Efficacy and Safety of Very Low Achieved LDL-Cholesterol in Patients with Prior Ischemic Stroke

Background: Patients with prior ischemic stroke are at high risk for recurrent stroke and other major adverse cardiovascular events (MACE). The benefits of achieving very low levels of low-density lipoproteins-cholesterol (LDL-C) in such patients is unclear. Methods: We analyzed patients with prior ischemic stroke enrolled in FOURIER, a randomized placebo-controlled trial studying evolocumab in patients with stable atherosclerotic cardiovascular disease (median follow-up 2.2 years), and through the open-label extension (FOURIER-OLE) period (additional median follow-up 5 years), to examine the relationship between achieved LDL-C and the long-term incidence of the primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization) and stroke-related endpoints. Results: The analysis included 5,291 patients with prior ischemic stroke (more than 4 weeks old). A total of 666 (12.6%), 1410 (26.6%), 586 (11.1%), 508 (9.6%) and 2121 (40.1%) patients achieved LDL-C values of <20, 20 to <40, 40 to <55, 55 to <70 and ≥70 mg/dL, respectively. The incidence of the primary endpoint, all stroke, and ischemic stroke each decreased in a monotonic fashion with lower achieved LDL-C levels on a continuous scale (P trend <0.001, 0.002 and 0.002, respectively). Compared with patients with LDL-C ≥70 mg/dL, those who achieved levels <40 mg/dL had incidence rate ratios (IRRs) (95% CI) of 0.69 (0.57-0.84), 0.73 (0.53-0.99), and 0.75 (0.54-1.05) for the outcomes of the primary endpoint, all stroke, and ischemic stroke, respectively. Hemorrhagic strokes were infrequent and unrelated to achieved LDL-C (P trend =0.85). Conclusions: In patients with prior ischemic stroke, it appeared that the lower the LDL-C, down to levels below 40 mg/dL, the lower the risk of MACE, including recurrent stroke, without a clear increase in risk of hemorrhagic stroke. These findings support the concept that more intensive LDL-C lowering in patients with prior ischemic stroke may be warranted.