General Information

Zontivity (vorapaxar) is a protease-activated receptor-1 (PAR-1) antagonist.

Zontivity is specifically indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD).

Zontivity is supplied as a tablet for oral administration. The recommended dose is one tablet (2.08 mg) orally once daily, with or without food.

Mechanism of Action

Zontivity (varapaxar) s a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long half-life makes it effectively irreversible. Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in in vitro studies. Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect coagulation parameters ex vivo. PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells, but the pharmacodynamic effects of vorapaxar in these cell types have not been assessed.

Side Effects

The most frequently reported side effect associated with the use of Zontivity is bleeding, including life-threatening and fatal bleeding.

Clinical Trial Results

The FDA approval of Zontivity was based on TRA 2°P - TIMI 50. TRA 2°P was a multicenter, randomized, double-blind, placebo-controlled study conducted in patients who had evidence or a history of atherosclerosis involving the coronary, cerebral (ischemic stroke), or peripheral vascular systems. Subjects were randomized to receive daily treatment with Zontivity (n=13,225) or placebo (n=13,224) in addition to standard of care. The study’s primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR). The composite of cardiovascular death, MI, and stroke was assessed as key secondary endpoint. The median follow-up was 2.5 years (up to 4 years). The findings in all randomized patients for the primary efficacy composite endpoint show a 3-year K-M event rate of 11.2% in the Zontivity group compared to 12.4% in the placebo group. The findings for the key secondary efficacy endpoint show a 3-year Kaplan-Meier (K-M) event rate of 9.3% in the Zontivity group compared to 10.5% in placebo group.