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Randomized Controlled Trial
. 2025 Nov;45(11):2111-2123.
doi: 10.1161/ATVBAHA.124.322336. Epub 2025 Sep 25.

Multiplex Apolipoprotein Panel Improves Cardiovascular Event Prediction and Cardiovascular Outcome by Identifying Patients Who Benefit From Targeted PCSK9 Inhibitor Therapy

Esther Reijnders  1 , Patrick M Bossuyt  2 , J Wouter Jukema  3   4 , L Renee Ruhaak  1 , Fred P H T M Romijn  1 , Michael Szarek  5   6   7 , Stella Trompet  8 , Deepak L Bhatt  9 , Vera A Bittner  10 , Rafael Diaz  11 , Sergio Fazio  12 , Irena Stevanovic  13 , Shaun G Goodman  14   15 , Robert A Harrington  16 , Harvey D White  17 , Philippe Gabriel Steg  18 , Gregory G Schwartz  5 , Christa M Cobbaert  1
Affiliations
Randomized Controlled Trial

Multiplex Apolipoprotein Panel Improves Cardiovascular Event Prediction and Cardiovascular Outcome by Identifying Patients Who Benefit From Targeted PCSK9 Inhibitor Therapy

Esther Reijnders et al. Arterioscler Thromb Vasc Biol. 2025 Nov.

Abstract

Background: Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine.

Methods: Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed.

Results: The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel (P<0.0001): AUC, 0.659 (0.637-0.681) for MACE and 0.724 (0.691-0.756) for all-cause death. Higher risk for MACE based on the baseline apolipoprotein panel was found to predict greater treatment benefit with alirocumab.

Conclusions: A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future.

Keywords: acute coronary syndrome; alirocumab; apolipoproteins; prognosis; risk.

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Conflict of interest statement

