Extension of the GRACE score for non-ST-elevation acute coronary syndrome: a development and validation study in ten countries

Florian A Wenzl¹, Klaus F Kofoed², Moa Simonsson³, Gareth Ambler⁴, Niels M R van der Sangen⁵, Erik Lampa⁶, Francesco Bruno⁷, Mark A de Belder⁸, Jiri Hlasensky⁹, Matthias Mueller-Hennessen¹⁰, Maria A Smolle¹¹, Peizhi Wang¹², José P S Henriques⁵, Wouter J Kikkert¹³, Henning Kelbæk¹⁴, Luboš Bouček¹⁵, Sergio Raposeiras-Roubín¹⁶, Emad Abu-Assi¹⁶, Jaouad Azzahhafi¹⁷, Matthijs A Velders¹⁸, Konstantinos Stellos¹⁹, Thomas Engstrøm²⁰, Dean R P P Chan Pin Yin¹⁷, Clive Weston²¹, David Adlam²², Hans Rickli²³, Evangelos Giannitsis²⁴, Dragana Radovanovic²⁵, Jiri Parenica⁹, Charalambos A Antoniades²⁶, Keith A A Fox²⁷, Fabrizio D'Ascenzo²⁸, Jurriën M Ten Berg²⁹, Lars V Køber²⁰, Stefan James³⁰, John Deanfield³¹, Thomas F Lüscher³²

Affiliations

¹ National Health Service England, London, UK; Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden. Electronic address: florian.wenzl1@nhs.net.
² Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Radiology, The Diagnostic Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Department of Medicine Solna, Karolinska Institute, Solna, Sweden.
⁴ Department of Statistical Science, University College London, London, UK.
⁵ Department of Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands.
⁶ Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
⁷ Division of Cardiology, Cardiovascular and Thoracic Department, Molinette Hospital, Città della Salute e della Scienza di Torino, Turin, Italy; Heart Division, Royal Brompton and Harefield Hospitals, London, UK.
⁸ National Institute for Cardiovascular Outcomes Research, NHS Arden and Greater East Midlands Commissioning Support Unit, Leicester, UK.
⁹ Department of Internal Medicine and Cardiology, University Hospital Brno and Faculty of Medicine of Masaryk University, Brno, Czechia.
¹⁰ Department of Internal Medicine III, Cardiology, University Hospital of Heidelberg, Heidelberg, Germany.
¹¹ Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.
¹² Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland; Department of Cardiology, National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹³ Department of Cardiology, Tergooi Hospital, Hilversum, Netherlands.
¹⁴ Department of Cardiology, Zealand University Hospital, Roskilde, Denmark.
¹⁵ Department of Laboratory Medicine, Division of Clinical Biochemistry, University Hospital Brno, Brno, Czechia.
¹⁶ Cardiology Department, Hospital Álvaro Cunqueiro, Pontevedra, Spain.
¹⁷ Department of Cardiology, St Antonius Hospital, Nieuwegein, Netherlands.
¹⁸ Department of Clinical Physiology, Västmanland County Hospital, Västerås, Sweden.
¹⁹ Department of Medicine VI, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; Department of Cardiovascular Research, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany; Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbru¨ck Center for Molecular Medicine in the Helmholtz Association (MDC) at the Heidelberg University, Heidelberg, Germany.
²⁰ Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
²¹ Glangwili General Hospital, Carmarthen, UK.
²² Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester, UK.
²³ Cardiology Division, Kantonsspital St Gallen, St Gallen, Switzerland.
²⁴ Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
²⁵ AMIS Plus Data Center, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.
²⁶ Acute Multidisciplinary Imaging and Interventional Centre, British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
²⁷ Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
²⁸ Division of Cardiology, Cardiovascular and Thoracic Department, Molinette Hospital, Città della Salute e della Scienza di Torino, Turin, Italy.
²⁹ Department of Cardiology, St Antonius Hospital, Nieuwegein, Netherlands; Department of Cardiology, University Medical Center Maastricht, Maastricht, Netherlands.
³⁰ Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
³¹ Institute of Cardiovascular Science, University College London, London, UK.
³² Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland; Heart Division, Royal Brompton and Harefield Hospitals, London, UK; National Heart and Lung Institute, Imperial College London, London, UK; School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK. Electronic address: cardio@tomluescher.ch.

PMID: 41107201
DOI: 10.1016/j.landig.2025.100907

Free article

Extension of the GRACE score for non-ST-elevation acute coronary syndrome: a development and validation study in ten countries

Florian A Wenzl et al. Lancet Digit Health. 2025.

