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This study evaluated the prognostic value of a combined HRP definition in stable chest pain patients with low-to-intermediate pretest probability of CAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>This prespecified analysis included participants randomized to the CT arm of the pragmatic, prospective 26-center European DISCHARGE trial (NCT02400229). The primary endpoint was major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke); the secondary endpoint was expanded MACE (transient ischemic attack and major procedure-related complications). Our combined HRP definition was any coronary plaque with positive remodeling, napkin-ring sign, low attenuation, or total calcium score \u2265 400 Agatston units.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 1745 participants (age: 60\u2009\u00b1\u200910 years, 990 female), 35 MACE and 47 expanded MACE occurred at a median follow-up of 3.5 years (IQR: 2.9\u20134.2). After risk factor adjustment, the combined HRP definition was associated with a higher risk of MACE (HR: 3.81; 95% CI: 1.01\u201314.6;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.050) and remained significantly associated with expanded MACE (HR: 0.21; 95% CI: 1.07\u20139.66;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.038). Patients with both HRP and obstructive CAD conferred the highest MACE (HR: 8.78; 95% CI: 2.90\u201326.6;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and expanded MACE risk (HR: 7.31; 95% CI: 3.06\u201317.48;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) compared with patients without HRP or obstructive CAD. HRP alone showed a prognostic impact comparable to obstructive CAD alone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HRP features on coronary CT provide incremental predictive value for MACE, comparable to obstructive CAD, after adjusting for traditional cardiovascular risk factors in this large pan-European cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT02400229.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>\n                      <jats:bold>\n                        <jats:italic>Question<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:italic>Do high-risk plaque (HRP) features on coronary CT have incremental prognostic value after adjustment for cardiovascular risk factors in stable chest pain?<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:bold>\n                        <jats:italic>Findings<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:italic>A combined definition of HRP features on coronary CT was independently associated with major adverse cardiovascular events, with similar prognostic value to obstructive coronary artery disease after risk adjustment.<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:bold>\n                        <jats:italic>Clinical relevance<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:italic>HRP features, including a coronary artery calcium score \u2265 400 Agatston units or traditional high-risk plaque characteristics on coronary CT, provide incremental prognostic value in predicting MACE in stable chest pain patients, offering a potential tool for improved risk stratification and management.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00330-025-12146-3","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:22:44Z","timestamp":1770985364000},"page":"5502-5517","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Association of high-risk CT coronary artery plaque features with major adverse cardiovascular events: a prespecified secondary analysis of the DISCHARGE 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He was supported by the J\u00e1nos Bolyai Research Scholarship of the Hungarian Academy of Sciences. Federico Biavati: MD\/PhD student in the BIOQIC graduate program (GRK 2260\/1) financed by the German Research Foundation (DFG). Charlotte S\u00f8rum received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Theodora Benedek: received funding from the EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Received grants from the Romanian Ministry of European Funds of the Romanian Government and the European Union (increasing the research capacity in the field of vulnerable plaque imaging, based on advanced nanoparticles, fusion imaging and computational simulation\u2014\u201cPlaqueImage\u201d nt no. 103544\/2016, contract number 26\/01.09.2016). Patrick Donnelly: received funding from the EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Jos\u00e9 Rodriguez-Palomares: received funding from the EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Andrejs Erglis: received funding from the EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Cyril \u0160t\u011bchovsk\u00fd: received funding from the EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Gintar\u0117 \u0160akalyt\u0117: received funding from the EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266); received payment or honoraria for lectures from Amgen (Clinical Financial Service), AstraZeneca (Novartis Baltics), Bayer (Sanofi Aventis), Berlin Chemie Menarini, Baltic (Servier Pharma) and IQVIA; reported support from servier; reported participation on a DSMB in Boehringer Ingelheim; Nada \u010cemerli\u0107 A\u0111i\u0107: None. Matthias Gutberlet: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266); received payment or honoraria for lectures from Bayer (Institution), Siemens (Institution), Bracco (Institution) and the German Roentgen Society (DRG) (Institution); Reported to be a member of the ESCR Scientific Committee ESCR (unpaid), and a member of the Committee of the Working Group on Cardiovascular Imaging of the German Roentgen Society (DRG) (unpaid). Jonathan