Oxidized Phospholipids on Apolipoprotein B-100 and Recurrent Ischemic Events Following Stroke or Transient Ischemic Attack

Abstract

Background: Biomarkers to predict recurrent stroke and targets of therapy to prevent stroke are lacking.

Objectives: This study evaluated whether patients with prior cerebrovascular events and elevated levels of oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), but without prior coronary artery disease (CAD), are at risk for recurrent stroke and CAD events following high-dose statin therapy.

Methods: In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, OxPL-apoB levels were measured in 4,385 patients with stroke or transient ischemic attack at baseline and in 3,106 patients at 5 years following randomization to placebo or 80 mg atorvastatin. The primary endpoint was the time from randomization to a second nonfatal or fatal stroke. Secondary endpoints included first major coronary events and any cardiovascular event.

Results: Patients with recurrent stroke had higher baseline median OxPL-apoB levels than patients without (15.5 nmol/l vs. 11.6 nmol/l; p < 0.0001). After multivariable adjustment, elevated baseline OxPL-apoB predicted recurrent stroke (hazard ratio [HR]: 4.3; p < 0.0001), first major coronary events (HR: 4.0; p < 0.0001), and any cardiovascular event (HR: 4.4; p < 0.0001). These comparisons for any endpoint did not differ by treatment, shown as a nonsignificant interaction test. The net reclassification improvement, integrated discrimination improvement, and area under the receiver-operating characteristic curve (AUC) were all significantly improved by adding OxPL-apoB to the models, with ΔAUC +0.0505 (p < 0.0001) for recurrent stroke, ΔAUC +0.0409 (p < 0.0001) for first major coronary event, and ΔAUC +0.0791 (p < 0.0001) for any cardiovascular event.

Conclusions: Elevated OxPL-apoB levels predicted recurrent stroke and first major coronary events in patients with prior stroke or transient ischemic attack. The lack of statin-OxPL-apoB treatment interaction suggested that OxPLs might be statin-independent therapeutic targets to reduce risk of cardiovascular events. (Lipitor in the Prevention of Stroke, for Patients Who Have Had a Previous Stroke [SPARCL]; NCT00147602).

Keywords: integrated discrimination improvement; net reclassification improvement; oxidation-specific epitope; risk factors; statin therapy.