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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 
1   Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
2   Department of Clinical Science, University of Bergen, Bergen, Norway
,
Michelle Røysland
1   Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
,
Thor Ueland
3   Department of Clinical Medicine, Thrombosis Research Center, UiT – The Arctic University of Norway, Tromsø, Norway
4   Faculty of Medicine, University of Oslo, Oslo, Norway
,
Pål Aukrust
4   Faculty of Medicine, University of Oslo, Oslo, Norway
5   Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
6   Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
,
Annika E. Michelsen
4   Faculty of Medicine, University of Oslo, Oslo, Norway
5   Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
,
Harry Staines
7   Sigma Statistical Services, Balmullo, United Kingdom of Great Britain and Northern Ireland
,
Ståle Barvik
1   Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
,
Frederic Kontny
2   Department of Clinical Science, University of Bergen, Bergen, Norway
8   Drammen Heart Center, Drammen, Norway
,
Jan Erik Nordrehaug
1   Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
2   Department of Clinical Science, University of Bergen, Bergen, Norway
,
Vernon V. S. Bonarjee
1   Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
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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

Ethical Statement

This study was approved by the Ethics Committee of Northern Norway and the biobank was licensed by the Ethics Committee of South-Eastern Norway. Biobank no. 10104, ref. 2009/330.


Supplementary Material



Publication History

Received: 04 July 2022

Accepted: 20 October 2022

Article published online:
31 December 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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