REVIEWS Novel antiplatelet agents in acute coronary syndrome Francesco Franchi and Dominick J. Angiolillo 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. Franchi, F. & Angiolillo, D. J. Nat. Rev. Cardiol. 12, 30–47 (2015); published online 7 October 2014; doi:10.1038/nrcardio.2014.156
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.2–4 Multiple platelet-signalling pathways are involved in thrombus formation and are potential targets for therapies.2–4 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 αIIbβ3) inhibitors.5–8 The synergistic platelet-inhibitory effects exerted by dual antiplatelet therapy (DAPT) consisting of aspirininduced blockade of COX‑1 in conjunction with P2Y12receptor inhibition led to more than 10 years of clinical trials in patients with manifestations of ACS, including unstable angina, non-ST-segment elevation (NSTE) Division of Cardiology, ACC Building 5th Floor, University of Florida College of Medicine‑Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA (F.F., D.J.A.). Correspondence to: D.J.A. dominick.angiolillo@ jax.ufl.edu
Competing interests D.J.A. declares that he has received honoraria from Abbott Vascular, AstraZeneca, Bayer, Bristol–Myers Squibb, Daiichi Sankyo, Eli Lilly, Evolva, Merck, PLx Pharma, Sanofi-Aventis, and The Medicines Company; has participated in review activities for CeloNova BioSciences, Johnson & Johnson, St. Jude Medical, and Sunovion Pharmaceuticals; and has received institutional payment for grants from AstraZeneca, Bristol–Myers Squibb, Daiichi Sankyo, Eli Lilly, Evolva, Gilead, GlaxoSmithKline, Otsuka, Sanofi-Aventis, and The Medicines Company. F.F. declares no competing interests.
30 | JANUARY 2015 | VOLUME 12
myocardial infarction (MI) and ST-segment elevation MI (STEMI).5–10 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.5–8 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.12–15 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
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ 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
activation of platelets, as well as the generation of excessive levels of thrombin, which ultimately results in the formation of a fibrin-rich thrombus.1–4 NSTE-ACS is frequently characterized by a nonocclusive or transiently occlusive thrombus, whereas a more stable and occlusive Platelet adhesion
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 inter actions 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
Platelet activation
Platelet aggregation ADP Serotonin Epinephrine
ADP
Thromboxane A2
Serotonin Epinephrine Collagen Thrombin
vWF vWF receptor Collagen Collagen receptor GP IIb/IIIa receptor
Thromboxane A2
Thrombin
Fibrin
Prothrombin Thrombus
Tissue factor
Factor X
Factor Xa Factor Va Ca2+
Tissue factorFactor VII
Factor IXa
Factor VII
Factor IX
Factor V
Fibrinogen
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 receptors (GP VI and GP Ia) and collagen exposed at the site of vascular injury. Binding of collagen to GP VI induces the release of activating factors (ADP, thromboxane A 2, serotonin, epinephrine, and thrombin), which promote interactions between adherent platelets, as well as further recruitment and activation of circulating platelets. Platelet activation leads to changes in platelet shape, expression of proinflammatory molecules, platelet procoagulant activity, and activation of platelet integrin GP IIb/IIIa. Activated GP IIb/IIIa binds to the extracellular ligands fibrinogen and vWF, leading to platelet aggregation and thrombus formation. Vascular injury also exposes subendothelial tissue factor, which forms a complex with factor VIIa and sets off a chain of events that culminates in formation of the prothrombinase complex. Prothrombin is converted to thrombin, which subsequently converts fibrinogen to fibrin, generating a fibrin-rich clot. Abbreviations: GP, glycoprotein; vWF, von Willebrand factor.