Free article

. 2025 Oct 16:100907.

doi: 10.1016/j.landig.2025.100907. Online ahead of print.

Authors

Affiliations

¹ National Health Service England, London, UK; Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden. Electronic address: florian.wenzl1@nhs.net.
² Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Radiology, The Diagnostic Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Department of Medicine Solna, Karolinska Institute, Solna, Sweden.
⁴ Department of Statistical Science, University College London, London, UK.
⁵ Department of Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands.
⁶ Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
⁷ Division of Cardiology, Cardiovascular and Thoracic Department, Molinette Hospital, Città della Salute e della Scienza di Torino, Turin, Italy; Heart Division, Royal Brompton and Harefield Hospitals, London, UK.
⁸ National Institute for Cardiovascular Outcomes Research, NHS Arden and Greater East Midlands Commissioning Support Unit, Leicester, UK.
⁹ Department of Internal Medicine and Cardiology, University Hospital Brno and Faculty of Medicine of Masaryk University, Brno, Czechia.
¹⁰ Department of Internal Medicine III, Cardiology, University Hospital of Heidelberg, Heidelberg, Germany.
¹¹ Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.
¹² Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland; Department of Cardiology, National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹³ Department of Cardiology, Tergooi Hospital, Hilversum, Netherlands.
¹⁴ Department of Cardiology, Zealand University Hospital, Roskilde, Denmark.
¹⁵ Department of Laboratory Medicine, Division of Clinical Biochemistry, University Hospital Brno, Brno, Czechia.
¹⁶ Cardiology Department, Hospital Álvaro Cunqueiro, Pontevedra, Spain.
¹⁷ Department of Cardiology, St Antonius Hospital, Nieuwegein, Netherlands.
¹⁸ Department of Clinical Physiology, Västmanland County Hospital, Västerås, Sweden.
¹⁹ Department of Medicine VI, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; Department of Cardiovascular Research, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany; Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbru¨ck Center for Molecular Medicine in the Helmholtz Association (MDC) at the Heidelberg University, Heidelberg, Germany.
²⁰ Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
²¹ Glangwili General Hospital, Carmarthen, UK.
²² Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester, UK.
²³ Cardiology Division, Kantonsspital St Gallen, St Gallen, Switzerland.
²⁴ Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
²⁵ AMIS Plus Data Center, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.
²⁶ Acute Multidisciplinary Imaging and Interventional Centre, British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
²⁷ Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
²⁸ Division of Cardiology, Cardiovascular and Thoracic Department, Molinette Hospital, Città della Salute e della Scienza di Torino, Turin, Italy.
²⁹ Department of Cardiology, St Antonius Hospital, Nieuwegein, Netherlands; Department of Cardiology, University Medical Center Maastricht, Maastricht, Netherlands.
³⁰ Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
³¹ Institute of Cardiovascular Science, University College London, London, UK.
³² Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland; Heart Division, Royal Brompton and Harefield Hospitals, London, UK; National Heart and Lung Institute, Imperial College London, London, UK; School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK. Electronic address: cardio@tomluescher.ch.

PMID: 41107201
DOI: 10.1016/j.landig.2025.100907

Abstract

Background: The Global Registry of Acute Coronary Events (GRACE) scoring system guides the management of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) according to current guidelines. However, broad validation of the sex-specific GRACE 3.0 in-hospital mortality model, and corresponding models for predicting long-term mortality and the personalised effect of early invasive management, are still needed.

Methods: We used data of 609 063 patients with NSTE-ACS from ten countries between Jan 1, 2005, and June 24, 2024. A machine learning model for 1-year mortality was developed in 400 054 patients from England, Wales, and Northern Ireland. Both the in-hospital mortality model and the new 1-year mortality model were externally validated in patients from Sweden, Switzerland, Germany, Denmark, Spain, the Netherlands, and Czechia. A separate machine learning model to predict the individualised effect of early versus delayed invasive coronary angiography and revascularisation on a composite primary outcome of all-cause death, non-fatal recurrent myocardial infarction, hospital admission for refractory myocardial ischaemia, or hospital admission for heart failure at a median follow-up of 4·3 years was developed and externally validated in participants from geographically different sets of hospitals in the Danish VERDICT trial.

