AbstractBackgroundStatins are part of long‐term medical regimens for many older adults. Whether frailty modifies the protective relationship between statins, mortality, and major adverse cardiovascular events (MACE) is unknown.MethodsThis was a retrospective study of US Veterans ≥65, without CVD or prior statin use seen in 2002–2012, followed through 2017. A 31‐item frailty index was used. The co‐primary endpoint was all‐cause mortality or MACE (MI, stroke/TIA, revascularization, or cardiovascular death). Cox proportional hazards models were developed to evaluate the association of statin use with outcomes; propensity score overlap weighting accounted for confounding by indication.ResultsWe identified 710,313 Veterans (mean age (SD) 75.3(6.5), 98% male, 89% white); 86,327 (12.1%) were frail. Over mean follow‐up of 8 (5) years, there were 48.6 and 72.6 deaths per 1000 person‐years (PY) among non‐frail statin‐users vs nonusers (weighted Incidence Rate Difference (wIRD)/1000 person years (PY), −24.0[95% CI, −24.5 to −23.6]), and 90.4 and 130.4 deaths per 1000PY among frail statin‐users vs nonusers (wIRD/1000PY, −40.0[95% CI, −41.8 to −38.2]). There were 51.7 and 60.8 MACE per 1000PY among non‐frail statin‐users vs nonusers (wIRD/1000PY, −9.1[95% CI, −9.7 to −8.5]), and 88.2 and 102.0 MACE per 1000PY among frail statin‐users vs nonusers (wIRD/1000PY, −13.8[95% CI, −16.2 to −11.4]). There were no significant interactions by frailty for statin users vs non‐users by either mortality or MACE outcomes, p‐interaction 0.770 and 0.319, respectively. Statin use was associated with lower risk of all‐cause mortality (HR, 0.61 (0.60–0.61)) and MACE (HR 0.86 (0.85–0.87)).ConclusionsNew statin use is associated with a lower risk of mortality and MACE, independent of frailty. These findings should be confirmed in a randomized clinical trial.