Vorapaxar, an antiplatelet, is a first-in-class antagonist on the protease-activated receptor-1 (PAR-1).
Diana SobierajIn May 2014, FDA approved vorapaxar (Zontivity; Merck, Sharp and Dohme) to decrease thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD).
An antiplatelet, vorapaxar is a first-in-class antagonist on the protease-activated receptor-1 (PAR-1). The major human platelet receptor, PAR-1 is activated by thrombin. Vorapaxar blocks thrombin-mediated activation of PAR-1 without interfering with fibrin cleavage and therefore does not impact the coagulation cascade.
Owing to increased risk of intracranial hemorrhage, vorapaxar is contraindicated in patients with a history of a stroke, transient ischemic attack, or intracranial hemorrhage, as well as in patients with active pathologic bleeding.
The efficacy of vorapaxar was based on a randomized controlled trial (TRA 2P-TIMI 50) of 26,449 patients who were considered to have stable atherosclerotic disease and were receiving standard therapy. Qualifying diagnoses included a history of MI, ischemic stroke, or PAD. The qualifying diagnosis for the majority of enrolled patients was MI (67%); 94% of enrolled patients were taking aspirin and thienopyridine was common, especially among MI patients (78%).
Patients were randomized to receive vorapaxar 2.5 mg daily or placebo. Patients treated with vorapaxar 2.5 mg daily compared to placebo for a median of 30 months had a reduced risk of the composite outcome of death from cardiovascular cause, myocardial infarction, or stroke [hazard ratio (HR) 0.87 (0.80 to 0.94)].
When the individual components of the composite outcome were evaluated separately, only the risk of MI was significantly different between the two treatments, favoring vorapaxar vs. placebo [HR 0.83 (0.74 to 0.93)].
The major secondary outcome was a composite of cardiovascular death, MI, stroke, or urgent revascularization, which was significantly reduced with vorapaxar compared to placebo [HR 0.88 (0.82 to 0.95)].
Death due to any cause was not significantly different between the two groups, [HR 0.95 (0.85 to 1.07)].
The risk of major or minor bleeding according to GUSTO criteria was significantly greater in patients treated with vorapaxar vs. placebo [HR 1.66 (1.43 to 1.93)]. ICH was also higher in vorapaxar-treated patients compared to placebo [HR 1.94 (1.39 to 2.70)]. In patients with a history of stroke, the rate of ICH was even greater with vorapaxar treatment compared to placebo than in patients without a history of stroke.
After two years of follow-up, the data safety and monitoring board suggested stopping therapy in patients with a history of stroke due to the higher risk of ICH, hence the current contraindication in the drug label.
Aside from bleeding events, adverse reactions reported in at least 2% of patients treated with vorapaxar and at a rate greater than 10% above the placebo group include anemia, depression, and rashes/eruptions/exanthems. Iron deficiency, retinopathy or retinal disorders, and diplopia/oculomotor symptoms occurred in at least 40% more patients treated with vorapaxar vs. placebo.
Vorapaxar is dosed 2.08 mg daily, which is equivalent to 2.5 mg of vorapaxar sulfate. Vorapaxar should be used in combination with aspirin and/or clopidogrel according to their indications or standard of care, since experience using vorapaxar in other ways is limited. According to the drug label, vorapaxar should not be used in combination with strong CYP3A inhibitors and inducers.
There are no dose reductions specific to renal insufficiency. Vorapaxar is metabolized by the liver and excreted via the fecal route. No unchanged vorapaxar has been detected in urine.