Textbook of Interventional Cardiovascular Pharmacology - part 2 docx

On the contrary, in arterial thrombosis where inflammation promotes atheroma rupture, higher TF levels in atheroma, also expressed by monocytes and macrophage-derived foam cells, would be several times greater and, through enhancement of TF/FVIIa complex, will produce a strong platelets activation and thrombin generation. Blood flow changes (stasis) into a partial or total occluded vessel prevent activated factors and formed thrombin from dilution and together with platelet-erythrocyte interaction promotes thrombus to grow. 36 Principles of antiplatelet therapy NO . Inhibits platelet function and modifies monocytes, endotelial cells, and vascular smooth-muscle cells activity PF4, CXCL4 . Belongs to inflammatory cytokines family, mediates the relationship between monocytes and endothelial cells, induces neutrophil adhesion and secondary granule exocytosis, and influences macrophages adhesion to endothelial cell by triggering monocyte arrest in atherosclerotic arteries CD40L. Are important in inflammation and contributes significantly to the recruitment of inflammatory cells to damaged endothelium in vivo. Also present in lymphocytes B-cells, monocytes, macrophages, and endothelial cells. Regulate macrophage and smooth-muscle cells of the vascular wall. Induce cytokines secretion of endothelial cells PDGF. Induces proliferation of smooth-muscle cells of vascular wall RANTES. Is the most efficient arrest chemokine. Influences macrophages adhesion to endothelial cell TGF -␤. Inhibits the production of pro-inflammatory mediators in vitro and in vivo. Stimulates biosynthesis of smooth-muscle cells in vascular wall TSP-1 . Matricellular protein released from activated platelets. Induces the expression of VCAM-1 and ICAM-1 on endothelium. Increases monocyte attachment PSGL-1. Mediates the rolling of leukocytes on the endothelial cells allowing the recruitment of leukocytes to the inflamed tissue JAMs . Members of an immunoglobulin subfamily expressed by leukocytes, platelets, and endothelial cells, regulates leukocyte/platelet/endothelial cell interactions in the immune system, and promotes inflammatory vascular responses Abbreviations : CD40L, CD40 ligands; JAMs, junctional adhesion molecules; NO, nitric oxide; PDGF, platelet-derived grown factor; PF4, platelet factor 4; P-selectin glycoprotein ligand-1; RANTES, regulated on activation, normal T-cell expressed and secreted; TGF-␤, transforming growth factor-␤; TSP-1, thrombospondin-1; PSGL-1. Table 1 Inflammatory modulators expressed by platelets stream, by TFPI that locally inhibits TF/FVIIa activity, and by other natural coagulation inhibitors. This model of hemostasis (Fig. 7) is in line with the cell-based model of coagulation (25). One controversial issue is whether TF is present in platelets or TF circulates in blood in the form of cell-derived microparticles (2). Nevertheless, although platelets could not contain TF, they could generate thrombin through a TF-independent mechanism (25). Lesion Adhesion Platelet Aggregation TXA 2 Arachidonic Acid ADP Flip-Flop THROMBIN phosphatidilserine Platelet Activation Collagen von Willeb. others Endothelium/Platelets interaction Intrinsic pathway (Amplification) Tissue Factor Factor VII Factor VIIa Figure 7 Platelet participation in normal hemostasis. The hemostatic plug is the specific response to external vessel lesion and depends on the extent of vessel wall damage, the specific interaction between endothelial cells and activated platelets, release of the contents of platelets intracellular granules in response to activation, the conjoint activity of activated factor VII and platelet agonists, and the “open conditions” of blood flow. After activation, platelets also produce the externalization of membrane phosphatidylserine through the flip-flop mechanism that will support the function of the prothrombinase complex ending in thrombin generation and local clot formation. 1180 Chap02 3/14/07 11:22 AM Page 36 Based on the differences between hemostasis and throm- bosis mechanisms, which, even though similar, are developing through different routes, the practical point related to antithrombotic therapies is that increased concentrations of antithrombotic drugs will affect thrombosis as well as hemo- stasis but, as the latter is a weaker process than the former, any important increase in anticoagulant potential will produce a bleeding tendency before stopping thrombosis (26). Whether inhibition of TF will prevent acute arterial disease-associated thrombosis, where a lower possibility of bleeding can be expected, is a point that deserves to be investigated. Platelet’s contribution to inflammation and atherosclerosis Arterial disease and blood clotting are associated with platelet activation that can occur from one or more different stimuli. Patients with acute coronary