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Table 1.  

Properties of P2Y12 Receptor Antagonists

Table 2.  

A Summary of Randomized, Controlled, Phase III Trials of Ticlopidine in Cardiovascular Diseasea

Table 3.  

Summary of Pphase III, Randomized, Controlled Trials With Clopidogrel in Cardiovascular Disease; Part 1a

Table 4.  

Summary of Phase III, Randomized, Controlled Trials With Clopidogrel in Cardiovascular Disease; Part 2a

Box 1.  

P2Y12 antagonists
  • Clopidogrel
  • Prasugrel
  • AZD6140
  • Cangrelor
Thromboxane antagonists
  • Terutroban
Protease-activated receptor 1 antagonists
  • E5555
  • SCH530348
Glycoprotein IIb/IIIa antagonists
  • Abciximab
  • Tirofiban
  • Eptifibatide

A Summary of Agents That Inhibit Platelet Aggregation

Platelet ADP-receptor Antagonists for Cardiovascular Disease: Past, Present and Future

Authors: Nina C. Raju, MD ; John W. Eikelboom, MB BS, MSc, FRACP, FRCPA ; Jack Hirsh, MD, FCCPFaculty and Disclosures


Summary and Introduction


Aspirin is the foundation antiplatelet therapy for patients at risk of cardiovascular events. The thienopyridine, clopidogrel, is modestly more effective than aspirin and in patients with stroke seems to be as effective as the combination of aspirin and dipyridamole. The addition of clopidogrel to aspirin further reduces the risk of cardiovascular events in patients with acute coronary syndromes and those who undergo percutaneous coronary intervention, but uncertainty remains about whether this combination has incremental efficacy over clopidogrel monotherapy in patients with stroke or peripheral arterial disease. Clopidogrel has pharmacological limitations that have prompted the search for more effective ADP-receptor antagonists. Promising results have been achieved with the thienopyridine, prasugrel, which has been compared with clopidogrel in patients treated with aspirin. The nonthienopyridine P2Y12 inhibitors AZD6140 and cangrelor are presently being evaluated in phase III, randomized, controlled trials.


Platelets have a central role in the pathogenesis of atherothrombosis. In addition to being major components of arterial thrombi, they contribute to all phases of atherosclerosis; activated platelets promote coagulation on their surface[1] and express mediators of inflammation and smooth-muscle-cell proliferation. Rupture of an atherosclerotic plaque exposes collagen and von Willebrand factor (vWF), both of which are ligands that initiate platelet adhesion and activation. Subendotheliumbound vWF binds to the platelet glycoprotein 1b-IX-V complex present on platelets, and thereby tethers platelets from passing blood[2] and strengthens the binding of subendothelial collagen to platelets through glycoprotein VI and glycoprotein IIa/Ib receptors (Figure 1).[3]

Figure 1. (click image to zoom) Mechanisms of platelet adhesion and activation.
Abbreviations: GP = glycoprotein; PAI-1 = plasminogen activator inhibitor 1; PDGF = plateletderived growth factor; TXA2 = thromboxane A2; vWF = von Willebrand factor.

