratio of 0.15 (95% CI 0.03-0.76), never smokers 1.86 (1.12-3.10), and former smokers a null 1.65 (0.75-3.65). Risk attenuated across serum cotinine tertiles (p for linear interaction 0.013), with a continuous log-cotinine interaction p of 0.009.
Treat this as hypothesis-generating, not practice-changing. The never-smoker signal almost certainly reflects confounding by indication: people who take aspirin daily without a prior event often do so because a doctor judged their risk high, so aspirin use marks sicker people rather than causing deaths. That bias, plus a single baseline exposure measure, self-reported aspirin use and few events in some strata, probably explains the implausibly large 0.15 hazard ratio in smokers, whose wide interval (0.03 to 0.76) confirms how sparse the data are. Randomized evidence points the other way: ASPREE, ARRIVE and ASCEND showed little net benefit for primary prevention, with bleeding offsetting modest vascular gains, and ASPREE hinted at higher cancer mortality in older adults. Current guidelines have retreated from routine aspirin in primary prevention. A cotinine-based effect modifier is biologically interesting, since smoking drives platelet activation, but nobody should start or stop aspirin based on this. Smokers' best intervention remains quitting; anyone on aspirin should review it with their doctor.