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Antiplatelet Drug Vorapaxar (Zontivity) Shows Promise in Treatment of Peripheral Artery Disease

Phase III data to be presented at ACC conference

Positive results have been reported from two post hoc analyses of the TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) trial of vorapaxar (Zontivity, Merck), a once-daily tablet containing 2.08 mg of vorapaxar, equivalent to 2.5 mg of vorapaxar sulfate.

The new data on additional endpoints in subgroups of patients with peripheral artery disease (PAD) will be presented at the 2015 American College of Cardiology (ACC) Scientific Sessions, to be held March 14–16 in San Diego, California.

Vorapaxar inhibits protease-activated receptor-1 (PAR-1), the primary receptor for thrombin, which is considered to be the most potent activator of platelets. The PAR-1 pathway participates in the formation of blood clots through the activation and aggregation of platelets.

Vorapaxar is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or in patients with PAD. The drug’s May 2014 regulatory approval was based on results from the pivotal TRA 2°P TIMI 50 study, in which vorapaxar was shown to reduce the rate of a combined endpoint of CV death, MI, stroke, and urgent coronary revascularization when added to aspirin and/or clopidogrel.

The prescribing information for vorapaxar includes a boxed warning regarding the risk of bleeding, which states that vorapaxar is not for use in patients with a history of stroke, transient ischemic attack (TIA), intracranial hemorrhage (ICH), or active pathological bleeding. Antiplatelet agents, including vorapaxar, increase the risk of bleeding, including ICH and fatal bleeding.

The data being presented at the ACC meeting will include two post hoc subgroup analyses that explored the use of vorapaxar in certain patients with established PAD. PAD is generally defined as the obstruction of arteries supplying the lower extremities, most commonly due to atherosclerosis. People with PAD are at increased risk of heart attack, stroke, and cardiovascular death. People with PAD are also at risk of complications from ischemia involving the lower extremities, and this was the focus of the two subgroup analyses. Specifically, these analyses looked at rates of acute limb ischemia (ALI) and peripheral artery revascularization (PAR).

A total of 109 ALI events occurred in 3,787 patients enrolled in the TRA 2°P TIMI 50 trial whose qualifying diagnosis was symptomatic PAD (including 514 patients with a history of stroke or TIA in whom the use of vorapaxar was contraindicated). Most of the ALI events were due to acute surgical-graft thrombosis (54%) or in situ thrombosis in a native vessel (27%). In the new post hoc subgroup analysis, the researchers found that, in patients with symptomatic PAD, adding vorapaxar to standard care (which included aspirin and/or clopidogrel) yielded a 42% relative risk reduction in the incidence of ALI compared with aspirin and/or clopidogrel alone (3-year event rates: 2.3% vs. 3.9%, respectively; hazard ratio [HR]: 0.58).

The second post hoc subgroup analysis of the TRA 2ºP TIMI 50 trial involved 5,845 patients with a history of PAD. Vorapaxar added to aspirin and/or clopidogrel showed a consistent pattern of reduction in the need for PAR (via percutaneous or surgical procedures) compared with placebo plus aspirin and/or clopidogrel. This included a reduction in PAR for the treatment of claudication (event rates: 9.4% for vorapaxar vs. 11.6% for placebo; HR: 0.84). Adding vorapaxar also reduced the rate of surgical PAR procedures (event rates: 4.5% for vorapaxar vs. 7.7% for placebo; HR: 0.59). Approximately 20% of the 5,845 patients included in this analysis had a history of stroke or TIA, which are contraindications to the use of vorapaxar.

Vorapaxar was studied only as an addition to aspirin and/or clopidogrel and should be used with aspirin and/or clopidogrel according to their indications or standard of care. There is no experience with the use of vorapaxar alone as the only administered antiplatelet agent.

Vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH and in patients with active pathological bleeding, such as ICH or peptic ulcer.

Source: Merck; March 5, 2015.

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