syndromes have increased interactions between platelets and leukocytes (heterotypic aggregates) that contribute to atherothrombosis (13). It is now widely accepted that atherosclerosis is a chronic inflammatory arterial disease associated with risk factors, platelet, and other blood cells activities and their interactions with subendothelial cells. Activated platelets release active components from citosol and induce the externalization of phosphatidylserine through the flip-flop mechanism (23) that supports the function of the prothrombinase complex ending in thrombin generation. Platelets are considered as the key factors in arterial throm- bosis; recent studies indicate that they have an important regulatory role as the source of inflammatory mediators and directly initiate (Fig. 8) an inflammatory response of the vessel wall. Platelet and leukocyte recruitment on subendothelial cells is the early mechanism of vascular inflammatory damage. After vascular injury denudation of the endothelium and platelet adhesion, other blood cells are recruited: erythro- cytes release ADP and leukocyte infiltration occurs by their interaction with adhered platelets and fibrin. Additionally, leukocyte binding to platelets allows the recruitment of leuko- cytes and monocytes and constitutes a bridge between inflammation, thrombosis, and atherosclerosis. There are multicellular interactions that are important in inflammatory processes and in vascular remodeling. Activated platelets induce endothelial cells to secrete chemokines and to express adhesion molecules, indicating that platelets could initiate an inflammatory (Table 1) response of the vessel wall. Activated platelets promote leukocyte binding to inflamed or atherosclerotic lesions (27,28). Cell adhesion molecules (CAMs) are responsible for leukocyte–endothelium interac- tions. It plays a crucial role in inflammation and atherogenesis. Vascular CAM-1 (VCAM-1) and intracellular CAM-1 (ICAM- 1) promote monocyte recruitment to sites of injury and constitute a critical step in inflammation and in atherosclerotic plaque development. TSP-1, a matricellular protein released in abundance from activated platelets and accumulated in sites of vascular injury, induces the expression of VCAM-1 and ICAM-1 on endothelium and significantly increases the monocyte attachment (29). Leukocyte–platelet interaction is mediated in part by the ␤2-integrin Mac-1 (CD11b/CD18) and its counter-receptor on platelets; GPIb␣ is important in mediating leukocyte adhe- sion to a thrombus and leukocyte recruitment to a site of vascular injury (30). In this regard, recently described junc- tional adhesion molecules (JAMs) are members of an immunoglobulin subfamily expressed by leukocytes, platelets, and endothelial cells that regulate leukocyte/platelet/endothe- lial cell interactions in the immune system (31). Among these, JAM-1 is a platelet receptor involved in platelet adhesion and antibody-induced platelet aggregation and JAM-3, also called JAM-C, was described as a counter-receptor on platelets for the leukocyte ␤2-integrin Mac-1, which mediates leuko- cyte–platelet interactions and neutrophil transmigration and promotes inflammatory vascular responses (32). Platelet-derived chemokines CCL5 [regulated on activation, normal T-cell expressed and secreted (RANTES)] and CXCL4 (PF4) influence macrophages adhesion to endothelial cell by triggering monocyte arrest in atherosclerotic arteries. RANTES was the most efficient arrest chemokine (33). PF4 induced neutrophil adhesion and secondary granule exocytosis. Platelet’s contribution to inflammation and atherosclerosis 37 RISK FACTORS Circulating Non-activated Platelets INFLAMMATION Endothelial Cells ACTIVATED PLATELET Flip-flop mechanism Release of citosol components Interacts with leukocytes Source of inflammatory modulator Nitric oxide Platelet factor 4 CD 40 ligand PDGF RANTES Thrombospondin TGF-β, others Figure 8 Disrupted endothelium initiates hemostatic or thrombotic process with platelet adhesion, activation, and aggregation. Activated platelets release active components from citosol, induce the externalization of phosphatidylserine through the flip-flop mechanism, have a regulatory role as the source of inflammatory mediators, and interact with circulating white cells. Abbreviations : PDGF, plated derived growth factor; RANTES, regulated on activation, normal T-cell expressed and secreted; TGF-␤, transforming growth factor-␤. 