PAR-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease

Abstract

To assess the effect of vorapaxar on global thrombotic and thrombolytic status. The propensity for thrombus formation is determined by the balance between prothrombotic factors and endogenous thrombolysis. Impaired thrombolytic status increases cardiovascular risk. Vorapaxar is a novel, oral, protease-activated receptor-1 antagonist that inhibits thrombin-induced platelet activation. In the TRACER and TRA 2°P-TIMI 50 studies, patients with acute coronary syndromes and established atherosclerosis were randomized to vorapaxar 2.5 mg daily or placebo, in addition to standard care. In 57 patients enrolled in a single center, blood was tested with the point-of-care global thrombosis test, on and off treatment. This automated test employs non-anticoagulated blood to assess thrombotic and thrombolytic status, measuring the time required to form a shear-induced thrombus under physiological conditions (occlusion time, OT), and subsequently, the time to achieve endogenous lysis of the thrombus (lysis time, LT). Patients on vorapaxar exhibited longer OT on vs. off treatment [median 561 s (interquartile range 422-654) vs. 372 s(338-454), P = 0.003] and shorter LT on treatment than off [1,158 s(746-1,492) vs. 1,733 s(1,388-2,230), P = 0.016]. Patients on placebo showed no difference in OT [419 s(343-514) vs. 411 s(346-535), P = 0.658] or LT [1,236 s(985-1,594) vs. 1,400 s(1,092-1,686), P = 0.524] on and off treatment. During treatment, OT was longer in patients taking vorapaxar [561 s(422-654) vs. 419 s(343-514), P = 0.009], but LT was similar in vorapaxar and placebo arms [1,158 s(746-1,492) vs. 1,236 s(985-1,594), P = 0.277]. Vorapaxar prolongs OT and shortens LT, with favorable effects on thrombotic and thrombolytic status. In addition to its antiplatelet effect, vorapaxar may enhance endogenous thrombolysis, which is frequently impaired in coronary disease.

Protease-Activated Receptor 1 Inhibitors: Novel Antiplatelet Drugs in Prevention of Atherothrombosis

“…14 The antiplatelet effects are seen within 1-2 hours of oral dose. 3,10,12,18,19 There has not been much significant delay noted of vorapaxar in absorption with food and antacid administration. Therefore, it can be given without concern of antacids and meals.…”

“…These studies involved patients with ACS and atherosclerosis, who were randomized to receive vorapaxar or placebo in addition to standard antithrombotic care. 3 In the TRACER study, however, vorapaxar or placebo was given after a loading dose was administered. 3 The TRACER study is a phase III, prospective, randomized, double-blinded, placebo-controlled secondary prevention trial evaluating vorapaxar loading dose 40 mg and a daily maintenance dose of 2.5 mg with placebo for 1 year in 12,944 patients with recent NSTE MI.…”

“…3 In the TRACER study, however, vorapaxar or placebo was given after a loading dose was administered. 3 The TRACER study is a phase III, prospective, randomized, double-blinded, placebo-controlled secondary prevention trial evaluating vorapaxar loading dose 40 mg and a daily maintenance dose of 2.5 mg with placebo for 1 year in 12,944 patients with recent NSTE MI. 46 The primary endpoint of the TRACER study was when vorapaxar failed to reduce the composite of cardiovascular death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.…”

“…Vorapaxar is a novel oral antiplatelet drug belonging to the protease-activated receptor (PAR)-1 antagonist family. 3,4 Atopaxar is another novel orally active, potent, reversible PAR-1 antagonist. PARs have significant responsibilities in inflammation, coagulation, and vascular homeostasis.…”

Protease-activated receptors and their biological role—focused on skin inflammation

“…A new target in pharmacological use is the PAR 1 antagonist Vorapaxar, which is authorized in 2014 from Food and Drug Administration (FDA) for the secondary prophylaxis of myocardial infarction or peripheral arterial occlusive disease. Vorapaxar inhibits the PAR on the platelets and inhibits the platelet's aggregation [53,54]…”