I. C. Moschonas, Μ. Ι. Matsagkas, A. D. Tselepis
Abstract
Peripheral arterial disease (PAD) is a form of systemic cardiovascular disease (CVD) that affects the peripheral arteries, which is accompanied by decreased functionality of the extremities and increased risk of ischemic events. The main cause of PAD is atherosclerosis, a chronic inflammatory disease characterized by the formation of atheromatous plaques. Plaque rupture induces, among others, generation of thrombin, which participates in the coagulation cascade, while acting at the same time as an agonist for protease-activated receptors (PARs). Thrombin, via PAR-1, activates vessel wall cells, leading to further narrowing of the affected vessels. Vorapaxar is a potent and selective PAR-1 antagonist. The safety and efficacy of vorapaxar as an antiplatelet agent have been tested in two phase 3 clinical trials, which also included PAD patients. In one of these trials it was proved that, apart from its efficacy in patients with a previous myocardial infarction (MI), vorapaxar additionally offers clinical benefit in patients with a history of PAD. The latter is probably attributed to the inhibitory activity of vorapaxar regarding PAR-1, since PAR-1 is located not only on platelets but in the endothelium as well. Consequently, vorapaxar has been recently approved by the U.S. Food and Drug Administration (FDA) for the secondary prevention of patients with a history of MI or PAD. In the present review the pathophysiology of PAD, the main pharmacokinetic and pharmacodynamic properties of vorapaxar, as well as the most important findings of the clinical trials which justify its approval as a therapeutic agent in the above patients, are described.
Keywords: atherosclerosis, thrombin, peripheral arterial disease, protease-activated receptor 1, vorapaxar