By sarms4muscle | 20 March 2024 | 0 Comments

Vorapaxar 618385-01-6: A Paradigm Shift in Cardiovascular Thrombotic Event Prevention

Chemical Name: Vorapaxar
SCH 530348 MK-5348
CAS No.: 618385-01-6

The launch of Vorapaxar, also marketed as Zontivity, represented a revolution in the treatment of cardiovascular disease. Vorapaxar, developed by Schering-Plough and later acquired by Merck Sharp & Dohme, has sparked interest due to its unique strategy to lowering the risk of thrombotic events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD). The therapeutic agent obtained approval from both the European EMA in January 2015 and the U.S. FDA in May 2014, highlighting its potential to address a critical need in the management of cardiovascular health.

As a reversible antagonist of platelet-derived protease-activated receptor-1 (PAR-1), vorapaxar functions in a distinct manner. Although Vorapaxar is classified as reversible, its lengthy half-life makes it almost irreversible in its activity, providing a prolonged therapeutic impact. Vorapaxar's selectivity for PAR-1 allows it to decrease thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation while not influencing aggregation caused by other agents such as adenosine diphosphate (ADP), collagen, or thromboxane-like compounds. Notably, Vorapaxar does not change the parameters of coagulation in vitro, which shows that it works as intended.

Vorapaxar's clinical development has been both groundbreaking and forewarning. Two sizable Phase 3 clinical trials with thousands of participants each, TRACER and TRA2P, thoroughly examined it. While these studies verified Vorapaxar's efficacy in lowering thrombotic events, they also revealed a major concern associated with its use: an increased risk of bleeding, including fatal and cerebral hemorrhages. The aforementioned finding prompted the inclusion of a black box warning in the prescribing information for the United States, which prohibited the drug's use in patients who had experienced active pathological bleeding or had a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage.


A mid-trial design modification to concentrate on patients with a history of MI and exclude those with prior strokes was necessary due to the important insights into the safety profile of Vorapaxar offered by the TRA2P trial in particular. This adjustment underscored the delicate balance between therapeutic efficacy and safety, particularly in a population at risk for both thrombotic and bleeding events.

The acquisition of Zontivity by Aralez Pharmaceuticals Inc in 2016 further illustrates the evolving landscape of cardiovascular therapeutics and the ongoing quest to optimize patient outcomes. Despite the challenges associated with its bleeding risk, Vorapaxar remains a testament to the complexity of managing cardiovascular diseases and the need for individualized patient care strategies.

In conclusion, Vorapaxar from development to clinical application highlights the intricate interplay between innovation, efficacy, and safety in drug therapy. As we continue to navigate the challenges of cardiovascular disease management, Vorapaxar serves as a pivotal case study in the pursuit of therapeutic agents that can significantly reduce the burden of thrombotic events while carefully managing associated risks.

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