Novel antiplatelet agents in acute coronary syndrome

Nature Reviews Cardiology | Review   

Dual antiplatelet therapy (DAPT) with aspirin and the P2Y purinoceptor 12 (P2Y12)-receptor inhibitor clopidogrel has been considered the gold standard of care in patients with acute coronary syndrome (ACS). The FDA approval of the novel P2Y12-receptor antagonists prasugrel and ticagrelor, which are faster-acting and more potent than clopidogrel, in the past 5 years have improved clinical outcomes in patients with ACS. Even with these newer compounds, many patients continue to experience adverse ischaemic events. This Review will provide an overview of the antiplatelet agents currently used to treat patients with ACS. Furthermore, emerging antiplatelet therapies, including intravenous P2Y12 antagonists, oral PAR-1 antagonists and thromboxane-receptor inhibitors will be discussed.

Abstract

For more than 10 years, dual antiplatelet therapy with aspirin and clopidogrel has remained the cornerstone of treatment for patients with acute coronary syndrome (ACS). The novel oral P2Y purinoceptor 12 (P2Y₁₂)-receptor inhibitors prasugrel and ticagrelor were approved by the FDA for clinical use in 2009 and 2011, respectively. These agents have a faster-acting, more-potent, and more-predictable antiplatelet effect than clopidogrel, which translates into improved clinical outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, some patients continue to experience adverse ischaemic events despite treatment with aspirin and a P2Y₁₂-receptor antagonist, because platelets can remain activated via pathways not inhibited by these agents, such as the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin. Emerging antiplatelet therapies that might address these limitations include intravenous P2Y₁₂ antagonists, oral PAR-1 antagonists, and thromboxane-receptor inhibitors. In this Review, we provide an overview of these novel antiplatelet drugs, including newly approved agents and emerging compounds currently under clinical development, and also discuss evolving concepts and unmet needs related to antiplatelet therapy for the treatment of ACS.

At a glance

• Platelet adhesion, activation, and aggregation after plaque rupture or erosion are the major determinants of arterial thrombosis leading to acute coronary syndrome (ACS)
• Antiplatelet therapy, which targets pathways of platelet activation and aggregation, is pivotal in both the acute treatment and long-term secondary prevention of ischaemic events in patients with ACS
• Dual antiplatelet therapy with a combination of aspirin and either prasugrel or ticagrelor should be the treatment of choice in patients with ACS
• Drug selection should be based on contraindications and the individual patient's characteristics; clopidogrel should be used when both prasugrel and ticagrelor are contraindicated or not available
• Patients might continue to experience adverse events despite the use of prasugrel or ticagrelor
• New intravenous P2Y purinoceptor 12 inhibitors and agents that target other platelet-activation pathways have been developed

Figure 1: Mechanism of thrombus formation.

Plaque rupture exposes subendothelial components. Platelet adhesion during the rolling phase is mediated by interactions between vWF and GP Ib/V/IX receptor complexes located on the platelet surface, and between platelet collagen recep…

Figure 2: Platelet activation pathways targeted by current and novel antiplatelet agents.

Platelet adherence to injured vascular endothelium is mediated by binding of GP receptors to exposed extracellular matrix proteins (collagen and vWF). Complex intracellular signalling processes result in the local production and releas…

Figure 3: Mechanisms of action of P2Y₁₂ inhibitors.

Activation of P2Y₁₂ inhibits AC, causing a decrease in cAMP and VASP-P levels, and activation of P2Y₁ causes an increase in intracellular Ca²⁺ levels. These changes promote platelet aggregation by altering the ligand-binding properties…

Introduction

Arterial thrombosis after atherosclerotic plaque rupture or erosion is the major determinant of acute coronary syndrome (ACS).^{1, 2} Platelet adhesion, activation, and aggregation have important roles in the development of arterial thrombi; antiplatelet therapy is, therefore, pivotal in the treatment of ACS.^{2, 3, 4} Multiple platelet-signalling pathways are involved in thrombus formation and are potential targets for therapies.^{2, 3, 4} At present, three main classes of antiplatelet drugs are clinically approved for the treatment and secondary prevention of thrombotic complications in patients with ACS: oral cyclooxygenase-1 (COX-1; also known as prostaglandin G/H synthase 1) inhibitors, oral P2Y purinoceptor 12 (P2Y₁₂)-receptor inhibitors, and intravenous glycoprotein (GP) IIb/IIIa (also known as integrin α_IIbβ₃) inhibitors.^{5, 6, 7, 8}