1180 Chap02 3/14/07 11:22 AM Page 37 CD40 ligand (CD40L) is a cell-surface molecule that is expressed on activated T-cells and platelets. Platelet CD40L and its receptor CD40 are important in inflammation and contribute significantly to the recruitment of inflammatory cells to damaged endothelium in vivo (34). CD40L is a trimeric, transmembrane protein structurally related to the cytokine tumor necrosis factor-␣ present in lymphocytes, B-cells, monocytes, macrophages, and endothelial cells. Interaction of CD40L on T-cells with CD40 on B-cells is one of the determinants in the function of the humoral immune system and generates signals for the recruitment and extravasation of leukocytes at the site of injury. In patients with unstable coronary artery disease, elevation of soluble CD40L levels indicated an increased risk of cardiovascular events (35). Polymorphonuclear leukocyte adhesion to activated platelets is important for leukocyte recruitment at sites of damage and this is supported by P-selectin expressed on the surface of activated platelets to the leukocyte receptor, P- selectin GP ligand-1 (PSGL-1) (36). PSGL-1 mediates the rolling of leukocytes on the endothelial cells allowing the recruitment of leukocytes to the inflamed tissue, initiates intracellular signals during leukocytes activation, and upregu- lates the transcriptional activity of colony stimulating factor-1 (CSF-1) increasing the endogenous expression of CSF-1. Under shear flow conditions, there is a preferential recruit- ment of platelets by monocytes relative to neutrophils (37), an important point since the early development of lesions follows the invasion of the intima by monocytes, with transformation of monocyte-derived macrophages into foam cells when oxidized low-density lipoproteins are taken by monocytes contributing to the formation of atherosclerotic lesions. Macrophages release proteolytic enzymes called metallopro- teinases, a group of zinc-dependent endopeptidases, which break down collagen in the fibrous cap, inducing its rupture and the release of TF into the blood near to atheroma. TF, expressed by macrophage-derived foam cells within athero- sclerotic plaques and TF activity related substances, will enhance thrombin generation inducing thrombosis. Local thrombin generation not only results in a mixed fibrin/platelets clot but thrombin itself has pro-inflammatory activity and high- lights the interaction between inflammation, thrombosis, and atherosclerosis. Thrombin also activates platelets and other cells via cleav- age of PARs, specifically by PAR-1 and PAR-4, expressed, besides platelets, by other cells including endothelial cells and smooth-muscle cells (38). Within each of these cells, PAR signaling can impact the initiation, progression, and complica- tions of atherosclerosis. Other inflammatory mediators, activated macrophages, T-lymphocytes, and mast cells also attach themselves to the endothelium and lead to the release of additional mediators, (adhesion molecules, cytokines, chemokines, growth factors), with important roles in atherogenesis. Also platelet’s P-selectin induces TF and cytokine expression from monocytes (39). Lastly, eicosanoids are important pro-inflammatory media- tors derived from membrane metabolism. PLA 2 plays a key role in the production of eicosanoids, derived from arachi- donic acid of the phospholipids contained in the cell membrane (40,41). As mentioned earlier, arachidonic acid is liberated from the membrane-bound phospholipids by several forms of PLA 2 and is the substrate for COX-1, COX-2, and 12-lipoxygenases (LOX) involved in vascular inflammation. Besides 12-LOX in platelets, the 5-LOX isoforms are constitutive in neutrophils. Evidences indicate that LOXs are involved in inflammation diseases and in atherosclerosis. 5- LOX is the enzyme that catalyzes the formation of leukotrienes with potential role for leukocytes and platelets interaction and inflammation. After platelet and leukocyte stimulation, products of both COX-1 and 5-LOX pathways increase. COX-1 activity derivatives increase the vascular permeability mediated by prostaglandins and produce platelet aggregation mediated by TXA 2 . The product of the lipoxyge- nase pathway, 5-oxo-6,8,11,14-eicosatetraenoic acid (5-Oxo-ETE), induces leukocyte chemotaxis and inflamma- tion. 5-Oxo-ETE is formed by the oxidation of 5S-hydroxy-ETE (5-HETE) by 5-hydroxyeicosanoid dehy- drogenase (5-HEDH), a microsomal enzyme found in leukocytes and platelets (42). Leukotrienes increase vascular permeability, wall recruit- ment of leukocytes, endothelial-cell dysfunction, proliferation of smooth-muscle cells, immune reactivity and mediated vascular inflammation, and atherosclerosis (43). COX-2 are mainly involved in PGI 2 formation and in the inflammatory process. COX-2 is inducible, for example, by pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and the control of cell growth. It promotes early atherosclerotic lesion formation in LDL receptor-deficient mice in vivo, and COX-2 is the enzyme responsible for most of the metabolism of arachi- donic acid in the macrophage. In conclusion, we have described how platelets initiate and participate in the hemostatic and thrombotic processes, as well as many of the multiple interactions of platelet with endothelial cells and with other blood cells, and