Abstract 13322: Patients With a High Genetic Risk Score for Coronary Artery Disease May Receive Greater Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial

• Published in: Circulation (New York, N.Y.) Vol. 140; no. Suppl_1 Suppl 1; p. A13322
• Main Authors: Damask, Amy, Steg, Philippe G, Schwartz, Gregory G, Szarek, Michael, Hagstrom, Emil, Badimon, Lina, Banerjee, Poulabi, Manvelian, Garen, Hess, Sibylle, Abecasis, Goncalo R, Baras, Aris, Paulding, Charles
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 19.11.2019
• ISSN: 0009-7322
• DOI: 10.1161/circ.140.suppl_1.13322

IntroductionPolygenic risk scores (PRS) summarize disease risk over a number of genetic loci into a single risk score for each patient (pt), providing a promising tool for risk stratification and pt-guided treatment. Recent studies suggest that pts with a high coronary artery disease PRS (CAD-PRS) may receive greater benefit from statin treatment, both in primary and secondary prevention settings. To date, a PRS has not been evaluated as a predictor of response to an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9).HypothesisWe tested retrospectively if CAD-PRS was associated with greater benefit from treatment with alirocumab (PCSK9 inhibitor) in the ODYSSEY OUTCOMES trial.MethodsThe trial was a randomized, double-blind, placebo-controlled comparison of alirocumab or placebo on major adverse CV events (MACE) in 18,924 pts with a recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. A genome-wide CAD-PRS comprising ~6.5 million genetic variants was developed using 3 large genetic and clinical databases comprising data from ~730,000 individuals. Its performance was then evaluated in 11,953 trial pts for whom DNA was available.ResultsAmong pts assigned to placebo, those with CAD-PRS in the top decile had greater incidence of MACE (17.4% at 3 yrs) than pts with CAD-PRS below the top decile (11.5%). Pts with CAD-PRS in the top decile (>90%) had greater relative and absolute benefit from alirocumab treatment (HR for MACE 0.58; 95% CI 0.42-0.80; p = 0.001) than pts with CAD-PRS below the top decile (≤90%) (HR = 0.86; 95% CI 0.77-0.97; p = 0.014; PRS by-treatment interaction p= 0.029 Figure). The relation of CAD-PRS to the HR for MACE was independent of baseline LDL-C.ConclusionA polygenic risk score for CAD in the top decile identifies pts with high risk who receive greater benefit from alirocumab treatment. CAD-PRS may help to target treatment with alirocumab to pts who will derive greatest benefit.