D. Dodd: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266); is an Associate Editor for\n                      Radiology\n                      , a member of the Editorial Board for\n                      Radiology Cardiothoracic Imaging\n                      , and an Associate Editor for the\n                      Quarterly Journal of Medicine and Rrespirology\n                      (all non-paid); and receives royalties as a co-author of book chapters in the Stat-Dx book Series Diagnostic Imaging\u2014Cardiovascular and the textbook CT and MRI in Cardiology, Elsevier. Ignacio Diez: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Gershan Davis: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Elke Zimmermann: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266) and grants from Deutsche Forschungsgemeinschaft (Grant: Radiomics in SPP 2177\/1). Cezary K\u0119pka: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Radosav Vidakovic: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Marco Francone: Member of the Scientific Editorial Board of\n                      European Radiology\n                      (section editor: Cardiac), and as such did not participate in the selection nor review processes for this article. Ma\u0142gorzata Ilnicka-Suckiel: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Fabian Plank: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Juhani Knuuti: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266); received grants from AstraZeneca (Personal Fees: Study protocol review) and from GE Healthcare (Personal Fees: Study protocol review); received payment or honoraria for lectures from GE Healthcare, Merck, Lundbeck, Bayer, Boehringer-Ingelheim, Pfizer and Siemens (speaker\u2019s fee); and reported other financial or non-financial interests for the European Society of Cardiology (Dr. Knuuti is Chair of the European Society of Cardiology guidelines on chronic coronary syndrome. The work is on a voluntary basis and only remuneration of travel expenses occurs). Rita Faria: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Stephen Schr\u00f6der: None. Colin Berry: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266); received grants from AstraZeneca (grant and other: The University of Glasgow has received funding for research and consultancy work in the field of ischemic heart disease undertaken by Colin Berry in the course of his employment), Abbott Vascular (other: The University of Glasgow has received funding for research and consultancy work in the field of ischemic heart disease undertaken by Colin Berry in the course of his employment), GSK (grant and other: The University of Glasgow has received funding for research and consultancy work in the field of ischemic heart disease undertaken by Colin Berry in the course of his employment), HeartFlow (grant and other: The University of Glasgow has received funding for research and consultancy work in the field of ischemic heart disease undertaken by Colin Berry in the course of his employment), Menarini (grant and other: The University of Glasgow has received funding for research and consultancy work in the field of ischemic heart disease undertaken by Colin Berry in the course of his employment), Novartis (grant and other: The University of Glasgow has received funding for research and consultancy work in the field of ischemic heart disease undertaken by Colin Berry in the course of his employment), Siemens (other: The University of Glasgow has research agreements in the field of ischemic heart disease for work undertaken by Colin Berry in the course of his employment); and reported that the University of Glasgow received research funding from The British Heart Foundation (RE\/18\/6134217). Luca Saba: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Balazs Ruzsics: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Nina Rieckmann: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266) and a grant from the German Ministry of Education and Research (NAVICARE 01GY1911; PI of Grant (no own salary)). Christine Kubiak: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Kristian Schultz Hansen: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Jacqueline M\u00fcller-Nordhorn: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). P\u00e1l Maurovich-Horvat: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266) and reported to be a shareholder of Neumann Medical Ltd. Helena Dom\u00ednguez: Reported partnership with the private company Cortrium APS jointly related to a grant from Innovation Foundation (Danish Ministry of Science Innovation and Higher Education\u2014Grand Solutions grant CACTH 1061-00046A) 2022\u20132025. Imre Benedek: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266), a grant from the Romanian Ministry of European Funds, the Romanian Government, and the European Union (for promoting research in the field of vulnerable plaque imaging, based on advanced nanoparticles, fusion imaging and computational simulation\u2014\u201cPlaqueImage\u201d nt no. 103544\/2016, contract number 26\/01.09.2016). Clare Orr: None. Filipa Xavier Valente: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Ligita Zvaigzne: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Vojt\u011bch Such\u00e1nek: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Antanas Jankauskas: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Filip A\u0111i\u0107: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Michael Woinke: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Niall Mulvihill: None. I\u00f1igo Lecumberri: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Erica Thwaite: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Mariusz