their role in inflammation and atherosclerosis. From a practical point of view, these liaisons indicate that platelet inhibition could prevent thrombosis as well as inflammation and atheroscle- rosis. These potential properties have resulted in antiplatelets drugs being most commonly used as remedies for the prevention of acute arterial syndromes (Table 2). Although the main and most investigated activity of platelet inhibitors (aspirin, thienopyridines family, and GPIIb/IIIa inhibitors) is their capacity to affect platelet aggregation, they really are drugs with pluripotential effects that could contribute to their antithrombotic activities (44,45). On the way are antiplatelet combinations and new therapies for preventing platelet adhesion and activation (Table 2). Other target has been also used for acute throm- botic prevention. Selective COX-2 inhibitors are effective 38 Principles of antiplatelet therapy 1180 Chap02 3/14/07 11:22 AM Page 38 anti-inflammatory agents and even if some of them appear to prevent coronary events (46), others increase the cardiovas- cular risk because of their inhibitory effect on endothelial PGI 2 synthesis without affecting TXA 2 -dependent platelet function, although mechanisms unrelated to thromboxane production cannot be discarded (47). Additional trials and new combin- ing strategies will be required to assess the effects of selective COX-2 inhibitors (48). The ongoing chapters deal with these important issues. References 1 Gordon JL, Milner AJ. Blood platelets as multifunctional cells. In: Gordon JL, ed. Platelets in Biology and Pathology, ch. 1. New York: Elsevier/ North-Holland Biomedical Press, 1976:3–22. 2 Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol 2004; 24:1015–1022. 3 Ramasamy I. Inherited bleeding disorders: disorders of platelet adhesion and aggregation. Crit rev Oncol Hematol 2004; 49: 1–35. 4 Zwaal R, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cell. Blood 1997; 89:1121–1132. 5 Jurk K, Kehrel, B. Reliability of platelet function tests and drug monitoring platelets: physiology and biochemistry. Semin Thromb Hemost 2005; 31:381–392. 6 Kuijpers MJ, Schulte V, Oury C, et al. Facilitating roles of murine platelet glycoprotein Ib and alphaIIb beta3 in phosphatidylserine exposure during vWF-collagen-induced thrombus formation. J Physiol 2004; 558:403–415. 7 Nieswandt B,Watson S. Platelet–collagen interaction: is GPVI the central receptor? Blood 2003; 102:449–461. 8 Schmitz G, Rothe G, Ruf A, et al. European Working Group on clinical cell analysis: consensus protocol for the flow cyometric characterisation of platelet function. Thromb Haemost 1998; 79:885–896. 9 Shattil S, Newman P. Integrins: dynamic scaffolds for adhesion and signalling in platelets. Blood 2004; 104:1606–1615. 10 Lahav J, Jurk K, Hess O, et al. Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange. Blood 2002; 100:2472–2478. 11 Furie B, Furie BC, Flaumenhaft R. A journey with platelet Pselectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost 2001; 86:214–221. References 39 Drugs Main activity Aspirin and other nonsteroidal anti-inflammatory drugs Dose-related blockade of COX-1 and COX-2. Inhibit platelets PGG 2 , PGH 2 , and TXA 2 and endothelial PGI 2 formation TXA 2 synthase inhibitors and receptor antagonist Inhibit TXA 2 formation and blocks platelet TXA 2 effects (BM 573, picotamide, terbogrel) Thienopyridines (ticlopidina, clopidogrel, Inhibit platelet activation by preventing binding of ADP with it prasugrel, cangrelor, AZD6140) receptors, mainly P2Y 12 Inhibitors of phosphodiesterase (dipyridamole, cilostazol) Increase platelet cAMP-inhibiting platelet aggregation. prasugrel, cangrelor, AZD6140) Dipyridamole also prevents the uptake of adenosine Inhibitor of platelet vWF receptors Inhibits the link of vWF with their platelet receptor GPIb inhibiting platelet adhesion Blockade of fibrinogen ␥ -chain Inhibits fibrinogen link to their platelets receptors Blockers/inhibitors of platelets receptors GP IIb/IIIa Prevent the link of fibrinogen with platelet receptors inhibiting (integrin ␣IIb␤3) (abciximab, tirofiban, eptifibatide) platelet aggregation in front of different agonists PAR antagonist Inhibits thrombin. Potent potential effect for inhibiting platelet aggregation Collagen-GPVI inhibitors Inhibit platelet adhesion to subendothelium PGI 2 analog/mimetic (epoprostenol, FR181157) Sildenafil Inhibits platelet aggregation Inhibits type-5 phosphodiesterase and reduces platelet activation Note : Several of the described drugs are still under development (currently in phase 2 or phase 3 trial) and not yet available in the pharmaceutical market for human use. Others, such as sildenafil, reduce platelets activity but, to our knowledge, no specific trial is under way. Although not included in the table, also direct thrombin inhibitor (melagatran, dabigatran) in high dose prolongs bleeding