Vorapaxar: thrombin receptor antagonist

Vorapaxar: thrombin receptor antagonist

Vorapaxar is a new thrombin receptor antagonist which has been shown to reduce cardiovascular deaths and recurrent thrombotic events in patients with stable atherosclerotic vascular disease. This effect has been documented when added to standard antiplatelet therapy.

Vorapaxar is an orally active protease-activated-receptor-1 (PAR-1) antagonist capable of inhibiting thrombin induced platelet activation. Thrombin activates platelets through PAR-1 and PAR-4. PAR-1 is more important in the sense that it is activated by lower concentrations of thrombin than PAR-4 and mediates a more rapid response.

TRACER trial¹ showed that adding the drug to standard therapy did not reduce the composite endpoint of cardiovascular death, myocardial infarction, stroke, hospitalization for recurrent ischemia and urgent coronary revascularization in acute coronary syndrome. At the same time there was a significant increase in major bleeding including intracranial hemorrhage. In this trial vorapaxar did not have an effect on stent thrombosis.

An analysis of TRA 2°P-TIMI 50 Trial published in JACC² has shown that definite stent thrombosis as per Academic Research Consortium criteria is reduced in stable patients with coronary artery disease. The study included patients who had coronary stent implantation prior to randomization and those who had coronary stents implanted during the trial.

Median follow up was two and a half years. The reduction in stent thrombosis was noted in those who had previous percutaneous interventions, those with drug eluting stents, those on dual antiplatelet therapy and in those with diabetes at randomization. But in this study also vorapaxar increased GUSTO moderate and severe bleeding.

TRA 2°P-TIMI 50 Trial had 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease. They were randomized to receive vorapaxar or matching placebo and followed them for a median of 30 months. The study showed that vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. But it was noted to increase the risk of moderate or severe bleeding, including intracranial hemorrhage [3].

VORA-PRATIC Study published in 2020 concluded that in post myocardial infarction patients treated with potent antiplatelet agents prasugrel or ticagrelor, vorapaxar reduces platelet driven global thrombogenicity. The effect was attenuated in the absence of aspirin [4].

References

1. Tricoci P et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366:20-33.
2. Bonaca MP et al. Coronary Stent Thrombosis With Vorapaxar Versus Placebo: Results From the TRA 2°P-TIMI 50 Trial. J Am Coll Cardiol. 2014;64:2309-2317.
3. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, Fox KA, Lipka LJ, Liu X, Nicolau JC, Ophuis AJ, Paolasso E, Scirica BM, Spinar J, Theroux P, Wiviott SD, Strony J, Murphy SA; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012 Apr 12;366(15):1404-13. doi: 10.1056/NEJMoa1200933. Epub 2012 Mar 24. PMID: 22443427.
4. Franchi F, Rollini F, Faz G, Rivas JR, Rivas A, Agarwal M, Briceno M, Wali M, Nawaz A, Silva G, Shaikh Z, Maaliki N, Fahmi K, Been L, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Baber U, Mehran R, Jennings LK, Bass TA, Angiolillo DJ. Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y₁₂ Receptor Inhibitors With and Without Aspirin: Results of the VORA-PRATIC Study. J Am Heart Assoc. 2020 Apr 21;9(8):e015865. doi: 10.1161/JAHA.120.015865. Epub 2020 Apr 20. PMID: 32306797; PMCID: PMC7428520.