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Management of peripheral arterial disease in the elderly
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Vorapaxar is a novel antagonist of protease-activated receptor-1 (127,128). Vorapaxar has been approved by the US Food and Drug Administration to reduce the risk of myocardial infarction, stroke, cardiovascular death, and coronary revascularization in patients with a history of myocardial infarction or lower extremity PAD. Because of its increased risk of bleeding, vorapaxar should not be used in patients who have had a stroke, a transient ischemic attack, or bleeding in the head.
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Vorapaxar (Figure 7.15) is a thrombin receptor (protease-activated receptor, PAR-1) antagonist based on the natural product himbacine. It is given to patients with a history of myocardial infarction (heart attack) or persons with peripheral arterial disease [97].
Benefit-Risk Assessment for Platform Trials
Published in Zoran Antonijevic, Robert A. Beckman, Platform Trial Designs in Drug Development, 2018
Example 2. Vorapaxar for secondary prevention of CV events. The phase 3 study of Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P)–Thrombolysis in Myocardial Infarction (TIMI) 50 trial, was designed to evaluate the efficacy and safety of vorapaxar in reducing atherothrombotic events in patients with established atherosclerosis who were receiving standard therapy. At an interim analysis, after completion of enrollment and a median of 24 months of follow-up, the data and safety monitoring board (DSMB) reported an excess of intracranial hemorrhage in patients with a history of stroke in the treatment arm. The DSMB recommended discontinuation of the drug in all patients with previous stroke, including those with a new stroke during trial but continuation of the study in patients without a history of stroke (20). There was no significant heterogeneity for the benefit of vorapaxar on the primary efficacy endpoint across most of the major subgroups examined. Vorapaxar was eventually approved with an indication of reduction of thrombotic cardiovascular events in patients with a MI or PAD history. The heterogenous B-R profile seems driven by the difference in safety in this case.
Novel therapeutic perspectives for crescentic glomerulonephritis through targeting parietal epithelial cell activation and proliferation
Published in Expert Opinion on Therapeutic Targets, 2023
Yanjie Huang, Xueru Zhao, Qiushuang Zhang, Xiaoqing Yang, Gailing Hou, Chaoqun Peng, Mengzhen Jia, Li Zhou, Tatsuo Yamamoto, Jian Zheng
Protease-activated receptors consist of four members (PAR-1, −2, −3, and −4) [48]. PAR-1 and PAR-2 are the most abundant receptors and have been shown to be expressed in kidney vascular and tubular cells. PAR-1, also known as thrombin receptor, is the main receptor for thrombin. It is abundantly expressed in the kidneys of humans and rodents [49]. Under pathological conditions, thrombin can participate in the proliferation and inflammation of kidney cells in various kidney diseases by activating PAR-1 [50]. In 2019, it was demonstrated that high concentrations of thrombin could increase the expression level of PAR-1 [51]. In vivo, compared with those in wild-type mice, PAR-1 deficiency remarkably reduced the formation of glomerular crescent lesions, T cell and macrophage infiltration, and fibrin deposition [50,52], indicating that PAR-1 was involved in the formation of glomerular crescents. Vorapaxar can selectively antagonize PAR-1 and was approved by both the Food and Drug Administration and the European Medicines Agency as an add-on therapy for secondary prevention in patients with a history of acute myocardial infarction or peripheral artery disease. It can inhibit thrombin-induced platelet activation and has been approved for cardiovascular diseases by reducing thrombotic cardiovascular events [53,54]. Currently, it has been reported to reduce fibrosis and protect renal function during unilateral ureteral obstruction and acute kidney injury -to-chronic kidney disease [49]; however, its function in CrGN has not yet been reported.
New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans
Published in Platelets, 2022
Samira Merali, Zhaoqing Wang, Charles Frost, Mario Callejo, Michael Hedrick, Lester Hui, Stephanie Meadows Shropshire, Ke Xu, Michel Bouvier, Mary M. DeSouza, Jing Yang
Thrombin, the most potent platelet activator, may play a major role in atherothrombosis. Thrombin activates human platelets via proteolytic cleavage of two distinct G-protein-coupled receptors called protease-activated receptor 1 and 4 (PAR1 and PAR4) [4]. The high-affinity thrombin receptor PAR1 is the target of the antiplatelet agent vorapaxar, which has efficacy in reducing thrombotic events in patients with a history of myocardial infarction or with peripheral arterial disease [5]. In patients with history of myocardial infarction, vorapaxar showed 20% reduction in the combined endpoint of cardiovascular death, myocardial infarction, or stroke compared with placebo [6]. However, vorapaxar increased the risk of bleeding, including intracranial hemorrhage and fatal bleeding [5,6]. Vorapaxar, when added to standard of care in patients with acute coronary syndrome, was associated with increased bleeding risk while failing to provide additional benefit on the primary efficacy endpoint of recurrent ischemic cardiovascular events [7]. To identify an agent that could further improve clinical outcome without added bleeding risk, we sought to target PAR4, a low-affinity thrombin receptor believed to mediate a late stage of platelet activation, contributing to occlusive thrombus formation but playing a lesser role in primary hemostasis [8].
Clinical pharmacology of antiplatelet drugs
Published in Expert Review of Clinical Pharmacology, 2022
Georg Gelbenegger, Bernd Jilma
Vorapaxar is a competitive, reversible and orally active PAR1 antagonist that is rapidly absorbed with high bioavailability (>90%) [169]. Because of its dissociation half life of as long as 20 hours and terminal half life of 126–269 h, vorapaxar’s reversible inhibition becomes a seemingly irreversible PAR1 inhibition and provides consistent antiplatelet effects [170,171]. In addition to its inhibitory effect on platelets, vorapaxar also shows anti-inflammatory characteristics [172]. A single dose of vorapaxar 20 mg or 40 mg achieved complete inhibition (>80%) of thrombin receptor activating peptide (TRAP)- induced platelet aggregation within 1 hour with a sustained antiplatelet effect for at least 72 hours [173]. A vorapaxar maintenance dose of 2.5 mg o.d. was found to provide more consistent and complete platelet inhibition of TRAP-induced platelet inhibition at day 7 than a maintenance dose of 1 mg o.d., suggesting it may be the optimal maintenance dose, especially in patients who have not received a loading dose [170]. Vorapaxar is metabolized in the liver by CYP3A4 but metabolic conversion rate is low. However, drugs interfering with CYP3A4 activity (ketoconazole or rifampicin) significantly influence plasma levels of vorapaxar and could potentially affect its antiplatelet effects [174,175] (Table 3).