Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
Por:
Damask, A, Steg, PG, Schwartz, GG, Szarek, M, Hagstrom, E, Badimon, L, Chapman, MJ, Boileau, C, Tsimikas, S, Ginsberg, HN, Banerjee, P, Manvelian, G, Pordy, R, Hess, S, Overton, JD, Lotta, LA, Yancopoulos, GD, Abecasis, GR, Baras, A, Paulding, C
Publicada:
25 feb 2020
Resumen:
Background:
Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment.
Methods:
ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients.
Results:
The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (<= 90th percentile; P<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared with placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and a relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio, 0.63 [95% CI, 0.46-0.86]; P=0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78-0.98]; P=0.022; interaction P=0.04).
Conclusions:
A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
Filiaciones:
Damask, A:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Steg, PG:
Univ Paris, Hop Bichat, AP HP, INSERM U1148, Paris, France
Schwartz, GG:
Univ Colorado, Sch Med, Aurora, CO USA
Szarek, M:
SUNY Downstate Sch Publ Hlth, Dept Biostat & Epidemiol, Brooklyn, NY USA
Hagstrom, E:
Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden
Badimon, L:
IR Hosp Santa Creu i St Pau, CiberCV, Cardiovasc Program ICCC, Barcelona, Spain
Chapman, MJ:
Sorbonne Univ, Pitie Salpetriere Univ Hosp, Endocrinol Metab Div, Paris, France
Natl Inst Hlth & Med Res INSERM, Paris, France
Boileau, C:
Univ Paris, INSERM U1148, Paris, France
Univ Paris, Hosp Bichat Claude Bernard, AP HP, Genet Dept, Paris, France
Tsimikas, S:
Univ Calif San Diego, Sulpizio Cardiovasc Ctr, Div Cardiovasc Med, La Jolla, CA 92093 USA
Ginsberg, HN:
Columbia Univ, Irving Inst Clin & Translat Res, New York, NY USA
Banerjee, P:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Manvelian, G:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Pordy, R:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Hess, S:
Sanofi Aventis Deutschland GmbH, Biomarkers & Clin Bioanal, Translat Med & Early Dev, Frankfurt, Germany
Overton, JD:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Lotta, LA:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Yancopoulos, GD:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Abecasis, GR:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Baras, A:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
Paulding, C:
Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
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