time, indicating that by effect of a strong inhibition of thrombin activity, probably at concentrations exceeding the dose that inhibited thrombosis, relationships between platelet and endothelial cells could be modified toward an hemorrhage tendency. Abbreviations : ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; GP, glycoprotein; PAR, protease activated receptor; PGG 2 , prostaglandin G 2 ; PGH 2 , prostaglandin H 2 ; PGI 2 , prostacyclin; TXA2, thromboxane A 2 ; vWF, von Willebrand factor. Table 2 Effects of different molecules on platelet function used to reduce the risk of thrombosis 1180 Chap02 3/14/07 11:22 AM Page 39 12 Andre P, Prasad KS, Denis CV, et al. CD40L stabilizes arterial thrombi by a beta 3 integrin-dependent mechanism. Nat Med 2002; 8:247–252. 13 Freedman J. Molecular regulation of platelet dependent throm- bosis. Circulation 2005; 112:2725–2734. 14 Brass LF. Thrombin and platelet activation. Chest 2003; 124:18s–25s. 15 Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low- dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353:2373–2383. 16 Geiger J, Brich J, Höning-Liedl M, et al. Specific impairment of human platelet P2Y AC ADP receptor-mediated signalling by the antiplatelet drug Clopidogrel. Arterioscler Thromb Vasc Biol 1999; 19:2007–2011. 17 Minami T, Sugiyama A,Wu SQ, et al. Thrombin and phenotypic modulation of the endothelium. Arterioscler Thromb Vasc Biol 2004; 24:41–53. 18 Ishihara H, Connolly AJ, Zeng D, et al. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997; 386:502–506. 19 Luque A, Carpizo DR, Iruela-Arispe ML. ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and seques- tration of VEGF 165. J Biol Chem 2003; 278: 23656–23665. 20 Coughlin SR. Thrombin signalling and protease-activated recep- tors. Nature 2000; 407:258–264. 21 Dale GL, Friese P, Batar P, et al. Stimulated platelets use sero- tonin to enhance their retention of procoagulant proteins on the cell surface. Nature 2002; 415:175–179. 22 Altman R, Scazziota A, Rouvier J, Gonzalez C. Effect of sodium arachidonate on thrombin generation through platelet activation—inhibitory effect of aspirin. Thromb Haemost 2000; 84:1109–1112. 23 Lentz BR. Exposure of platelet membrane phosphatidylserine regulates blood coagulation. Prog Lipid Res 2003; 42:423–438. 24 Hemker HC, Béguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995; 74:134–138. 25 Monroe DM, Hoffman M, Oliver JA, Roberts HR. A possible mechanism of action of activated factor VII independent of tissue factor. Blood Coagul Fibrinolysis 1998; 9(suppl 1):S15–S20. 26 Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST- segment elevation acute coronary syndromes. JAMA 2005; 294:3108–3116. 27 Rainger GE, Buckley C, Simmons DL, Nash GB. Neutrophils rolling on immobilised platelets migrate into homotypic aggre- gates after activation. Thromb Haemost 1998; 79:1177–1183. 28 Eriksson EE. Mechanisms of leukocyte recruitment to athero- sclerotic lesions: future prospects. Curr Opin Lipidol 2004; 15:553–558. 29 Narizhneva NV, Razorenova OV, Podrez EA, et al. Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium. FASEB J 2005; 19:1158–1160. 30 Chavakis T, Santoso S, Clemetson KJ, et al. High molecular weight kininogen regulates platelet-leukocyte interactions by bridging Mac-1 and glycoprotein Ib. J Biol Chem 2003; 278:45375–45381. 31 Naik UP, Eckfeld K. Junctional adhesion molecule 1 (JAM-1). J Biol Regul Homeost Agents 2003; 17:341–347. 32 Chavakis T, Keiper T, Matz-Westphal R, et al. The junctional adhesion molecule-C promotes neutrophil transendothelia l migration in vitro and in vivo. J Biol Chem 2004; 279:55602–55608. 33 Baltus T, von Hundelshausen P, Mause SF, Buhre W, Rossaint R, Weber C. Differential and additive effects of platelet-derived chemokines on monocyte arrest on inflamed endothelium under flow conditions. J Leukoc Biol 2005; 78:435–441. 34 Buchner K, Henn V, Grafe M, de Boer OJ, Becker AE, Kroczek RA. CD40 ligand is selectively expressed on CD4+ T cells and platelets: implications for CD40-CD40L signalling in atheroscle- rosis. J Pathol 2003; 201:288–295. 35 Heeschen C, Dimmeler S, Hamm CW, et al. CAPTURE Study Investigators. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348:1104–1111. 36 Ba XQ, Chen CX, Xu T, Cui LL, Gao YG, Zeng XL. Engagement of PSGL-1 upregulates CSF-1 transcription via a mechanism that may involve Syk. Cell Immunol 2005; 237:1–6 37 Ahn KC, Jun AJ, Pawar P, et al. Preferential binding of platelets to monocytes over neutrophils under flow. Biochem Biophys Res Commun 2005; 329:345–355. 38 Coughlin R, Camerer E. Participation in inflammation. J Clin Invest 2003; 111:25–27. 39 Celi A, Pellegrini G, Lorenzet R, et al. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A 1994; 91:8767–8771. 40 DwyerJ H, Allayee H, Dwyer KM, et al. Arachidonate 5-lipoxy- genase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 2004; 350:29–37. 