Effects of vorapaxar on clot characteristics, coagulation, inflammation, and platelet and endothelial function in patients treated with mono‐ and dual‐antiplatelet therapy

Bliden, Kevin P.; Chaudhary, Rahul; Kuliopulos, Athan; Tran, Henry; Taheri, Hamid Reza; Tehrani, Behnam; Rosenblatt, Arnold; Navarese, Eliano Pio; Tantry, Udaya S.; Gurbel, Paul A.

doi:10.1111/jth.14616

Cited by 13 publications

(13 citation statements)

References 21 publications

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“…Inhibition of the PARs is not only of interest for antiplatelet therapy, but also for inflammation. Blocking PAR1 with vorapaxar showed some anti-inflammatory effects [ 138 ], for example by maintaining the endothelial barrier and proliferation of endothelial cells and thus protecting the endothelial cells [ 139 ]. During endotoxemia, PAR-1 inhibition decreased inflammation and endothelial activation [ 140 ].…”

Section: Discussionmentioning

confidence: 99%

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review

Bachler

Asmis

Koscielny

et al. 2022

Blood Coagulation &Amp; Fibrinolysis

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During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

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Section: Discussionmentioning

confidence: 99%

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review

Bachler

Asmis

Koscielny

et al. 2022

Blood Coagulation &Amp; Fibrinolysis

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“…This extra synergism on ADP inhibition was not observed in recent studies with the Food and Drug Administration-approved dose (2.08 mg) of vorapaxar at even up to 30 days of repeat administration. 13 …”

Section: Discussionmentioning

confidence: 99%

“…The limitations of vorapaxar include a very long pharmacodynamic half-life of ≥4 weeks and oral administration leading to a slow onset of pharmacodynamic effects during the PCI procedure and an elevated risk of bleeding. 13 There have been no reports of fast-acting parenteral PAR1 blockade in humans. The ability to rapidly and reversibly inhibit PAR1 signaling by a parenteral strategy would be an ideal in the high-risk patient undergoing PCI.…”

mentioning

confidence: 99%

PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization

Kuliopulos

Gurbel

Rade

et al. 2020

ATVB

Self Cite

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Objective: Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with cardiovascular disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (protease-activated receptor 1) on platelets and other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02–0.75); P =0.02. Conclusions: In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02561000.

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“…Vorapaxar is a reversible inhibitor that binds at or near the tethered ligand binding site within the second extracellular loop of the receptor [26]. It is highly selective and displayed no effect on other agonist-induced platelet aggregation responses in pre-clinical testing [6,27,28]. Vorapaxar was studied in two phase III trials: The Thrombin Receptor Antagonists for Clinical Event Reduction in acute coronary syndrome (TRACER) trial and the TRA 2P-TIMI trial [8,29].…”

Section: Why Target Par4 For Anti-thrombotic Therapy?mentioning

confidence: 99%

“…Despite five distinct drug targets, all of the currently available anti-platelet agents have shortcomings that limit their clinical efficacy and/or utility. For example, aspirin and P2Y 12 receptor antagonists are the leading agents for long-term preventative therapy yet prevent fewer than 20% of recurrent thrombotic events even when used in combination [1], phosphodiesterase inhibitors have a number of problematic side effects, such as arrhythmia [2], the αIIbβ3 antagonists all require intravenous administration and cause substantial bleeding, which precludes their use as long term preventatives [3,4,5], and vorapaxar causes an unacceptably high bleeding risk in several patient groups when administered in combination with aspirin and/or clopidogrel [6,7,8]. These limitations have driven ongoing efforts to identify new targets for anti-platelet drugs that have the potential to improve on efficacy and/or provide fewer side effects, particularly on bleeding.…”

Section: Introductionmentioning

confidence: 99%

Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

Li¹,

Tarlac²,

Hamilton³

2019

IJMS

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Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved PAR antagonist is the PAR1 inhibitor, vorapaxar—the sole anti-platelet drug against a new target approved in the past 20 years. However, there are two PARs on human platelets, PAR1 and PAR4, and more recent efforts have focused on the development of the first PAR4 antagonists, with first-in-class agents recently beginning clinical trial. Here, we review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions.

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Effects of vorapaxar on clot characteristics, coagulation, inflammation, and platelet and endothelial function in patients treated with mono‐ and dual‐antiplatelet therapy

Cited by 13 publications

References 21 publications

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review

PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization

Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

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