Curriculum in Cardiology
Oral antiplatelet therapy for atherothrombotic disease: Current evidence and new directions

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Despite the proven efficacy of dual antiplatelet therapy with aspirin and one of the first-generation P2Y12 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 A2 (by aspirin) and adenosine diphosphate (by P2Y12 antagonist) platelet activation pathways that are essential to hemostasis.

The second-generation P2Y12 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 P2Y12 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 P2Y12 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.

Section snippets

Aspirin

Trials with aspirin have demonstrated a reduction of ischemic events in patients with ACS6 and those scheduled for percutaneous coronary intervention (PCI).6, 16 A meta-analysis of 16 randomized trials (43,000 patient-years) that evaluated aspirin versus no treatment for secondary prevention demonstrated a significant, approximately 20% reduction in major coronary events in patients receiving aspirin (risk ratio 0.87, 95% CI 0.78-0.98).17 The risk of major extracranial bleeding, including

Clopidogrel

The CAPRIE trial evaluated the efficacy of clopidogrel monotherapy versus aspirin monotherapy in secondary prevention of atherothrombotic disease. Monotherapy with clopidogrel demonstrated modestly greater efficacy versus aspirin monotherapy (Table I7, 8, 9, 10, 18, 19, 20, 21, 22, 23, 24), whereas the bleeding rates were comparable among the groups (Table II7, 8, 9, 10, 19, 20, 21, 22, 23, 24).7 Treatment with aspirin alone led to a higher rate of intracranial hemorrhage versus clopidogrel

Prasugrel

Prasugrel (Figure 1, Figure 4) is an oral, irreversible thienopyridine P2Y12 antagonist (Table III10, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) with a faster onset of action time and greater potency versus clopidogrel.37 In TRITON-TIMI 38, which enrolled 13,608 patients with ACS undergoing PCI, the combination of prasugrel plus aspirin significantly reduced the risk of the composite end point of death from CV causes, nonfatal MI, or nonfatal stroke versus the combination of clopidogrel plus

Ticagrelor

Ticagrelor (Figure 1, Figure 4) is a nonthienopyridine, direct-acting, and selective inhibitor of the P2Y12 ADP receptor with rapid onset of action (2 hours to peak platelet inhibition) (Table III).43 Importantly, ticagrelor binding to the P2Y12 ADP receptor is reversible (Figure 4), with partial recovery of platelet aggregation within 12 hours after discontinuation of treatment.37 This feature of ticagrelor may be advantageous because rapid reversal of platelet inhibition after discontinuation

Conclusion

Single antiplatelet therapy with aspirin and dual antiplatelet therapy with aspirin and a P2Y12 antagonist (clopidogrel or prasugrel) have documented efficacy in the prevention and treatment of atherothrombotic disease. Dual antiplatelet therapy has been associated with improved efficacy over single-agent therapy, but bleeding rates are increased, and there remains an unmet need in continuing high ischemic event rates. Ticagrelor has been shown to reduce mortality versus clopidogrel, although

Acknowledgements

The author would like to thank Charlene Nell, team support administrator, Green Lane Cardiovascular Research Unit, for excellent secretarial assistance.

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  • Cited by (0)

    Dr White has received research grants from Sanofi-Aventis, Eli Lilly, Medicines Company, NIH, Pfizer, Roche, Johnson & Johnson, Schering Plough, Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi-Sankyo Pharma Development, and Bristol-Myers Squibb. He has also received a consultancy fee from Regado Biosciences.

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