Kruk: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266) and a grant from National Science Center (Poland) (Payment to the institution) and reported patents for EP3157444B1 (granted); WO2015193847A1 (pending); WO2013060883A4 (pending). Aleksandar N. Neskovic: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Massimo Mancone: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Donata Ku\u015bmierz: None. Gudrun Feuchtner: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Mikko Pietil\u00e4: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Vasco Gama Ribeiro: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Tanja Drosch: None. Christian Delles: None. Alberto Boi: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Michael Fisher: None. Bela Merkely: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266), a grant from Biotronik, Medtronic and Abbott (personal fees), and a grant from Boston Scientific. Thomas Fritz Hansen: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Rosca Aurelian: None. Stephanie Kelly: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Bruno Garcia del Blanco: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Ainhoa Rubio: None. Melinda Boussoussou: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Tem J\u00f8rgensen: None. Ioana Rodean: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Susan Regan: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Hug Cu\u00e9llar Calabria: None. Borb\u00e1la Vattay: None. Roxana Hodas: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Adriane E. Napp: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Robert Haase: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Sarah Feger: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Mahmoud Mohamed: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Lina M. Serna-Higuita: None. Konrad Neumann: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Henryk Dreger: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Matthias Rief: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Received a grant from Deutsche Forschungsgemeinschaft (Grant: Radiomics in SPP 2177\/1). Viktoria Wieske: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Michelle Williams: is supported by the British Heart Foundation (FS\/ICRF\/20\/26002). She has given talks for Canon Medical Systems, Siemens Healthineers and Novartis. Melanie Estrella: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Maria Bosserdt: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Peter Martus: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266). Klaus F. Kofoed: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266), financial support from Rigshospitalet, University of Copenhagen, during the conduct of the study, and grants from AP M\u00f8ller og hustru Chastine McKinney M\u00f8llers Fond, Danish Heart Foundation, The Danish Agency for Science, Technology and Innovation by The Danish Council for Strategic Research, and Health Insurance Company Denmark. He additionally received unrestricted research grants from Canon Medical Corporation and GE Healthcare. Marc Dewey: received funding from EU-FP7 Framework Program (DISCHARGE EU FP EC-GA 603266), grant support from German Research Foundation (DFG) in the Heisenberg Program (DE 1361\/14-1, DFG project number: 213705389), the graduate program on quantitative biomedical imaging (BIOQIC, GRK 2260\/1, DFG project number: 289347353), for fractal analysis of myocardial perfusion (DE 1361\/18-1, DFG project number: 392304398), the DFG Priority Programme Radiomics (DFG project number: 402688427) for the investigation of coronary plaque and coronary flow (DE 1361\/19-1 [DFG project number: 428222922] and DE 1361\/20-1 [DFG project number: 428223139] in SPP 2177\/1), the GUIDE-IT project on data sharing of medical imaging trials (DE 1361\/24-1 [DFG project number: 495697118]), the Quantitative Cardiovascular Imaging (QCI) meeting (DE 1361\/22-1), and the Future of Medical Imaging meeting (DE 1361\/28-1). He also received funding from the Berlin University Alliance (GC_SC_PC 27) and from the Digital Health Accelerator of the Berlin Institute of Health and reported a patent on fractal analysis of perfusion imaging, jointly with Florian Michallek, on dynamic perfusion analysis using fractal analysis (PCT\/EP2016\/071551 and USPTO 2021 10,991,109 approved). M.D. is European Society of Radiology (ESR) Publications Chair (2022\u20132025); and the opinions expressed in this article are the author\u2019s own and do not represent the view of ESR. Per the guiding principles of ESR, the work as Publications Chair is on a voluntary basis and only remuneration of travel expenses occurs. He is also the editor of\n                      Cardiac CT\n                      , published by Springer Nature, and offers hands-on courses on CT imaging (\n                      \n                      ).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Two authors have significant statistical expertise and performed the analyses.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Statistics and biometry"}},{"value":"Written informed consent was obtained from all subjects (patients) in this study.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"Institutional Review Board approval was obtained.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The primary trial results (10.1056\/NEJMoa2200963), the design of the trial (10.1007\/s00330-016-4620-z), and the comparative effectiveness of computed tomography and invasive coronary angiography in women and men (10.1136\/bmj-2022-071133) were described previously.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Study subjects or cohorts overlap"}},{"order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Methodology"}}]}}