The synergistic platelet-inhibitory effects exerted by dual antiplatelet therapy (DAPT) consisting of aspirin-induced blockade of COX-1 in conjunction with P2Y₁₂-receptor inhibition led to more than 10 years of clinical trials in patients with manifestations of ACS, including unstable angina, non-ST-segment elevation (NSTE) myocardial infarction (MI) and ST-segment elevation MI (STEMI).^{5, 6, 7, 8, 9, 10} Clopidogrel is the most broadly investigated P2Y₁₂-receptor inhibitor, owing to its favourable safety profile compared with ticlopidine.¹¹

Therefore, clopidogrel in combination with aspirin is still the cornerstone of treatment in patients with ACS.^{5, 6, 7, 8} However, despite the undisputable benefits of DAPT, a considerable number of patients continue to experience adverse thrombotic events.¹² These adverse events have been in part attributed to the nonuniform platelet inhibitory effects induced by clopidogrel, also known as interindividual clopidogrel response variability, where individuals who persist with high platelet reactivity despite clopidogrel therapy are at an increased risk of atherothrombotic recurrences.^{12, 13, 14, 15} Moreover, despite adequate COX-1 and P2Y₁₂-receptor blockade,^{3, 4} other platelet signalling pathways continue to be activated, and can contribute to thrombus formation. These observations have prompted the development of novel antithrombotic agents.

In this Review, we provide an overview of advances in antiplatelet therapy in the setting of ACS, focusing on novel drugs that have already been approved for clinical use, in addition to emerging agents at different phases of clinical development. However, a detailed description of the role of novel oral anticoagulants is beyond the scope of this Review, and the use of such agents is only briefly mentioned.

Mechanisms of atherothrombosis

Plaque rupture, fissure, or erosion exposes the subendothelial layer and leads to the recruitment and activation of platelets, as well as the generation of excessive levels of thrombin, which ultimately results in the formation of a fibrin-rich thrombus.^{1, 2, 3, 4} NSTE-ACS is frequently characterized by a nonocclusive or transiently occlusive thrombus, whereas a more stable and occlusive thrombus is typical in STEMI.¹ Platelet-activated thrombosis involves three principal steps: platelet adhesion, activation and recruitment of additional platelets, and platelet aggregation (Figure 1).^{3, 4, 16} Platelet adhesion during the initial rolling phase is mediated by interactions between the GP Ib/V/IX receptor complex, located on the surface of the platelet, and von Willebrand factor (vWF) bound to collagen exposed at the site of vascular injury.¹⁷ Rolling also brings the collagen receptors GP VI and GP Ia on platelets into contact with collagen.¹⁷ Binding of collagen to these receptors initiates platelet activation and triggers intracellular mechanisms that shifts platelet integrins to a high-affinity state, which induces the release of activating factors, in turn promoting aggregation, further recruitment, and further activation of circulating platelets.^{3, 4, 16, 17} These factors include ADP, epinephrine, serotonin, thrombin, and thromboxane A₂.^{3, 4} Platelet activation by these and other mediators (such as collagen) induces changes in platelet shape, expression of proinflammatory molecules (such as P-selectin and soluble CD40 ligand) and platelet procoagulant activity.^{3, 4, 16} The final step in platelet aggregation and thrombus formation involves the conversion of platelet GP IIb/IIIa (the main receptor mediating platelet aggregation) into its active form, which subsequently binds to the extracellular ligands fibrinogen and vWF, leading to platelet aggregation and thrombus formation mediated by platelet–platelet interaction.^{17, 18} In addition, vascular injury also exposes subendothelial tissue factor, which forms a complex with factor VIIa, activating the clotting cascade and leading to thrombin generation.¹⁹ However, only a modest amount of thrombin is produced as a result of the coagulation cascade; its main source within a platelet plug is the surface of activated platelets.^{16, 20} Thrombin converts fibrinogen to fibrin, generating a fibrin-rich clot, and further activates platelets by binding to protease-activated receptor (PAR)-1 and PAR-4.^{3, 4, 21, 22} Pathogenic thrombosis, therefore, involves a complex interplay between platelets and plasma components (coagulation factors) that interact in an auto-amplified process (Figure 1).

Francesco Franchi^1, & Dominick J. Angiolillo^1,

Nature Reviews Cardiology Year published: (2014) DOI: doi:10.1038/nrcardio.2014.156