24 Flávio de Souza Brito and Pierluigi Tricoci Duke University Medical Center, Duke Clinical Research Institute, Durham, NC, USA Secondary prevention strategies in patients with coronary artery disease are centered upon the use of antiplatelet therapies. Currently recommended agents are aspirin and P2Y12 receptor antagonists. Their use in combination reduces the risk of ischemic events in patients presenting with acute coronary syndromes (ACS) and is pivotal in the management of patients undergoing percutaneous coronary intervention (PCI) [1, 2]. Dual antiplatelet therapy also increased risk of bleeding, and in addition to this, occurrence of ischemic events continues to occur at a significant rate [3, 4]. Therefore, additional and alternative mechanisms to modulate platelet function have been investigated. Thrombin is known to be a potent platelet activator, and continued increased thrombin generation has been demonstrated in patients treated with dual antiplatelet therapy [5]. Antagonists of platelets’ thrombin receptor have been developed. In this chapter, we will describe the mode of action of thrombin receptor on platelets and pharmacological strategies to antagonize thrombin-mediated platelet activation, with particular emphasis on vorapaxar, to date the most studied thrombin receptor antagonist. Thrombin, a serine protease, is the main effector protease of the coagulation cascade and the most potent platelet activator [6, 7]. The action of thrombin on platelets is mediated by the platelet protease-activated receptors (PARs), which are G protein-coupled receptors members of the seven-transmembrane domain receptor superfamily. Thrombin activates PARs by cleaving a peptide bond (Arg41-Ser42) in the receptor’s extracellular domain that discloses a new N-terminus of the receptor, referred to as a tethered ligand [8, 9]. This new “tail” of the receptor interacts with a distinct domain of the cleaved receptor and causes its activation. To date, four subtypes of PARs were described: PAR-1, PAR-2, PAR-3, and PAR-4 [10]. Among them, only PAR-1 and PAR-4 were identified on human platelets [11]. PARs are not only located on platelets, but they are elsewhere including smooth muscle cells, endothelial cells, fibroblasts, and the brain [12]. The PAR-1 is recognized to be the main platelet thrombin receptor in light of the very high affinity to thrombin, while the role of PAR-4 in humans (which requires higher thrombin concentration) is not completely understood. A pivotal concept behind the development of thrombin receptor antagonist was that thrombin-mediated platelet activation was not essential to normal hemostasis, and therefore, blocking PAR-1 would not increase the risk of clinically significant bleeding. This concept derives from studies in mice, which showed that PAR-4 -/- mice (PAR-4 in mice is equivalent to PAR-1 in humans) were totally unresponsive to thrombin-mediated platelet activation, and despite so, they had normal platelet shape, they did not have increased tendency to bleed, and females could tolerate a pregnancy [13]. Preliminary investigations have also suggested that platelet activation by thrombin is necessary for platelet thrombus propagation, but not for initial platelet thrombus formation in injured vessels [14]. Two PAR-1 antagonists have been developed and tested in clinical studies: a synthetic derivative of natural himbacine (vorapaxar) and a synthetic compound based on the bicyclic amidine motif (atopaxar). Vorapaxar is a potent, selective PAR-1 inhibitor. It is rapidly absorbed after oral administration with a slow elimination with a half-life of up to 311 h. After a single loading dose of vorapaxar, platelet function recovers (returns to >50% of baseline) within 2–3 weeks. Vorapaxar is extensively metabolized by the liver, particularly the CYP3A4 enzyme. The routes of elimination are mainly via feces and secondarily by renal clearance (<5%). In patients with end-stage renal disease, a performed study showed similar overall exposure and bioavailability compared with normal subjects. Dialysis did not appear to affect elimination [15]. Hepatic impairment did not change the pharmacokinetics of vorapaxar [16]. In Folts thrombosis models, an intravenous vorapaxar analog (SCH 602539) alone or in combination with P2Y12 inhibitor cangrelor showed synergistic effect on inhibition of thrombosis, while there was no increase in surgical bleeding in cynomolgus monkeys [17]. The first large experience of vorapaxar in clinical trials was a phase II clinical trial among 1030 patients undergoing angiography and intent to perform PCI. Before coronary angiography, patients were randomized 3:1 to one of three loading doses (10, 20, or 40 mg) or matching placebo, in addition to standard of care. Patients who actually received PCI (56% of all patients), defined as the primary cohort, were further randomized to a 60-day maintenance treatment of 0.5, 1, or 2.5 mg/day of vorapaxar, or matching placebo. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding was not different between aggregated vorapaxar and placebo groups. A trend toward reduced myocardial rates was observed with the highest vorapaxar loading dose [18]. Vorapaxar was evaluated in two large phase III trials: Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) and Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P)-TIMI 50, totaling nearly 40,000 patients enrolled. The TRACER trial was an international, multicenter, double-blind, randomized trial that compared vorapaxar against placebo on top of standard of care in 12,944 patients who presented with ACS without ST-segment elevation. Patients were randomly assigned in a 1:1 ratio to receive vorapaxar 40 mg, followed by 2.5 mg daily maintenance dose or placebo. Nearly 90% of patients were treated with dual antiplatelet therapy (aspirin and clopidogrel); therefore, TRACER largely tested vorapaxar in the context of “triple” antiplatelet therapy. The trial was prematurely discontinued by the Data Safety Monitoring Board (DSMB) during follow-up phase (5 months prior to planned end) after a target number of events had been achieved and in view of increase risk of bleeding. After a median follow-up of 502 days, the primary end point (a composite of death from cardiovascular (CV) causes, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) occurred 18.5% of vorapaxar versus 19.9% of placebo patients (hazard ratio (HR), 0.92; CI 95%, 0.85–1.01; P = 0.07); thus, the superiority of vorapaxar on the primary end point was not achieved (Table 24.1). However, there was a nominally statistically significant reduction of the key secondary end point, a composite of death from CV causes, MI, or stroke (14.7% and 16.4%, respectively; HR, 0.89; 95% CI, 0.81–0.98; P
Thrombin Receptor Antagonists
Introduction
Protease-activated receptors (PARs) and thrombin-induced platelet activation
Thrombin receptor antagonists: pharmacokinetics and pharmacodynamics
Vorapaxar
Clinical trials of vorapaxar
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