41 Coffey MJ, Jarvis GE, Gibbins JM, et al. Platelet 12-lipoxygenase activation via glycoprotein VI. Involvement of multiple signaling pathways in agonist control of H(P)ETE synthesis. Circ Res 2004; 94:1598–1605. 42 Powell WS, Rokach J. Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE. Prog Lipid Res 2005; 44:154–183. 43 Lotzer K, Spanbroek R, Hildner M, et al. Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis. Arterioscler Thromb Vasc Biol 2003; 23:E32–E36. 44 Judge HM, Buckland RJ, Holgate CE, Storey RF. Glycoprotein IIb/IIIa and P2Y12 receptor antagonists yield additive inhibition of platelet aggregation, granule secretion, soluble CD40L release and procoagulant responses. Platelets 2005; 16: 398–407. 45 Altman R, Luciardi HL, Muntaner J, Herrera RN. The antithrombotic profile of aspirin. Aspirin resistance, or simply fail- ure? Thromb J 2004; 2:1. 46 Altman R, Luciardi HL, Muntaner J, et al. Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study. Circulation 2002; 106: 191–195. 47 Jones SC. Relative thromboembolic risks associated with COX- 2 inhibitors. Ann Pharmacother 2005; 39:1249–1259. 48 Grosser T, Fries S, Fitzgerald AG. Biological basis for the cardio- vascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006; 116:4–15. 40 Principles of antiplatelet therapy 1180 Chap02 3/14/07 11:22 AM Page 40 Platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor inhibitors are widely used to prevent thrombotic vascular events, especially in patients with acute coronary syndromes (ACS) or in those undergoing intravascular interventional procedures. The purpose of this chapter is to evaluate the quality and magni- tude of the clinical trial evidence in support of their use. In addition, key issues regarding their optimal application in clinical practice will be discussed. Platelet physiology and the rationale for glycoprotein IIb/IIIa inhibitors GPIIb/IIIa receptor is a major platelet integrin that plays a central role in platelet aggregation (1,2). It is uniquely and abundantly expressed on the platelet surface (~50,000–80,000 copies) with an additional internal pool in ␣ -granules that can be rapidly mobilized to the platelet surface upon activation (1,2). Although GPIIb/IIIa has no ligand- binding activity in unstimulated platelets, it undergoes a confor- mational change upon platelet activation allowing it to bind to its ligands, fibrinogen and von Willebrand factor. Both ligands have multiple binding sites for activated GPIIb/IIIa and thereby induce platelet aggregation by cross- linking adjacent platelets (1,2). Activation of this integrin is considered the “common final pathway” since all the signal- ing pathways utilize this molecule at the last step toward aggregation (1,2) (Fig. 1). Several experimental observations provide the rationale for blockade of GPIIb/IIIa receptors as a desirable therapeutic strategy in ischemic cardiovascular disease (3): (i) platelet thrombus formation is the key initiating factor in occlusive vascular disease; (ii) the GPIIb/IIIa receptor is a key element in the final common pathway leading to platelet aggregation and consequently platelet thrombus formation; (iii) the GPIIb/IIIa receptor is platelet specific; and (iv) inhibition of the GPIIb/IIIa receptor inhibits platelet aggregation without inter- fering in platelet adhesion, thereby reducing the risk of occurrence of serious bleeding. Pharmacology of glycoprotein IIb/IIIa inhibitors Three intravenous GPIIb/IIIa inhibitors are currently available for clinical use: abciximab, tirofiban, and eptifibatide (4–7). Their mechanisms of action, important differences in phar- macology as well as approved indications and dosing regimens are listed in Table 1. Abciximab is the Fab fragment of a chimeric human–mouse monoclonal antibody directed against the human GPIIb/IIIa receptor. It is a nonspecific blocker exhibiting cross-reactivities with vitronectin and the leukocyte integrin Mac-1, with a tight receptor binding and slow (~48 hours) reversibility of platelet inhibition after cessation of treatment (4,5). The pharmaco- dynamic and clinical significance of the cross-reactivities is, however, not entirely clear. Tirofiban is a tyrosine derivative, nonpeptide mimetic of the RGD (Arg-Gly-Asp) recognition sequence (4,5). Eptifibatide is a cyclic heptapeptide based on the KGD (Lys-Gly-Asp) sequence of the snake venom barbourin, a natural disintegrin (4,5). Both eptifibatide and tirofiban are highly selective inhibitors of the GPIIb/IIIa receptor with rapid onset of action, short half-lives, and 3 Glycoprotein IIb/IIIa inhibitors Sanjay Kaul 1180 Chap03 3/14/07 11:22 AM Page 41 recovery of platelet function within two to four hours after cessation of treatment (4,5). Target receptor blockade of Ͼ80% is required for a pharmacodynamic effect of these inhibitors (4,5). Clinical evaluation of glycoprotein IIb/IIIa inhibitors