Vorapaxar on Thrombin Generation and Coagulability
Condition: Coronary Artery Disease; Peripheral Vascular Disease; Myocardial Infarction
MeSH terms: Coronary Artery Disease; Myocardial Infarction; Vascular Diseases; Peripheral Vascular Diseases; Peripheral Arterial Disease; Infarction
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Vorapaxar; Vorapaxar and Aspirin; Vorapaxar and Clopidogrel; Vorapaxar, Aspirin, and Clopidogrel
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Vorapaxar is the principle study drug and will be given to all subjects.; Subjects in groups 3 will be on Aspirin when they begin Vorapaxar therapy.; Subjects in groups 2 will be on Clopidogrel when they begin Vorapaxar therapy.; Subjects in groups 4 will be on both Aspirin and Clopidogrel when they begin Vorapaxar therapy.
Other intervention name(s): Group 1; Group 3; Group 2; Group 4
Intervention MeSH terms: Aspirin; Clopidogrel; Vorapaxar
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Health Services Research
Keywords: Anti-Platelet Therapy