VORAPAXAR (ZONTIVITY®)

• ACRONYMS AND DEFINITIONS

• CVD - Cardiovascular disease
• PI - Package Insert
• PAR-1 - Protease-Activated Receptor-1
• RCT - Randomized controlled trial

• DRUGS IN CLASS

• Protease-activated receptor-1 (PAR-1) antagonist
• Vorapaxar (Zontivity®)

• MECHANISM OF ACTION

• Vorapaxar is a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets
• Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide-induced platelet aggregation
• Vorapaxar has a long half-life, so its action is effectively irreversible
• 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 [1]
• Illustration of platelet activation

• FDA-APPROVED INDICATION

• Vorapaxar (Zontivity®) - vorapaxar is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease. Vorapaxar has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization.

• SECONDARY PREVENTION OF CVD

• Overview
• The effectiveness of vorapaxar in the secondary prevention of CVD was evaluated in the TRA 2P-TIMI 50 trial detailed below

• Professional recommendations
• Vorapaxar is not mentioned in any recent AHA guidelines
• See antiplatelet therapy in CAD

• Summary
• Vorapaxar slightly improved the primary outcome in the TRA 2P-TIMI 50 trial, but at a cost of more bleeding events
• The "Net Clinical Outcome" that included bleeding events and the primary outcome found no significant benefit for vorapaxar
• The study was stopped early in patients with a history of stroke due to an increased risk of intracranial hemorrhage
• The overall benefits of vorapaxar, if any, are unclear at this time. Most patients in the study were also taking aspirin. Vorapaxar may have some benefit in patients who have an indication for antiplatelet therapy but cannot take aspirin.

• SIDE EFFECTS

• Bleeding
• The primary mechanism of vorapaxar is to inhibit blood clotting, therefore it will inherently also cause unwanted bleeding
• In the TRA 2P-TIMI trial, 4.2% of patients on vorapaxar had moderate to severe bleeding events compared to 2.5% of patients taking placebo. Almost all of the patients in the trial were also taking aspirin, and most were taking a P2Y12 inhibitor. Patients with a history of stroke had significantly more intracranial bleeds on vorapaxar, and the trial was stopped early for them. [2]


• Other
• In trials, no adverse event in the vorapaxar group (besides bleeding) was reported that had an incidence that was ≥ 1% more than placebo [1]

• CONTRAINDICATIONS

• History of stroke, transient Ischemic attack (TIA), or intracranial hemorrhage - DO NOT USE. May increase risk of intracranial hemorrhage.
• Active bleeding - DO NOT USE. May worsen.

• PRECAUTIONS

• Kidney disease
• No dose adjustment is necessary in mild, moderate, or severe kidney disease

• Liver disease
• Mild and moderate liver disease: No dose adjustment necessary
• Severe liver disease: not recommended

• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.


• Vorapaxar
• CYP3A4 strong inhibitors and inducers - Vorapaxar is a CYP3A4 sensitive substrate. It should not be taken with CYP3A4 strong inhibitors and inducers.
• Drugs that increase the risk of bleeding - drugs that inhibit coagulation may increase the risk of bleeding when taken with vorapaxar
• Drugs that may increase the risk of bleeding include:
• Anagrelide (Agrylin®)
• Aspirin
• Direct thrombin inhibitors (dabigatran)
• Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
• Fish oil (e.g. Vascepa®)
• P2Y12 inhibitors (e.g. clopidogrel, ticagrelor, prasugrel)
• NSAIDs (e.g. ibuprofen, naproxen)
• SSRIs and SNRIs (e.g. fluoxetine, venlafaxine)
• Warfarin (Coumadin®)

• Metabolism and clearance
• CYP3A4 - sensitive substrate
• CYP2J2 - substrate
• P-glycoprotein - minor inhibitor

• STOPPING BEFORE PROCEDURES

• Vorapaxar has a very long half-life (8 days)
• Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected at 4 weeks after discontinuation of daily doses of 2.08 mg
• The manufacturer's PI makes no recommendations on stopping before procedures, but notes that "significant inhibition of platelet aggregation remains 4 weeks after discontinuation" [1]

• LONG TERM SAFETY

• Vorapaxar was FDA-approved in 2014
• There is no long-term safety data for the medication

• DOSING

• Dosage form
• 2.08 mg tablet
• No generic. 30 tablets costs >$300


• Dosage
• 1 tablet once daily


• Food
• May take without regard to food

• BIBLIOGRAPHY

• 1 - Vorapaxar PI
• 2 - PMID 22443427 - TRA 2P-TIMI 50