Recent Developments in the Use of Antiplatelet Agents to Prevent Cardiovascular Events

Stefan Lischke; David J Schneider

Future Cardiol. 2011;7(3):403-413.

Platelet Activation Pathways & Targets of Anti-thrombotic Agents

Platelets are critical to the response to vascular injury, particularly in arteries where sheer forces are greater.^[6,7] Intimal injury that occurs after rupture of an atherosclerotic plaque or the placement of an intracoronary stent exposes collagen and von Willebrand factor in the subendothelium. Adhesion of platelets to these molecules is not dependent on the activation of platelets. The two primary stimuli for platelet activation are collagen exposed by a break in the endothelium and thrombin generated by the coagulation cascade.^[7] The activation of platelets is accompanied by shape change, a conformational change in glycoprotein (GP) IIb-IIIa, a change in platelet surface that supports assembly of coagulation factors and the release of granular products.^[6] Among the products released are thromboxane A2 (TXA2) and ADP, which are platelet agonists. Change in the conformation of GP IIb-IIIa reveals a binding site for fibrinogen. Because each molecule of fibrinogen can bind two platelets, fibrinogen serves to cross-link (aggregate) platelets.^[6] Thrombosis is an exaggerated response to endothelial injury that occludes arteries whereas hemostasis is the physiologic response to vessel injury that keeps us from bleeding to death. Antiplatelet therapy seeks to prevent thrombosis while maintaining hemostasis.

Therapeutic targets of antiplatelet agents include:

Cyclooxygenase 1 – its acetylation by aspirin prevents formation of TXA2;
ADP receptor P2Y₁₂, blocked by clopidogrel, prasugrel, cangrelor and ticagrelor;
GP IIb-IIIa – its inhibition by abciximab, tirofiban or eptifibatide prevents aggregation of previously activated platelets;
Thrombin receptor – protease-activated receptor 1 (PAR-1) antagonists that inhibit thrombin-mediated platelet aggregation.

Although not generally described as antiplatelet agents, anticoagulants that reduce thrombin generation also attenuate the activation of platelets.

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Cite this: Recent Developments in the Use of Antiplatelet Agents to Prevent Cardiovascular Events - Medscape - May 01, 2011.

Abstract and Introduction
Need for Novel Antiplatelet Drugs
Platelet Activation Pathways & Targets of Anti-thrombotic Agents
Ideal Anti-thrombotic Agent
Individualized Dosing Using Platelet Function Testing: GRAVITAS
Oral Antiplatelet Therapy
Intravenous Antiplatelet Agents
Conclusion
Future Perspective
References
Sidebar

Sidebar

Executive Summary

Antiplatelet therapy is the cornerstone of secondary prevention of cardiovascular events but its use must balance prevention of thrombosis with maintenance of hemostasis.
Wheras CYP2C19 and ABCB1 polymorphisms do not influence the efficacy of prasugrel or ticagrelor, they are associated with variability of the pharmacodynamic effect and adverse cardiovascular events in patients treated with clopidogrel.
Concomittant use of proton pump inhibitors with clopidogrel is probably safe; however, it should be reserved for patients with specific indications.
The Gauging Responsiveness with a VerifyNow ® Assay Impact on Thrombosis And Safety (GRAVITAS) trial failed to demonstrate that a single determination of platelet reactivity with the VerifyNow device can be used to guide therapy.
The more powerful antiplatelet effects of prasugrel may be most appropriately targeted to patients at high risk of stent thrombosis and secondary events – patients with diabetes and STEMI, in whom greater therapeutic benefit was not associated with an increased risk of bleeding.
Ticagrelor, the first oral reversible P2Y12 receptor antagonist, demonstrated broad benefit with a reduction in mortality and a modest increase in the risk of bleeding events.
Intravenous P2Y12 antagonism with cangrelor requires additional study, perhaps reflecting a change in our paradigm of treatment. Earlier coronary intervention may obscure the ability to distinguish myocardial infarction-complicating procedures from evolving myocardial infarction.
Vorapaxar, a promising protease activated receptor 1 antagonist, which inhibits thrombin-mediated platelet aggregation without interfering with primary hemostasis, is in Phase III trials.
Abciximab and tirofiban may improve microvascular reperfusion in patients with STEMI.
Upstream administration of eptifibatide in patients with acute coronary syndrome undergoing PCI did not improve clinical outcome and was associated with an increased risk of bleeding.
The availability of more powerful and rapid acting oral antiplatelet agents has led to the reevaluation of parenteral glycoprotein IIb-IIIa antagonists.

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