Vorapaxar on Thrombin Generation and Coagulability

Overview

This investigation will be conducted in patients 18-75 years of age with multiple coronary artery disease risk factors (antiplatelet naïve patients) and patients with prior MI or PVD on antiplatelet therapy. Pharmacodynamics will be assessed at multiple time points to assess onset-, maintenance-, and offset-effect of vorapaxar on thrombin generation, platelet reactivity, and plasma/platelet endothelial and inflammatory biomarkers. Safety assessment will be assessed throughout the study.

The occurrence of coronary arterial thrombotic events during acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI) are critically dependent on reactive platelets. Antiplatelet therapy plays a central role in preventing stent thrombosis and recurrent myocardial infarction in these high risk patients. Platelet activation involves multiple signaling pathways activated by thrombin, thromboxane A2, adenosine diphosphate (ADP) and collagen that interact with specific receptors. Simultaneous and optimal blockade of these pathways is essential to ensure effective inhibition of platelet function and attenuation of thrombotic events. However, it remains unclear which pathway is central to the generation of thrombotic events in an individual patient. Emerging data suggests that activation of the protease-activated receptors (PARs) by thrombin and platelet-dependent thrombin generation may be patient specific. Evidence for this concept is present in the significant residual risk (\~10%) present in high risk patients treated with potent P2Y12 blockers and ASA. Translational antiplatelet therapy studies thus far have largely focused on the measurement of platelet aggregation and agglutination to fibrinogen-coated beads in anticoagulated blood. These studies ignore the characteristics of platelet-fibrin clot formation as a potential contributor to the development of adverse events (i.e. no study of platelet-fibrin interactions). In addition to platelet function, thrombin mediated platelet-fibrin clot characteristics may play an important role in the development of ischemic events and stent restenosis. In support of this hypothesis, the POST-STENTING study clearly demonstrated that studying platelet function in isolation may have an important limitation in predicting ischemic events as well as determining effective strategies to reduce recurrent adverse events. In the latter study, we found that high platelet reactivity was a comparatively poor indicator of ischemic events following stenting, relative to measurements of platelet-fibrin clot characteristics. Adverse events were more or less equally distributed in the middle two quartiles of post-treatment platelet aggregation. Most importantly, thrombin-induced maximum platelet-clot strength (TIP-FCS) measured at discharge was the most powerful predictor of 6 months post-stenting ischemic events with a sensitivity of 74%, specificity of 89%, and odds ratio 22.6 ( 1st quartile vs. 4th quartile). In the latter study, 74% of patients with ischemic events had high TIP-FCS (\>72 mm, upper quartile value). These results indicate that platelet-fibrin clot strength may play important roles in the development of adverse ischemic events. Those subjects who form the most robust platelet-fibrin clots carry the greatest risk for recurrent thrombotic event occurrence. Of critical importance, these results also indicate that current long term antiplatelet therapies are inadequate to reduce adverse events in selected patients. Novel, longer-term treatment strategies directed at reducing thrombin function in selected patients may have significant impact in reducing adverse events. Thrombin potently activates platelets through the protease-activated receptor (PAR-1). PAR-1 receptor inhibition is an emerging therapeutic strategy in patients who have suffered ACS. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. In the TRA 2P trial, in patients with a history of heart attack or with peripheral arterial disease (PAD) who had no history of stroke or transient ischemic attack (TIA), vorapaxar added to standard of care was associated with a significant 17 percent relative risk reduction over the three years in the combined events of cardiovascular (CV) death, myocardial infarction (MI), stroke, and urgent coronary revascularization (UCR) \[event rate 10.1 percent vs. 11.8 percent for placebo\]. For the key secondary composite efficacy endpoint of CV death, MI, and stroke alone, vorapaxar produced a significant 20 percent relative risk reduction in these patients \[7.9 percent vs. 9.5 percent for placebo\]. Based on these results, the U.S. Food and Drug Administration recently approved Zontivity (vorapaxar) to reduce the risk of heart attack, stroke, and cardiovascular death for secondary prevention in patients with a history of MI and peripheral vascular disease. Currently, there are no data available regarding the effect of vorapaxar on clot generation kinetics or TIP-FCS when added to standard of care antiplatelet regimens. Potential reduction of TIP-FCS and clot generation kinetics by vorapaxar may assist in our understanding of the mechanism of action and in personalizing therapy in high risk patients to effectively reduce recurrent thrombotic event occurrences.

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