Abstract Body (Do not enter title and authors here): BACKGROUND: Patients with prior ischemic stroke are at high risk for recurrent stroke and other major adverse cardiovascular events (MACE). The incremental benefit of achieving very low LDL-C in such patients remains undefined.

HYPOTHESIS: In stable ASCVD patients with prior ischemic stroke, achieving very low LDL-C is associated with a lower risk of MACE without an excess in hemorrhagic stroke.

METHODS: Participants with history of ischemic stroke were selected for the current analysis from the FOURIER trial, a randomized placebo-controlled trial studying evolocumab in patients with stable ASCVD (median follow-up 2.2 years) and the open-label extension study (median follow-up extended by 5 years) at participating sites. Using a modified-Poisson regression models, we examined the relationship between achieved LDL-C with the incidences of the composite primary endpoint (CV death, myocardial infarction, stroke, and hospitalization for unstable angina or coronary revascularization) and stroke-related endpoints (all type, ischemic, and hemorrhagic) adjusted for clinical covariates.

RESULTS: A total of 5,291 patients with history of ischemic stroke, occurring at a median of 3.3 years prior to enrollment, were followed for a total of 14,418 patient years (max follow-up 8.6 years). Median achieved LDL-C with evolocumab was 31.5 mg/dl (IQR 21.5-47.0 mg/dL). Patients with lower achieved LDL-C (modeled continuously) exhibited significantly lower annualized incidence rates (IR) of the primary composite endpoint (P_trend <0.001, panel A). When LDL-C was modeled categorically, the lowest IRs for the primary endpoint and for stroke were observed in patients whose achieved LDL-C was below 40 mg/dl, whereas there was no difference in hemorrhagic stroke (panel B).

CONCLUSION: In patients with prior ischemic stroke, achieving very low LDL-C (<40 mg/dl) was associated with a lower long-term risk of MACE, including recurrent stroke, without an increase in hemorrhagic stroke. These findings suggest to lower LDL-C target in patients with prior ischemic stroke further than current guidelines.