NATURE REVIEWS | CARDIOLOGY
VOLUME 12 | JANUARY 2015 | 31 © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS PAR-1 antagonists ■ Vorapaxar ■ Atopaxar
Thromboxane receptor antagonists ■ Terutroban ■ Seratrodast ■ Sulotroban ■ Ridogrel* ■ Daltroban ■ Picotamide* ■ Ifetroban ■ Terbogrel* ■ Ramatroban ■ EV-077* ■ Linotroban
Thrombin
PAR-4
Thromboxane A2 TPα-R PAR-1 G q
Thromboxane A2
Gq Gq
G12/G13
TPβ-R
COX-1 inhibitor ■ Aspirin
Thromboxane A2
G12/G13
ADP
ADP Gq G12/G13
Intracellular signalling activation
Gi
ADP 5-HT2A
GPIIb/IIIa
Serotonin 2A antagonists ■ APD-791 ■ Naftidrofuryl ■ Sarpogrelate ■ AT-1015
GP Iba/IIa– GP IX–GP V
GP Ia/IIa GP VI
Fibrinogen Endothelium
Collagen
Activation inhibitors Adhesion inhibitors Aggregation inhibitors
P2Y12
Platelet
COX-1
P2Y1
Gq
Thrombin TXS
P2Y12 receptor antagonists ■ Ticlopidine ■ Clopidogrel ■ Prasugrel ■ Ticagrelor ■ Cangrelor ■ Elinogrel
P2Y1 receptor antagonists ■ A2P5P ■ A3P5P ■ MRS2179 ■ MRS2279 ■ MRS2500
■ C1q TNF-related protein 1 ■ DZ-697b ■ RG12989
vWF
GP Ia/IIa inhibitor ■ EMS16
GP VI inhibitors ■ Monoclonal antibodies
GP IIb/IIIa inhibitors ■ Abciximab ■ Eptifibatide ■ Tirofiban
Platelet
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 release of multiple agonists, including thromboxane A2, ADP, and thrombin. These factors bind to their respective G‑protein-coupled receptors, mediating paracrine and autocrine platelet activation. Further, they potentiate each other’s actions (for example, P2Y 12 signalling modulates thrombin generation). Platelet integrin GP IIb/IIIa mediates the final common step of platelet activation by undergoing a conformational change, binding fibrinogen and vWF, leading to platelet aggregation and, ultimately, formation of a fibrin-rich thrombus. Current and emerging antiplatelet therapies are based on blockade of the thromboxane pathway, inhibition of platelet activation, and serotonin receptor 2A antagonism. *Combined thromboxane-receptor antagonists and TXS inhibitors. Abbreviations: 5‑HT2A, serotonin receptor 2A; COX, cyclooxygenase; GP, glycoprotein; PAR, protease-activated receptor; TP, thromboxane prostanoid receptor; TXS, thromboxane A2 synthase; vWF, von Willebrand factor. Permission obtained from Oxford University Press © Angiolillo, D. J., Capodanno, D. & Goto, S. Platelet thrombin receptor antagonism and atherothrombosis. Eur. Heart J. 31, 17–28 (2010).
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 32 | JANUARY 2015 | VOLUME 12
plasma components (coagulation factors) that interact in an auto-amplified process (Figure 1). Various receptors and signalling pathways are involved in the process leading to arterial thrombosis. Conse quently, numerous antiplatelet agents have been developed to target different parts of these signalling pathways (Figure 2).
