Despite the proven efficacy of dual antiplatelet
therapy with
aspirin and one of the first-generation P2Y(12) antagonists (
clopidogrel,
prasugrel) in patients with atherothrombotic disease, residual ischemic risk remains substantial, and
bleeding rates are increased. Incomplete protection against ischemic events can be attributed to the fact that these
therapies each target a single platelet activation pathway, allowing continued platelet activation via other pathways, including the
protease-activated receptor-1 (PAR-1) pathway stimulated by
thrombin. Increased
bleeding with dual antiplatelet
therapy can be attributed to blockade of the
thromboxane A(2) (by
aspirin) and
adenosine diphosphate (by P2Y(12)
antagonist) platelet activation pathways that are essential to hemostasis. The second-generation P2Y(12) inhibitor
ticagrelor plus
aspirin demonstrated superior ischemic outcomes, including reduction in total mortality, versus
clopidogrel plus
aspirin, but event rates remain high, and major
bleeding not related to
coronary artery bypass grafting is increased. The novel P2Y(12) antagonist
elinogrel, available in intravenous and oral formulations, may have a more favorable benefit-to-risk profile than existing agents in this class because of reversible and competitive binding to the P2Y(12) receptor. Inhibition of PAR-1 is an attractive, novel approach in antiplatelet
therapy because it may provide incremental ischemic protection without increasing
bleeding. The PAR-1 antagonist
vorapaxar (
SCH 530348) has been associated with favorable efficacy and safety in phase 2 trials. Two phase 3 trials are evaluating the efficacy and safety of
vorapaxar in patients presenting with non-ST-segment elevation
acute coronary syndromes and in patients with documented atherothrombotic disease.