Credibility assessment of a mechanistic model of atherosclerosis to predict cardiovascular outcomes under lipid-lowering therapy
Demonstrating cardiovascular (CV) benefits with lipid-lowering therapy (LLT) requires long-term randomized clinical trials (RCTs) with thousands of patients. Innovative approaches such as in silico trials applying a disease computational model to virtual patients receiving multiple treatments offer a complementary approach to rapidly generate comparative effectiveness data. A mechanistic computational model of atherosclerotic cardiovascular disease (ASCVD) was built from knowledge, describing lipoprotein homeostasis, LLT effects, and the progression of atherosclerotic plaques leading to myocardial infarction, ischemic stroke, major acute limb event and CV death. The ASCVD model was successfully calibrated and validated, and reproduced LLT effects observed in selected RCTs (ORION-10 and FOURIER for calibration; ORION-11, ODYSSEY-OUTCOMES and FOURIER-OLE for validation) on lipoproteins and ASCVD event incidence at both population and subgroup levels. This enables the future use of the model to conduct the SIRIUS programme, which intends to predict CV event reduction with inclisiran, an siRNA targeting hepatic PCSK9 mRNA.
Authors
- Emmanuel Peyronnet
- Philippe Gabríel Steg (ORCID: https://orcid.org/0000-0001-6896-2941)
- Bertrand Cariou (ORCID: https://orcid.org/0000-0002-1580-8040)
- Alexandre Bastien
- Emmanuelle Bechet
- Franck Boccara (ORCID: https://orcid.org/0000-0002-6908-9678)
- Evgueni Jacob (ORCID: https://orcid.org/0000-0002-0630-5871)
- Pierre Amarenco (ORCID: https://orcid.org/0000-0002-3842-1236)
- Lolita Portal
- Guillaume Mahé (ORCID: https://orcid.org/0000-0003-1318-4745)
- Denis Angoulvant (ORCID: https://orcid.org/0000-0003-0788-8092)
- Solène Granjeon-Noriot
- Alizée Diatchenko
- Yishu Wang (ORCID: https://orcid.org/0000-0003-2340-0333)
- Eulalie Courcelles
- Solène Porte
- Jean-Pierre Boissel
Institutions
- Université de Tours (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Population Health Research Institute (CA)
- Sorbonne Université (FR)
- Novartis (France) (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Saint-Antoine (FR)
- CIC Rennes (FR)
- Laboratoire de Recherche Vasculaire Translationnelle (FR)
- Centre de Recherche Saint-Antoine (FR)
- Institut du Thorax (FR)
- Hôpital Bichat-Claude-Bernard (FR)
- Centre Hospitalier Universitaire de Rennes (FR)
- Complications Cardiovasculaires et Métaboliques chez les patients vivant avec le VIH
- Université de Rennes (FR)
- Nantes Université (FR)
- McMaster University (CA)
Publication Details
- Journal
- npj Digital Medicine
- Published
- 2025-03-19
- DOI
- https://doi.org/10.1038/s41746-025-01557-7
- Citations
- 3
- Primary Topic
- Lipoproteins and Cardiovascular Health
- Type
- article
- Field-Weighted Citation Impact
- 6.02