Findings: The in-hospital mortality model (area under the receiver operating characteristic curve [AUC] 0·90, 95% CI 0·89-0·91) and the 1-year mortality model (time-dependent AUC 0·84, 95% CI 0·82-0·86) showed excellent discriminative abilities on external validation across all countries. Both models were well calibrated and decision curve analyses suggested favourable clinical utility. Compared with score version 2.0, both models provided improved discrimination and risk reclassification. The individualised treatment effect model effectively identified patients who would benefit from early invasive management on external validation. Patients with high predicted benefit had reduced risk of the composite outcome when randomly assigned to early invasive management (hazard ratio 0·60, 95% CI 0·41-0·88), whereas patients with no-to-moderate predicted benefit did not (1·06, 0·80-1·40; p_interaction=0·014). The individualised treatment effect model suggested that the group of patients with NSTE-ACS who benefit from early intervention might be incompletely captured by current treatment strategies.

Interpretation: The updated GRACE 3.0 scoring system provides a validated, practical tool to support personalised risk assessment in patients with NSTE-ACS. Prediction of an individual's long-term cardiovascular benefit from early invasive management could refine future trial design.

Funding: Swiss Heart Foundation, University of Zurich Foundation, Kurt and Senta Herrmann Foundation, Theodor and Ida Herzog-Egli Foundation, and Foundation for Cardiovascular Research-Zurich Heart House.

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Conflict of interest statement