P.M. Bossuyt discloses the following relationships: Advisory Board: the Netherlands Healthcare Institute, Owlstone; Editorial Board: Radiology, Clinical Chemistry; Funding Committees: Cancer Research UK Early Detection, Dutch Cancer Foundation Biomarkers, Belgium, the Netherlands Funding of International Trials, Independent Research Fund Denmark. J.W. Jukema has received research grants from and/or was a speaker (with or without lecture fees) on a.o. (Continuing Medical Education accredited) meetings sponsored/supported by Abbott, Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Edwards Lifesciences, GE Healthcare Johnson and Johnson, Lilly, Medtronic, Merck-Schering-plow, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands (CVON), the Netherlands Heart Institute, and the European Community Framework KP7 program. M. Szarek receives salary support from Colorado Prevention Center (CPC), a nonprofit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between July 2021 and July 2024 from the following organizations: Abbott Laboratories, Agios Pharmaceuticals Inc, Alexion Pharma Godo Kaisha, Amgen Inc., Anthos Therapeutics Inc, ARCA biopharma Inc, Arrowhead Pharmaceuticals, AstraZeneca Pharma India, AstraZeneca UK Ltd, Bayer, Bayer Aktiengesellschaft, Bayer Pharma AG, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, LLC, Bristol Myers Squibb, Cleerly Inc, Colorado Dept of Public Health and Environment, Congress Inc, Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics Inc, EPG Communication Holdings Ltd., Esperion Therapeutics Inc, Faraday Pharmaceuticals Inc, HeartFlow Inc, Insmed, Ionis Pharmaceuticals, IQVIA Inc., Janssen Pharmaceuticals Inc, Janssen Research & Development, LLC, Janssen Scientific Affairs LLC, Lexicon Pharmaceuticals Inc, Medpace Inc, Medscape, Merck Sharp & Dohme Corp., Nectero Medical Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Inc, Pfizer, PPD Development, L.P., Prothena Biosciences Limited, Regeneron, Regents of the University of Colorado, Sanifit Therapeutics S.A., Sanofi, Silence Therapeutics PLC, Stanford University, Stealth BioTherapeutics Inc., The Brigham and Women’s Hospital, Thrombosis Research Institute, Tourmaline Bio Inc, University of Colorado, University of Colorado Denver, University of Pittsburgh, VarmX, Verve Therapeutics, WraSer, LLC. Michael Szarek serves as a consultant for and/or has received research support from Lexicon, Amarin, NewAmsterdam, Silence, Sanofi, Regeneron Pharmaceuticals, and Tourmaline. D.L. Bhatt discloses the following relationships: Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Stasys; Tourmaline Bio; Board of Directors: American Heart Association (AHA), New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, Corcept Therapeutics, GlaxoSmithKline, Hims, SFJ, Summa Therapeutics, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial [Macitentan for the Treatment of Portopulmonary Hypertension]), funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial [Pulmonary Embolism Thrombolysis]), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE-TAVI AF trial [Edoxaban Versus Vitamin K Antagonist for Atrial Fibrillation After TAVR]), funded by Daiichi Sankyo; for the ABILITY-DM trial (Randomized Comparison of Abluminus DES+ Sirolimus-Eluting Stents Versus Everolimus-Eluting Stents in Coronary Artery Disease Patients With Diabetes Mellitus Global), funded by Concept Medical; for Alleviant ALLAY-HF Study, funded by Alleviant Medical, Novartis, Population Health Research Institute; Rutgers University (for the National Institutes of Health [NIH]–funded MINT trial [Myocardial Ischemia and Transfusion]); Honoraria: American College of Cardiology (ACC; Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute); AEGIS-II (ApoA-I Event Reducing in Ischemic Syndromes II - AEGIS-II) executive committee funded by CSL Behring, Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the ACC (Guest Editor; Associate Editor), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease] operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Cleerly. V.A. Bittner reports having completed contracts between University of Alabama at Birmingham and sponsor: DalCor, Esperion—National Coordinator, and ongoing contracts between UAB and sponsor: Amgen—EVOLVE-MI (Evolocumab Very Early After Myocardial Infarction; site PI), Novartis—ORION (A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease; site Principal Investigator), Wake Forest Health (National Institute on Aging [NIA] subcontract): RehabHFpEF, and past contract between UAB and sponsor: Sanofi and Regeneron: Odyssey Outcomes and UAB contract ended in 2018/9, but publications are ongoing. Furthermore, she is a consultant at New Amsterdam Pharma, Pfizer (both completed, but within the 3-year time frame), and Data and Safety Monitoring Board (DSMB; ongoing): Eli Lilly; Verve Therapeutics. R. Diaz reports research grants from Sanofi, DalCor Pharmaceuticals, Population Health Research Institute, Duke Clinical Research Institute, the TIMI (Thrombolysis in Myocardial Infarction) group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit; and personal fees, as a member of the Executive Steering Committee, from Amgen and Cirius. Dr Fazio is an employee of Regeneron Pharmaceuticals Inc. I. Stevanovic is a Sanofi employee. S.G. Goodman received research grant support (eg, steering committee or data and safety monitoring committee) and/or is speaker/consulting honoraria (eg, advisory boards) from: Alnylam, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd., Daiichi Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Roche, Sanofi, Servier, Tolmar Pharmaceuticals, Valeo Pharma; and salary support/honoraria from the Canadian Heart Failure Society, Canadian Heart Research center and MD Primer, Canadian VIGOUR Center, Cleveland Clinic Coordinating center for Clinical Research, Duke Clinical Research Institute, Jewish General Hospital\Centre intégré universitaire de santé et de services sociaux (CIUSSS) Center-Ouest-de-l’Ile-de-Montreal, New York University Clinical Coordinating center, PERFUSE Research Institute, Peter Munk Cardiac center Clinical Trials and Translation Unit, Ted Rogers center for Heart Research, TIMI Study Group (Brigham Health). R.A. Harrington reports research grants/contracts (active) Randomized controlled trial: National Heart, Lung, and Blood Institute (NHLBI; ISCHEMIA), Duke/PCORI (Patient-Centered Outcomes Research Institute) Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term (ADAPTABLE), Janssen (factor XIa inhibitor), CSL, and DSMB: Baim Institute, UColorado, Harvard/BWH (Brigham and Women’s Hospital; TIMI). Consulting and advisory roles for NHLBI (COVID/CONNECTS), Atropos Health, Azurna, Basking Bioscience, Bitterroot Bio, BMS, Bridge Bio, Chiesi, Colorado Prevention Center, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, WebMD, and is part of the board of directors for AHA, Cytokinetics. H.D. White has received grant support paid to the institution and fees for serving on Steering Committees from Sanofi-Aventis, Regeneron Pharmaceuticals, Omthera Pharmaceuticals, American Regent, DalCor Pharma UK Inc, CSL Behring, National Health Institutes, Sanofi-Aventis Australia Pty Ltd, Janssen Research and Development LLC, Esperion Therapeutics Inc, and NIH. P.G. Steg reports research grants from Amarin, AstraZeneca, and Bayer; consulting for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Janssen, Pfizer, PhaseBio, Novartis, NovoNordisk, Regeneron, Sanofi, and Servier; and has a patent issued as co-inventor of the use of alirocumab to reduce cardiovascular risk (patent assigned to Sanofi). G.G. Schwartz has received research support to the University of Colorado from AstraZeneca, Sanofi, and Silence Therapeutics; and support for travel to trial meetings from the University of Oxford. C.M. Cobbaert has a research collaboration with and grant from Roche Diagnostics. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.
Clinical performance of prediction models on major adverse cardiovascular event (MACE) and all-cause death. Receiver operating characteristic (ROC) curves of clinical performance for MACE (top) and all-cause death (bottom) based on the prognostic models based on the apolipoprotein panel (left) consisting of baseline apolipoproteins and ApoE phenotype, the lipid panel (center) consisting of baseline total cholesterol, high-density lipoprotein cholesterol, and triglycerides, and the combination of the 2 panels (right).
Figure 2.
Figure 2.
Model-based calculated risk fraction in the placebo and targeted treatment group of the apolipoprotein panel for major adverse cardiovascular event (MACE) and all-cause death. Scatter plots of model-based calculated risk if allocated to placebo or alirocumab for MACE (A) and all-cause death (C). B and D, Stacked distribution of risk in the subgroups defined to achieve meaningful benefit or not for MACE and all-cause death (absolute risk reduction with alirocumab of ≥2.1% for MACE and ≥0.7% for all-cause death). Risk is calculated based on the apolipoprotein panel.
Figure 3.
Figure 3.
Probability thresholds for treatment allocation based on estimated treatment benefit by the apolipoprotein panel. A and B, Clinical decision limit at 8% and 17% estimated risk of major adverse cardiovascular event (MACE) and the resulting sensitivity and specificity, respectively. C, The sensitivity or specificity at specific probability thresholds. D, Table with 5 examples of probability thresholds and the resulting sensitivity and specificity.
See this image and copyright information in PMC

