What is Vorapaxar (thrombin receptor antagonist)?

Vorapaxar: A PAR-1 Antagonist Antiplatelet Agent

Vorapaxar is a potent and specific competitive inhibitor of protease-activated receptor-1 (PAR-1) that prevents thrombin-induced platelet aggregation and is FDA-approved for reducing thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease who have no history of stroke or transient ischemic attack. 1, 2

Mechanism of Action

Vorapaxar works through a unique mechanism compared to other antiplatelet agents:

• It is a reversible antagonist of PAR-1, a G-protein-coupled receptor expressed on platelets that is activated by thrombin 1
• Despite being technically reversible, vorapaxar's long half-life makes it effectively irreversible in clinical practice 2
• It specifically inhibits thrombin- and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation 2
• Unlike other antiplatelet agents, it does not affect platelet aggregation induced by ADP, collagen, or thromboxane mimetics 2
• It also does not affect thrombin-mediated conversion of fibrinogen to fibrin or coagulation parameters 2

Pharmacokinetics

Vorapaxar has several distinctive pharmacokinetic properties:

• Excellent oral bioavailability (approximately 100%) 2
• Long half-life: effective half-life of 3-4 days and terminal elimination half-life of 8 days 2
• Inhibits TRAP-induced platelet aggregation for up to 4 weeks after discontinuation 1, 2
• Metabolized primarily by CYP3A4 and CYP2J2 2
• Can be taken with or without food 2
• No dose adjustment required for renal impairment 2

Clinical Use and Efficacy

Vorapaxar is approved for:

• Secondary prevention in patients with a history of myocardial infarction (MI) 2, 3
• Patients with peripheral arterial disease (PAD) 2, 3

In clinical trials, vorapaxar demonstrated:

• Significant reduction in the composite endpoint of cardiovascular death, MI, and stroke (7.9% vs 9.5%, HR 0.80) when added to standard therapy 4
• Reduction in the rate of recurrent acute limb ischemia in PAD patients 3
• Efficacy as an adjunctive therapy to standard antiplatelet regimens (typically aspirin and/or clopidogrel) 3, 4

Safety Considerations and Contraindications

Important safety concerns include:

• Increased risk of bleeding, including life-threatening bleeding 2, 3
• Contraindicated in patients with:
  • History of stroke
  • History of transient ischemic attack (TIA)
  • History of intracranial hemorrhage
  • Active pathological bleeding 2, 3
• Not recommended in patients with severe hepatic impairment 2
• No antidote or reversal agent is available; platelet transfusion is not expected to be beneficial 2
• Effects persist for weeks after discontinuation due to long half-life 2

Clinical Pearls

• Vorapaxar is used in addition to aspirin and/or clopidogrel, not as a replacement 3, 4
• The standard dose is 2.08 mg (equivalent to 2.5 mg vorapaxar sulfate) orally once daily 5
• No loading dose is required 5
• PAR-1 is also expressed on endothelial cells, smooth muscle cells, fibroblasts, and cardiac myocytes, which may contribute to vorapaxar's effects beyond platelet inhibition 1
• Unlike other P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor), vorapaxar targets a different platelet activation pathway 1

Monitoring

• No standard test is available to assess bleeding risk in overdose situations 2
• No routine laboratory monitoring is required for vorapaxar therapy 2
• Careful clinical monitoring for bleeding complications is essential 2, 3

Vorapaxar represents an important addition to the antiplatelet armamentarium with its unique mechanism of action, but its use must be carefully balanced against the increased bleeding risk, particularly in patients with risk factors for hemorrhagic complications.