Aspirin
Aspirin irreversibly blocks COX‑1, which is the enzyme responsible for generation of thromboxane A2 from arachidonic acid. Accordingly, aspirin decreases platelet activation mediated by the G‑protein-coupled thromboxane A2 receptor and thromboxane prostanoid (TP) receptors (Figure 2).23 Several trials have consistently demonstrated an important reduction in cardiovascular events with aspirin treatment in patients with ACS.24
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Table 1 | Pharmacological properties of P2Y12-receptor inhibitors Property
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Elinogrel
Receptor blockade
Irreversible
Irreversible
Reversible
Reversible
Reversible
Route of administration
Oral
Oral
Oral
Intravenous
Intravenous and oral
Frequency
Once daily
Once daily
Twice daily
Bolus plus infusion
Bolus plus twice daily
Prodrug
Yes
Yes
No*
No
No
Onset of action
2–8 h
30 min–4 h‡
30 min–4 h‡
2 min
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.2–4 Multiple platelet-signalling pathways are involved in thrombus formation and are potential targets for therapies.2–4 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 αIIbβ3) inhibitors.5–8 The synergistic platelet-inhibitory effects exerted by dual antiplatelet therapy (DAPT) consisting of aspirininduced blockade of COX‑1 in conjunction with P2Y12receptor inhibition led to more than 10 years of clinical trials in patients with manifestations of ACS, including unstable angina, non-ST-segment elevation (NSTE) Division of Cardiology, ACC Building 5th Floor, University of Florida College of Medicine‑Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA (F.F., D.J.A.). Correspondence to: D.J.A. dominick.angiolillo@ jax.ufl.edu
Competing interests D.J.A. declares that he has received honoraria from Abbott Vascular, AstraZeneca, Bayer, Bristol–Myers Squibb, Daiichi Sankyo, Eli Lilly, Evolva, Merck, PLx Pharma, Sanofi-Aventis, and The Medicines Company; has participated in review activities for CeloNova BioSciences, Johnson & Johnson, St. Jude Medical, and Sunovion Pharmaceuticals; and has received institutional payment for grants from AstraZeneca, Bristol–Myers Squibb, Daiichi Sankyo, Eli Lilly, Evolva, Gilead, GlaxoSmithKline, Otsuka, Sanofi-Aventis, and The Medicines Company. F.F. declares no competing interests.
30 | JANUARY 2015 | VOLUME 12
myocardial infarction (MI) and ST-segment elevation MI (STEMI).5–10 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.5–8 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.12–15 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
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ 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
activation of platelets, as well as the generation of excessive levels of thrombin, which ultimately results in the formation of a fibrin-rich thrombus.1–4 NSTE-ACS is frequently characterized by a nonocclusive or transiently occlusive thrombus, whereas a more stable and occlusive Platelet adhesion
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 inter actions 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
Platelet activation
Platelet aggregation ADP Serotonin Epinephrine
ADP
Thromboxane A2
Serotonin Epinephrine Collagen Thrombin
vWF vWF receptor Collagen Collagen receptor GP IIb/IIIa receptor
Thromboxane A2
Thrombin
Fibrin
Prothrombin Thrombus
Tissue factor
Factor X
Factor Xa Factor Va Ca2+
Tissue factorFactor VII
Factor IXa
Factor VII
Factor IX
Factor V
Fibrinogen
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 receptors (GP VI and GP Ia) and collagen exposed at the site of vascular injury. Binding of collagen to GP VI induces the release of activating factors (ADP, thromboxane A 2, serotonin, epinephrine, and thrombin), which promote interactions between adherent platelets, as well as further recruitment and activation of circulating platelets. Platelet activation leads to changes in platelet shape, expression of proinflammatory molecules, platelet procoagulant activity, and activation of platelet integrin GP IIb/IIIa. Activated GP IIb/IIIa binds to the extracellular ligands fibrinogen and vWF, leading to platelet aggregation and thrombus formation. Vascular injury also exposes subendothelial tissue factor, which forms a complex with factor VIIa and sets off a chain of events that culminates in formation of the prothrombinase complex. Prothrombin is converted to thrombin, which subsequently converts fibrinogen to fibrin, generating a fibrin-rich clot. Abbreviations: GP, glycoprotein; vWF, von Willebrand factor.