Platelet agonists interact with their respective G-protein-coupled receptors via a series of intracellular signaling cascades to amplify platelet activation and aggregation. Binding of the three primary platelet agonists-vWF, collagen and thrombin-to their corresponding receptors on the platelet surface stimulates the extracellular release of secondary agonists such as ADP and thromboxane A2 into the blood plasma. ADP binds the Gq-protein-linked P2Y1 receptor on platelets, which causes a change in cell shape, mobilization of calcium, and initiation of reversible aggregation,[4] and binds the Gi-linked P2Y12 receptor to amplify aggregation via adenylylcyclase-mediated cyclic AMP production.[5] The resulting platelet activation triggers a conformational change in glycoprotein IIb/IIIa receptors, which increases their affinity for fibrinogen and vWF. These ligands then bind to the receptors to form bridges between adjacent platelets, which results in aggregation. Sustained ADP-induced platelet aggregation requires activation of both P2Y1 and P2Y12 receptors.[6] Of the two, however, the P2Y12 receptor is the more attractive therapeutic target because its expression has a less widespread distribution and it has a dominant role in platelet aggregation. Activated platelets also promote the generation of thrombin-the most potent of all platelet agonists. Thrombin acts predominantly via protease-activated receptors 1 and 4 (PAR1 and PAR4) expressed on platelets.[7] Thrombin cleaves a portion of these receptors' N-terminus, which unmasks the sequence that serves as its ligand;[8] this modification activates the receptor and triggers multiple signal transduction pathways that modulate thrombosis, coagulation and inflammation. Protease-activated receptors are widely distributed in the vascular system and occur on platelets, endothelial cells, leukocytes and vascular smooth muscle cells.[9] PAR1 is more potent when activated than PAR4,[7] and thus PAR1 is the preferred target for developing therapies.

Antiplatelet agents that target critical steps in thrombogenesis have been developed; drugs that block thromboxane A2 synthesis, those that block receptors for ADP, thrombin and thromboxane A2, and agents that block fibrinogen and other ligands from binding to activated glycoprotein IIb/IIIa receptors (Figure 2 and Box 1 ). However, as the pathways that promote thrombosis are also critical to hemostasis, treatment with antiplatelet drugs is usually associated with an increased risk of bleeding. Furthermore, as several agonists can initiate platelet activation, increased antithrombotic efficacy can reasonably be expected to be obtained by blocking more than one pathway of platelet activation, but such strategies incur the cost of an increased risk of bleeding.

Figure 2. (click image to zoom) Sites of action of platelet inhibitors. Platelet aggregation can be inhibited by agents that target cyclo-oxygenase 1 and therefore block the production of thromboxane, or by agents that target platelet receptors (e.g. the TXA2 receptor, P2Y12, PAR1, and GP IIb/IIIa receptors) and thus block the action of platelet agonists. The various antiplatelet agents and their drug classes are listed in Box 1.
Abbreviations: GP = glycoprotein; PAR = protease-activated receptor; TXA2 = thromboxane A2.

Antiplatelet agents are effective in the treatment of arterial thrombosis. Aspirin, the first antiplatelet agent to be evaluated, can reduce the risk of vascular death by 15%, nonfatal myocardial infarction (MI) by 30% and nonfatal stroke by 25% in a broad range of high-risk patients.[10] However, room for improvement remains. Despite aspirin therapy, 10-20% of patients have recurrent vascular events in the 5 years after their incident event.[11] As aspirin inhibits the synthesis of only one platelet agonist (thromboxane A2), its limited efficacy as an antithrombotic agent is not surprising. The thienopyridines-ticlopidine and clopidogrel-block ADP-mediated platelet activation. In patients with a broad spectrum of cardiovascular disease, these ADP antagonists are modestly more effective than aspirin in the prevention of major cardiovascular events (MI, stroke or death) and, in patients with stroke, clopidogrel is as effective as aspirin and dipyridamole in combination. In certain cardiovascular disorders clopidogrel combined with aspirin has additive beneficial effects when compared with clopidogrel alone. Of the two thienopyridines, clopidogrel is associated with fewer adverse effects. Clopidogrel does, however, have limitations, which has prompted the development of new ADP antagonists ( Table 1 ). Over the past few years antiplatelet agents have also been developed that block thromboxane-A2-mediated platelet activation (terutroban) and thrombin-mediated platelet activation (SCH530348 and E5555). In preliminary clinical trials, both classes of antiplatelet drugs show promise.

This Review focuses on the role of ADP-receptor antagonists in the treatment of cardiovascular disorders. We examine evidence for the effectiveness and safety of clopidogrel when used alone and in combination with aspirin, and address controversies over the optimum loading dose and duration of treatment with clopidogrel. We also explore the new ADP-receptor antagonists prasugrel, AZD6140 and cangrelor, and examine their therapeutic potential relative to each other and to clopidogrel.

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