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FDA Approves Zontivity (Vorapaxar) to Reduce Risk of Heart Attack, Stroke in High-Risk Patients

Antiplatelet agent is first PAR-1 antagonist

The FDA has approved Zontivity (vorapaxar, Merck) to reduce the risk of heart attack, stroke, cardiovascular death, and the need for procedures to restore blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs.

Vorapaxar is the first in a new class of drugs called protease-activated receptor-1 (PAR-1) antagonists. It is an antiplatelet agent designed to decrease the tendency of platelets to clump together to form a blood clot. By decreasing the formation of clots, vorapaxar decreases the risk of heart attack and stroke.

In a clinical trial involving more than 25,000 participants, vorapaxar, added to other antiplatelet agents (generally aspirin and clopidogrel), reduced the rate of a combined endpoint of heart attack, stroke, cardiovascular death, or urgent coronary revascularization (UCR) compared with placebo.

The TRAP 2oP trial was a randomized, placebo-controlled, end-event–driven study involving 26,499 subjects with at least one of three atherosclerotic conditions: prior myocardial infarction (MI), prior ischemic stroke, or established peripheral arterial disease (PAD). The subjects were randomly assigned to receive vorapaxar 2.5 mg or placebo once daily along with standard care. The median follow-up period was 2.2 years. The trial’s primary endpoint was the time to the composite of cardiovascular death, MI, stroke, or UCR. The key secondary endpoint was the time to CV death, MI, or stroke.

The trial’s primary endpoint was met in 9.5% (1,259/13,225) of the vorapaxar group compared with 10.7% (1,417/13,224) of the placebo group (hazard ratio [HR], 0.88; P = 0.001). Similarly, the study’s key secondary endpoint was met in 7.8% (1,028/13,225) of the vorapaxar group compared with 8.9% (1,176/13,224) of the placebo group (HR, 0.87; P < 0.001).

However, there was a substantially increased risk of intracranial hemorrhage in subjects in the vorapaxar arm with a history of stroke combined with no observed benefit of vorapaxar for the primary endpoint in that subset. The study’s Data and Safety Monitoring Board recommended the discontinuation of study treatment in subjects with a history of stroke or a stroke after randomization. The study leadership accepted this recommendation, and, in addition, discontinued follow-up in many of the affected patients. The study continued as planned in the remaining subjects (i.e., those with no history of stroke at baseline and no stroke during the study).

The prescribing information for Zontivity (vorapaxar) includes a boxed warning to alert health care professionals about the risk of bleeding. Vorapaxar must not be used in patients who have had a stroke, transient ischemic attack, or intracranial hemorrhage because the risk of such hemorrhage is too great.

Sources: FDA; May 8, 2014; and CRDAC Briefing Document; January 15, 2014.

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