Young Sup Byun1, Xiaohong Yang2, Weihang Bao3, David DeMicco3, Rachel Laskey3, Joseph L Witztum4, Sotirios Tsimikas5. 1. Division of Cardiovascular Diseases, University of California, San Diego, La Jolla, California; Division of Cardiology, Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of South Korea. 2. Division of Cardiovascular Diseases, University of California, San Diego, La Jolla, California. 3. Pfizer, Inc., New York, New York. 4. Division of Endocrinology/Metabolism, University of California, San Diego, La Jolla, California. 5. Division of Cardiovascular Diseases, University of California, San Diego, La Jolla, California. Electronic address: stsimikas@ucsd.edu.
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 toplacebo 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).
RCT Entities:
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).
Authors: Ayelet Gonen; Soo-Ho Choi; Phuong Miu; Colin Agatisa-Boyle; Daniel Acks; Angela M Taylor; Coleen A McNamara; Sotirios Tsimikas; Joseph L Witztum; Yury I Miller Journal: J Lipid Res Date: 2018-12-18 Impact factor: 5.922
Authors: Max L Senders; Xuchu Que; Young Seok Cho; Calvin Yeang; Hannah Groenen; Francois Fay; Claudia Calcagno; Anu E Meerwaldt; Simone Green; Phuong Miu; Mark E Lobatto; Thomas Reiner; Zahi A Fayad; Joseph L Witztum; Willem J M Mulder; Carlos Pérez-Medina; Sotirios Tsimikas Journal: J Am Coll Cardiol Date: 2018-01-23 Impact factor: 24.094