Efficacy and Safety of Very Low Achieved LDL Cholesterol in Patients With Previous Ischemic Stroke.

Abstract

Patients with previous ischemic stroke are at high risk for recurrent stroke and other major adverse cardiovascular events. The benefits of achieving very low levels of low-density lipoprotein cholesterol (LDL-C) in such patients is unclear. We analyzed patients with previous ischemic stroke enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 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 end point (cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization) and stroke-related end points. The analysis included 5291 patients with previous ischemic stroke (>4 weeks). Of these, 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 end point, all stroke, and ischemic stroke each decreased in a monotonic fashion with lower achieved LDL-C levels on a continuous scale (<i>P</i>_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 of 0.69 (95% CI, 0.57-0.84), 0.73 (95% CI, 0.53-0.99), and 0.75 (95% CI, 0.54-1.05) for the outcomes of the primary end point, all stroke, and ischemic stroke, respectively. Hemorrhagic strokes were infrequent and unrelated to achieved LDL-C (<i>P</i>_trend=0.85). In patients with previous ischemic stroke, it appeared that the lower the LDL-C, down to levels <40 mg/dL, the lower the risk of major adverse cardiovascular events, 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 previous ischemic stroke may be warranted. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633/NCT01764633.