The Effect of Protease-Activated Receptor-1 (PAR-1) Inhibition on Endothelial-Related Biomarkers in Patients with Coronary Artery Disease

Dennis W. T. Nilsen; Michelle Røysland; Thor Ueland; Pål Aukrust; Annika E. Michelsen; Harry Staines; Ståle Barvik; Frederic Kontny; Jan Erik Nordrehaug; Vernon V. S. Bonarjee

doi:10.1055/s-0042-1760256

Thrombosis and Haemostasis, Inhaltsverzeichnis

CC BY-NC-ND 4.0 · Thromb Haemost 2023; 123(05): 510-521
DOI: 10.1055/s-0042-1760256

Endothelium and Angiogenesis

The Effect of Protease-Activated Receptor-1 (PAR-1) Inhibition on Endothelial-Related Biomarkers in Patients with Coronary Artery Disease

Dennis W. T. Nilsen

¹Department of Cardiology, Stavanger University Hospital, Stavanger, Norway

²Department of Clinical Science, University of Bergen, Bergen, Norway

,

Michelle Røysland

¹Department of Cardiology, Stavanger University Hospital, Stavanger, Norway

,

Thor Ueland

³Department of Clinical Medicine, Thrombosis Research Center, UiT – The Arctic University of Norway, Tromsø, Norway

⁴Faculty of Medicine, University of Oslo, Oslo, Norway

,

Pål Aukrust

⁴Faculty of Medicine, University of Oslo, Oslo, Norway

⁵Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway

⁶Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway

,

Annika E. Michelsen

⁴Faculty of Medicine, University of Oslo, Oslo, Norway

⁵Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway

,

Harry Staines

⁷Sigma Statistical Services, Balmullo, United Kingdom of Great Britain and Northern Ireland

,

Ståle Barvik

¹Department of Cardiology, Stavanger University Hospital, Stavanger, Norway

,

Frederic Kontny

²Department of Clinical Science, University of Bergen, Bergen, Norway

⁸Drammen Heart Center, Drammen, Norway

,

Jan Erik Nordrehaug

¹Department of Cardiology, Stavanger University Hospital, Stavanger, Norway

²Department of Clinical Science, University of Bergen, Bergen, Norway

,

Vernon V. S. Bonarjee

¹Department of Cardiology, Stavanger University Hospital, Stavanger, Norway

› Institutsangaben

Abstract

Background Vorapaxar has been shown to reduce cardiovascular mortality in post-myocardial infarction (MI) patients. Pharmacodynamic biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has short follow-up (FU) duration and is mainly focused on platelets rather than endothelial cells.

Aim This article assesses systemic changes in endothelial-related biomarkers during vorapaxar treatment compared with placebo at 30 days' FU and beyond, in patients with coronary heart disease.

Methods Local substudy patients in Norway were included consecutively from two randomized controlled trials; post-MI subjects from TRA2P-TIMI 50 and non-ST-segment elevation MI (NSTEMI) patients from TRACER. Aliquots of citrated blood were stored at –80°C. Angiopoietin-2, angiopoietin-like 4, vascular endothelial growth factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, von Willebrand factor, thrombomodulin, and plasminogen activator inhibitor-1 and -2 were measured at 1-month FU and at study completion (median 2.3 years for pooled patients).

Results A total of 265 consecutive patients (age median 62.0, males 83%) were included. Biomarkers were available at both FUs in 221 subjects. In the total population, angiopoietin-2 increased in patients on vorapaxar as compared with placebo at 1-month FU (p = 0.034). Angiopoietin-like 4 increased (p = 0.028) and plasminogen activator inhibitor-2 decreased (p = 0.025) in favor of vorapaxar at final FU. In post-MI subjects, a short-term increase in E-selectin favoring vorapaxar was observed, p = 0.029. Also, a short-term increase in von Willebrand factor (p = 0.032) favoring vorapaxar was noted in NSTEMI patients.

Conclusion Significant endothelial biomarker changes during PAR-1 inhibition were observed in post-MI and NSTEMI patients.

Keywords

PAR-1 inhibition - vorapaxar - myocardial infarction (MI) - post-MI - NSTEMI - biomarkers - endothelium

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Referenzen

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