These agents have been tested in various conditions where platelet activation plays a major role, in particular in patients undergoing percutaneous coronary intervention (PCI), patients admitted with ACS, and patients receiving throm- bolytic therapy for acute myocardial infarction (MI) (Fig. 2). Glycoprotein IIb/IIIa inhibitors and percutaneous coronary intervention Several large placebo-controlled randomized trials have evalu- ated adjunctive therapy with GPIIb/IIIa inhibitors in a broad cross-section of patients undergoing PCI (8–16): two trials focused on high-risk [acute MI, unstable angina (UA)] PCI [EPIC (8), RESTORE (9)], one selected refractory UA patients (CAPTURE) (10), five trials enrolled patients undergoing elec- tive or urgent PCI with a wide array of interventional devices such as angioplasty, atherectomy, or stenting [EPILOG (11), Initiation Management Predischarge Process for Assessment of Carvedilol Therapy (IMPACT)-II (12), EPISTENT (13), ESPRIT (14), ISAR-REACT (15)], and one trial concentrated on early PCI in patients with ACS (ISAR-REACT 2) (16). Aside from CAPTURE where the study drug was administered for 18 to 24 hours prior to PCI and one hour thereafter, the study drug was administered as a bolus immediately before coronary intervention, followed by infusions at 12 hours (abciximab) and 18 to 36 hours (eptifibatide or tirofiban). The primary outcome measure in these trials was a composite endpoint (typically death, nonfatal MI, or target vessel reintervention) with major bleeding as secondary safety endpoint. Follow-up ranged from 48 hours (ESPRIT) to 30 days in the rest. The primary results reported for these trials are summarized in Table 2. Reductions in ischemic endpoints were observed in all trials except ISAR-REACT (15) with beneficial effects ranging from a minimum of 13% risk reduction in IMPACT II (12) to a maximum of 54% risk reduction in EPILOG (11). Post hoc analyses suggest a treatment effect by subgroup (observed in high-risk patients such as those with cardiac biomarker eleva- tion, ST depression on electrocardiogram angiographically complex lesion or visible thrombus, diabetes, or history of prior antiplatelet treatment), time to treatment (greater bene- fit in patients treated earlier), and by endpoint (soft endpoints of periprocedural biomarker elevation and urgent reinterven- tion being reduced to a much greater degree compared to hard endpoints of Q-wave MI or death) (6,8–16). The lack of treatment benefit observed in RESTORE and IMPACT II have been attributed to suboptimal doses of study drug (6,9,12). However, had the RESTORE investigators used urgent, instead of any, target vessel revascularization (TVR) (consis- tent with the endpoint used in abciximab trials), a nearly statistically significant treatment effect would have been observed in favor of tirofiban [24% relative risk reduction (RRR), P ϭ 0.052] (6,9). This finding underscores the impact of choice of endpoints on overall results. Bleeding complications were doubled with GPIIb/IIIa block- ade in early studies (8,10). However, the use of weight-adjusted low dose of heparin [activated clotting time (ACT) target of 200–250 seconds] and optimal management of vascular access site (rapid sheath removal within four to 42 Glycoprotein IIb/IIIa inhibitors EPIC EPILOG IMPACT-II CAPTURE RESTORE PRISM PRISM-PLUS PARAGON A & B PURSUIT GUSTO-IV ACS USAP Non ST Elev. MI PTCA ST Elev. MI STENT + Fibrinolysis + Primary PCI + Facilitated PCI PARADIGM IMPACT-AMI TAMI-8 TIMI-14 SPEED IN TRO-AMI SK-Eptifibatide IN TEGRITI ENTIRE-TIMI 23 GUSTO-V ASSENT-III EPIC RESTORE RAPPORT ISAR II STOP AMI ADMIRAL CADILLAC ACE TIGER-PA On-TIME BRAVE FINESSE Coronary Heart Disease EPISTENT ERASER ESPRIT TARGET TACTICS-TIMI-18 ISAR-REACT ISAR-REACT 2 Figure 2 Randomized clinical trials evaluating glycoprotein IIb/IIIa inhibitors in different clinical settings. Epinephrine ADP Shear stress Collagen Thrombin • Heparin • LMWH • Hirudin • Aspirin • Thromboxane synthetase inhibitors • Thromboxane receptor antagonists Cyclooxygenase Arachadonic Acid TxA 2 PGI 2 GPIIb/IIIa antagonists Platelet Aggregation PGG 2 • Ticlopidine • Clopidogrel (P 2Y12 receptor) GPIIb/IIIa Receptor Figure 1 Platelet activation cascade in response to different agonists and the site of action of different antiplatelet agents. 