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

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.

Recombinant hirudin suppresses angiogenesis of diffuse large B‐cell lymphoma through regulation of the PAR‐1‐VEGF

“…Some studies have verified that thrombin can activate Gαq and Gα12 signaling by cleavage in Arg41 to activate PAR‐1 (Marinissen et al., 2003). Vorapaxar is an active antiplatelet molecule, so it is always used as an inhibitor of PAR‐1 (Nilsen et al., 2023). Our study transfected sh‐NC and sh‐PAR‐1 with SUDHL2 cells or processed SUDHL2 cells through added thrombin, Vorapaxar, and Na 2 S 2 O 4 .…”

Suppression of Heart Failure With PAR1 Pepducin Technology in a Pressure Overload Model in Mice

“…Vorapaxar (SCH530348), a US Food and Drug Administration-approved PAR1 inhibitor used in clinical trials as an antiplatelet agent on top of dual antiplatelet therapy, has had limited clinical uptake likely due to side effects of bleeding as reflected by a very long antiplatelet pharmacodynamic half-life of >4 weeks. 42 A recent publication 43 suggests that post-myocardial infarction or NSTEMI patients (N=265) receiving daily vorapaxar for 1 month may have increases in activated endothelial cells compared with the placebo cohort as indicated by significantly increased systemic levels of von Willebrand factor and E selectin, specific markers of endothelial cell activation. By comparison, PZ-128 is a reversible PAR1 antagonist with 50% recovery of PAR1 activity on platelets by 24 hours and 75% recovery by 8 to 14 days with no significantly increased bleeding in nonhuman primates 44 or coronary artery disease/acute coronary syndrome patients taking concomitant P 2 Y12 inhibitor (clopidogrel, prasugrel, and ticagrelor) and aspirin.…”

Species Differences in Platelet Protease-Activated Receptors

“…A phase 4 trial recently demonstrated that addition of vorapaxar to mono-or dual-antiplatelet therapy had no effect on clot characteristics or coagulation in patients with a history of MI or PAD, though it may have anti-inflammatory effects [54]. A more recent study examined endothelial cell biomarkers in a follow-up to the TRACER trial [52] and reported increases in pro-inflammatory biomarkers such as angiopoietin-like 4 (ANGPTL4) in patients who received vorapaxar treatment, suggesting that vorapaxar causes endothelial dysfunction [55].…”