NATURE REVIEWS | CARDIOLOGY
VOLUME 12 | JANUARY 2015 | 31 © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS PAR-1 antagonists ■ Vorapaxar ■ Atopaxar
Thromboxane receptor antagonists ■ Terutroban ■ Seratrodast ■ Sulotroban ■ Ridogrel* ■ Daltroban ■ Picotamide* ■ Ifetroban ■ Terbogrel* ■ Ramatroban ■ EV-077* ■ Linotroban
Thrombin
PAR-4
Thromboxane A2 TPα-R PAR-1 G q
Thromboxane A2
Gq Gq
G12/G13
TPβ-R
COX-1 inhibitor ■ Aspirin
Thromboxane A2
G12/G13
ADP
ADP Gq G12/G13
Intracellular signalling activation
Gi
ADP 5-HT2A
GPIIb/IIIa
Serotonin 2A antagonists ■ APD-791 ■ Naftidrofuryl ■ Sarpogrelate ■ AT-1015
GP Iba/IIa– GP IX–GP V
GP Ia/IIa GP VI
Fibrinogen Endothelium
Collagen
Activation inhibitors Adhesion inhibitors Aggregation inhibitors
P2Y12
Platelet
COX-1
P2Y1
Gq
Thrombin TXS
P2Y12 receptor antagonists ■ Ticlopidine ■ Clopidogrel ■ Prasugrel ■ Ticagrelor ■ Cangrelor ■ Elinogrel
P2Y1 receptor antagonists ■ A2P5P ■ A3P5P ■ MRS2179 ■ MRS2279 ■ MRS2500
■ C1q TNF-related protein 1 ■ DZ-697b ■ RG12989
vWF
GP Ia/IIa inhibitor ■ EMS16
GP VI inhibitors ■ Monoclonal antibodies
GP IIb/IIIa inhibitors ■ Abciximab ■ Eptifibatide ■ Tirofiban
Platelet
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 release of multiple agonists, including thromboxane A2, ADP, and thrombin. These factors bind to their respective G‑protein-coupled receptors, mediating paracrine and autocrine platelet activation. Further, they potentiate each other’s actions (for example, P2Y 12 signalling modulates thrombin generation). Platelet integrin GP IIb/IIIa mediates the final common step of platelet activation by undergoing a conformational change, binding fibrinogen and vWF, leading to platelet aggregation and, ultimately, formation of a fibrin-rich thrombus. Current and emerging antiplatelet therapies are based on blockade of the thromboxane pathway, inhibition of platelet activation, and serotonin receptor 2A antagonism. *Combined thromboxane-receptor antagonists and TXS inhibitors. Abbreviations: 5‑HT2A, serotonin receptor 2A; COX, cyclooxygenase; GP, glycoprotein; PAR, protease-activated receptor; TP, thromboxane prostanoid receptor; TXS, thromboxane A2 synthase; vWF, von Willebrand factor. Permission obtained from Oxford University Press © Angiolillo, D. J., Capodanno, D. & Goto, S. Platelet thrombin receptor antagonism and atherothrombosis. Eur. Heart J. 31, 17–28 (2010).
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 32 | JANUARY 2015 | VOLUME 12
plasma components (coagulation factors) that interact in an auto-amplified process (Figure 1). Various receptors and signalling pathways are involved in the process leading to arterial thrombosis. Conse quently, numerous antiplatelet agents have been developed to target different parts of these signalling pathways (Figure 2).
Aspirin
Aspirin irreversibly blocks COX‑1, which is the enzyme responsible for generation of thromboxane A2 from arachidonic acid. Accordingly, aspirin decreases platelet activation mediated by the G‑protein-coupled thromboxane A2 receptor and thromboxane prostanoid (TP) receptors (Figure 2).23 Several trials have consistently demonstrated an important reduction in cardiovascular events with aspirin treatment in patients with ACS.24
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Table 1 | Pharmacological properties of P2Y12-receptor inhibitors Property
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Elinogrel
Receptor blockade
Irreversible
Irreversible
Reversible
Reversible
Reversible
Route of administration
Oral
Oral
Oral
Intravenous
Intravenous and oral
Frequency
Once daily
Once daily
Twice daily
Bolus plus infusion
Bolus plus twice daily
Prodrug
Yes
Yes
No*
No
No
Onset of action
2–8 h
30 min–4 h‡
30 min–4 h‡
2 min