Declaration of interests FAW declares no competing interests related to this manuscript but reports research grant support for the present work from the research fund for excellent research of the University of Zurich Foundation, the Kurt and Senta Herrmann Foundation, the Theodor and Ida Herzog-Egli Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. Outside of the present work, FAW reports research support from the Swiss Heart Foundation, the Swiss Society of Cardiology, the European Society of Cardiology, the Fund for Fostering Young Scientists at the University of Zurich, the Medical University of Graz, Amgen Switzerland, 4TEEN4 Pharmaceuticals, PAM Theragnostics, and Sphingotec; personal support for attending meetings or travel from the Foundation for Cardiovascular Research—Zurich Heart House, the Swiss Society of Cardiology, the European Society of Cardiology, the Critical Care Clinical Trialists Workshop, 4TEEN4 Pharmaceuticals, PAM Theragnostics, and Sphingotec; equipment, materials, drugs, medical writing, gifts, or other services from Roche Diagnostics, 4TEEN4 Pharmaceuticals, PAM Theragnostics, and Sphingotec; and membership of the Steering Committee of the National Registry of Acute Myocardial Infarction in Switzerland–AMIS Plus and the European Society of Cardiology Digital Cardiology and Artificial Intelligence Committee. KFK has received funding from the Danish Agency for Science, Technology and Innovation by the Danish Council for Strategic Research and the AP Møller og hustru Chastine McKinney Møllers Fond; grants from Novo Nordisk Foundation, Sygeforsikringen Danmark, Canon Medical Corporation, GE HealthCare, and Novo Nordisk; and honoraria for lectures from the speaker's bureau of Canon Medical Corporation and GE HealthCare. MS has received honoraria for lectures from Amgen, Boehringer Ingelheim, Bayer, Novo Nordisk, and Novartis, and has participated on an advisory board for AstraZeneca. EL has received consulting fees from Biogen outside of the submitted work. MAdB is a member of the Steering Committee of the DAPA MI Trial for AstraZeneca and chair of the Data Monitoring and Ethics Committee of the UK GRIS Trial. MM-H has received grants from Roche Diagnostics and consulting fees from Zoll Cardiac Management Solutions. MAS has received travel grants from Alphamed Fischer, ImplanTec, Implantcast, and PharmaMar outside of the submitted work. JPSH has received institutional research grants from Abbott Vascular, AstraZeneca, B. Braun, Getinge, Ferrer, Infraredx, and ZonMw. KS has received grants from the European Research Council under the EU’s Horizon 2020 Research and Innovation Programme and from the German Research Foundation (Deutsche Forschungsgemeinschaft), the Health + Life Science Alliance Heidelberg Mannheim, and the Helmholtz Association. KS is chair of the Professional/Public Education and Publications Committee of the Council of Genomic and Precision Medicine of the American Heart Association; a member of the Brain and Heart Committee, Heart Failure Association; an ex-officio member of the Working Group of Atherosclerosis and Vascular Biology, European Society of Cardiology; a principal investigator of the German Centre for Cardiovascular Research partner site Heidelberg Mannheim; a principal investigator of the Helmholtz Institute for Translational Angio-Cardiac-Science; and an associate editor of the European Heart Journal, an associate editor of Cardiovascular Research, an editorial board member of Circulation: Genomic and Precision Medicine, and an associate editor of Frontiers in Immunology. TE has received honoraria for lectures from Novo Nordisk, Abbott, and Boston Scientific, and is member of advisory boards for Abbott and Novo Nordisk. CW has received honoraria for educational meetings from AstraZeneca and is the Clinical Lead of the Myocardial Ischaemia National Audit Project registry. DA has received research grants from Cancer Research UK and the British Heart Foundation for the submitted work; has received research grants from the UK National Institute for Health and Care Research (NIHR), Abbott Vascular, and Beat SCAD outside of the submitted work; has received royalties from Elsevier; holds patents (cardiac arrest device [EP3277337A1] and heart failure shunt device [patent application number 2211616.4]); and is a member of the Phoenix trial, a member of the advisory board of Beat SCAD, and chair of the ESC-EORP SCAD Registry. EG has received consulting fees from Roche Diagnostics, BRAHMS Deutschland, Boehringer Ingelheim, and AstraZeneca; honoraria for lectures from AstraZeneca, Roche Diagnostics, Lilly Deutschland, Daiichi Sankyo, Amgen, and Bayer Vital; and is a member of the Advisory Board for Cancer Therapy of Boehringer Ingelheim. JP received research grants from the Ministry of Health of the Czech Republic, Roche, and Siemens; declares consulting fees from AstraZeneca and Boehringer Ingelheim; and declares payments and honoraria from Amgen, Bayer, and Novartis. CAA has received grants from the British Heart Foundation (CH/F/21/90009, TG/19/2/34831, and RG/F/21/110040, Oxford CRE) and the NIHR Oxford Biomedical Research Centre (Cardiovascular and Imaging Themes) for the submitted work; has received grants from the US National Institutes of Health (HSR01920), the British Heart Foundation (FS/CRTF/23/24460), the British Heart Foundation Oxford Centre of Research Excellence (RG/18/3/34214), Innovate UK (grant 104688), The Secretary of State for Health and Social Care (UK National Health Service artificial intelligence award AI_AWARD02443 and AI_AWARD02013), and EU MAESTRIA (grant agreement number 965286) outside of the submitted work; holds patents (as inventor US10695023B2, PCT/GB2017/053262, GB2018/1818049.7, GR20180100490, and GR20180100510 [patents licensed to Caristo Diagnostics and royalties paid to Oxford University Innovation]; as co-inventor US10695023B2 [patent licensed to Caristo Diagnostics and royalties paid to Oxford University Innovation]); has received personal consulting fees from Caristo Diagnostics, Silence Therapeutics, Abcentra, and Amgen; has received personal fees for lectures from Amarin, Covance, and Hunan University; is past chair of the British Atherosclerosis Society, vice chair of several Marie Curie Panels, and a member of several national committees in the UK and the British Heart Foundation; and holds stock options of Caristo Diagnostics. JMtB has received institutional research grants from ZonMw (Dutch government) and AstraZeneca. LVK has received speaker’s honoraria from AstraZeneca, Boehringer, Novartis, and Novo Nordisk. SJ reports research contracts of his institution with AstraZeneca, Jansen, Amgen, Medtronic, and Edwards; has received honoraria for lectures from Medtronic JD; has received grants from Alzheimer’s Research UK and the British Heart Foundation; has received consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer; and has received honoraria for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer. TFL declares no competing interests related to this manuscript, but declares support from the Swiss National Science Foundation (Special Programme University Medicine Acute Coronary Syndromes [SPUM] 33CM30-124112 and 32473B_163271), the Swiss Heart Foundation, Abbott, Amgen, Anylam, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Cytokinetics, Daichi_Sankyo, Eli Lilly, Novartis, Novo Nordisk, Pfizer, Sanofi, and Vifor. TFL does no longer accept any honoraria from industry, but holds leadership positions at the European Society of Cardiology, the Swiss Heart Foundation, the Foundation for Cardiovascular Research—Zurich Heart House, and the London Heart House. All other authors declare no competing interests.

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Extension of the GRACE score for non-ST-elevation acute coronary syndrome: a development and validation study in ten countries

Affiliations

Extension of the GRACE score for non-ST-elevation acute coronary syndrome: a development and validation study in ten countries

Authors

Affiliations

Abstract

Conflict of interest statement

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