References

    1. Reijnders E, van der Laarse A, Jukema JW, Cobbaert CM. High residual cardiovascular risk after lipid-lowering: prime time for predictive, preventive, personalized, participatory, and psycho-cognitive medicine. Front Cardiovasc Med. 2023;10:1264319. doi: 10.3389/fcvm.2023.1264319 - PMC - PubMed
    1. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005;46:1225–1228. doi: 10.1016/j.jacc.2005.07.006 - PubMed
    1. Langlois MR, Chapman MJ, Cobbaert C, Mora S, Remaley AT, Ros E, Watts GF, Borén J, Baum H, Bruckert E, et al. ; European Atherosclerosis Society (EAS); the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Joint Consensus Initiative. Quantifying atherogenic lipoproteins: current and future challenges in the era of personalized medicine and very low concentrations of LDL cholesterol. A consensus statement from EAS and EFLM. Clin Chem. 2018;64:1006–1033. doi: 10.1373/clinchem.2018.287037 - PubMed
    1. Sandesara PB, Virani SS, Fazio S, Shapiro MD. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr Rev. 2019;40:537–557. doi: 10.1210/er.2018-00184 - PMC - PubMed
    1. Ginsberg HN, Packard CJ, Chapman MJ, Borén J, Aguilar-Salinas CA, Averna M, Ference BA, Gaudet D, Hegele RA, Kersten S, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society. Eur Heart J. 2021;42:4791–4806. doi: 10.1093/eurheartj/ehab551 - PMC - PubMed

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