Abstract Body (Do not enter title and authors here): Introduction: Small, dense low-density lipoprotein (sdLDL) particles are believed to be a highly atherogenic subfraction of LDL due to prolonged residence time in circulation, greater adherence to and penetration of vascular endothelium, and higher susceptibility to oxidation. Automated biochemical measurement of sdLDL cholesterol (sdLDL-C) has demonstrated good fidelity to gold standard gradient ultracentrifugation or NMR spectroscopy. We evaluated the relationship of sdLDL-C and conventional LDL-C to risk of major adverse cardiovascular events (MACE) and treatment benefit of alirocumab in patients with recent acute coronary syndrome (ACS) receiving high-intensity or maximum-tolerated statin treatment.
Methods: The analysis included 11,837 participants in the ODYSSEY OUTCOMES trial (NCT01663402) with recent ACS and LDL-C ≥70 mg/dL despite optimized statin treatment. At baseline prior to randomized treatment with the PCSK9 monoclonal antibody alirocumab (N=5917) or placebo (N=5920), sdLDL-C was measured using the Denka (Nigata, Japan) method on a Roche cobas autoanalyzer and LDL-C was calculated with the Friedewald formula. In the placebo group, natural cubic splines depicted the relationships of sdLDL-C, LDL-C, and their ratio to the risk of MACE (CV death, non-fatal myocardial infarction or ischemic stroke, hospitalization for unstable angina, and ischemia-driven coronary revascularization) and treatment hazard ratio (HR: alirocumab/placebo) as a function of sdLDL-C and LDL-C.
Results: In Figure Panel A, the risk of MACE in the placebo group increased with concentrations of baseline sdLDL-C and LDL-C, with nearly superimposable splines. In Panel B, the relationship of sdLDL-C/LDL-C to risk of MACE in the placebo group (adjusted for LDL-C) showed no evidence of greater risk with greater sdLDL-C fraction. Overall, alirocumab reduced the risk of MACE (HR 0.87, 95% CI 0.79, 0.95). Panel C shows that the treatment HR did not vary significantly across the range of either LDL-C or sdLDL-C.
Conclusion: In patients with recent ACS and LDL-C ≥70 mg/dL on optimized statin treatment, sdLDL-C and conventional LDL-C similarly predict risk of MACE and benefit of treatment with alirocumab. Measurement of sdLDL-C does not appear to provide additional prognostic or predictive information.