1180 Chap03 3/14/07 11:22 AM Page 42 six hours) in the latter studies (11,13,14) were crucial in substantially reducing the bleeding complications. In general, treatment with GPIIb/IIIa inhibitors increases the rate of major bleeding by 1%, thrombocytopenia (Ͻ100,000/mm 3 ) by 1%, and profound thrombocytopenia (Ͻ50,000/mm 3 ) by 0.4% (6). Intracerebral hemorrhage is an uncommon complication of GPIIb/IIIa inhibitors occurring in Ͻ0.2% of patients (6). Glycoprotein IIb/IIIa inhibitors in unstable angina and non-ST elevation myocardial infarction Systematic use of GPIIb/IIIa inhibitors in addition to standard treatment with aspirin and unfractionated heparin has been studied in six large randomized trials in patients with ACS of UA and non-ST elevation MI (NSTEMI) who were managed predominantly with medical management: two with tirofiban [PRISM (17), PRISM-PLUS (18)], one with eptifibatide (PURSUIT) (19), two with lamifiban [PARAGON-A (20), PARAGON-B (21)], and one with abciximab (GUSTO-IV ACS) (22). Table 3 summarizes the primary results of these trials. Overall the use of GPIIb/IIIa inhibitors was associated with a modest, but significant reduction in the primary endpoint in PRISM, PRISM-PLUS, and PURSUIT. Treatment benefit was confined to early time points in PRISM (48 hours) and PRISM- PLUS (seven days), but not sustained at 30 days (17,18). In contrast, treatment with eptifibatide reduced the incidence of composite endpoint by 1.5% absolute risk difference (ARD) in PURSUIT which was observed within four days and main- tained for 30 days without attenuation or amplification (19). Clinical evaluation of glycoprotein IIb/IIIa inhibitors 43 Abciximab (ReoPro) Tirofiban (aggrastat) Eptifibatide (integrilin) Structure Antibody Fab fragment Nonpeptide mimetic Cyclic heptapeptide Molecular weight 47.6 kDa 0.495 kDa 0.832 kDa Receptor specificity Nonspecific (GPIIb/IIIa, Specific for GPIIb/IIIa Specific for GPIIb/IIIa Vitronectin, Mac-1) Receptor binding Long acting, high affinity Short acting, low affinity Short acting, low affinity Mechanism of Irreversible; steric hindrance Reversible; competitive Reversible; competitive inhibition receptor inhibition and conformational change inhibition (RGD recognition (KGD recognition sequence) sequence) Plasma half-life 10–30 min ~2 hr ~2.5 hr Platelet function Slow (~48 hr) Fast (2–4 hr) Fast (2–4 hr) recovery Elimination route Senescent platelets (RES) Renal (70%) Ͼ Renal (50%) hepatic (30%) FDA-approved Adjunct to PCI; early Medical management Adjunct to PCI; medical indication (Ͻ24 hr) PCI in ACS of ACS management of ACS FDA-approved dose PCI: 0.25 mg/kg IV bolus ACS: 0.4 mcg/kg/min PCI: 180 mcg/kg IV bolus pre-PCI 0.125 mcg/kg/min IV infusion ϫ 30 min; pre-PCI 2.0 mcg/kg/min IV (max. 10mcg/min) IV 0.1mcg/kg/min ϫ 48–108 hr infusion Second 180 mcg/kg infusion x 12 hr post-PCI bolus after 10 min. Infusion ACS with planned PCI: continues until hospital discharge 0.25 mg/kg IV bolus or for 18–24 hr post PCI 10 mcg/min IV infusion ϫ (whichever comes first) ACS: 18–24 hr pre-PCI and ϫ 180 mcg/kg IV bolus 1 hr post-PCI* 2 mcg/kg/min (max 15 mg/hr) ϫ 72—96 hr Dosage adjustment NA CrCl Ͻ30 mL/min: decrease SCr Ͼ2.0mg/dL: decrease bolus rate and infusion rate infusion to 1.0mcg/kg/min; by 50% SCr Ͼ4.0 mg/dL or requires hemodialysis (contraindicated) Abbreviations : ACS, acute coronary syndromes; GP, glycoprotein; PCI, percutaneous coronary intervention. Table 1 Comparison of platelet glycoprotein IIb/IIIa inhibitors 1180 Chap03 3/14/07 11:22 AM Page 43 44 Glycoprotein IIb/IIIa inhibitors Trial Clinical Number of PEP rate (%) Risk ratio (95% CI) Major bleeding (%) Risk ratio (95% CI) setting patients PEP Follow-up New Control New Control EPIC (8) Abciximab in 2099 Death, 30 day 8.3 12.8 0.68 (0.45–0.89) 14.0 7.0 2.12 (1.52–2.95) high-risk PCI MI, UR (11.2) RESTORE (9) Tirofiban in Death, MI, 30 day 10.3 12.2 0.85 (0.67–1.07) 5.3 3.7 1.42 (0.96–2.11) high-risk PCI 2139 any TVR CAPTURE (10) Abciximab in 1265 Death, 30 day 11.3 15.9 0.71 (0.53–0.94) 3.8 1.9 2.02 (1.02–4.00) PCI in UA MI, UR EPILOG (11) Abciximab in 2792 Death, 30 day 5.2 11.7 0.46 (0.33–0.964) 3.8 3.1 1.23 (0.76–2.00) elective or MI, UR urgent PCI IMPACT II (12) Eptifibatide in 4010 Death, 30 day 9.2, 11.4 0.81 (0.65–1.01) 5.1 4.8 1.13 (0.82–1.54) b elective or MI, UR 9.9 a 0.87 (0.70–1.09) a urgent PCI EPISTENT (13) Abciximab in 2399 Death, 30 day 5.3 10.8 0.49 (0.34–0.70) 2.1 1.4 1.57 (0.74–3.34) elective or MI, UR urgent PCI ESPRIT (14) Eptifibatide in 2064 D, MI, UR, 48 hr 6.6 10.5 0.63 (0.47–0.84) 1.3 0.4 3.2 (1.05–9.78) non-urgent PCI bailout GPI use ISAR-REACT (15) Abciximab inL 2159 D, MI, UR 30 day 4.2 4.0 1.05 (0.78–1.58) 1.1 0.7 1.50 (0.62–3.66) nonurgent PCI ISAR-REACT 2 (16) Abciximab in 2022 D, MI, UR 30 day 8.9 11.9 0.75 (0.58–0.97) 1.4 1.4 1.00 (0.50–2.08) high-risk PCI a High-dose lamifiban. b Based on red blood cell transfusion. Abbreviations: MI, myocardial infarction; PCI, percutaneous coronary intervention; PEP, primary endpoint; TVR, target vessel revascularization; UR, urgent reintervention. Table 2 Randomized clinical trials of platelet glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention 1180 Chap03 3/14/07 11:22 AM Page 44 Clinical evaluation of glycoprotein IIb/IIIa inhibitors 45 Trial GPI Number PEP Follow-up PEP Risk ratio Major Risk ratio of patients rate (%) (95% CI) bleeding (%) (95% CI) New Control New Control PRISM (17) Tirofiban 3232 Death, 48 hr 3.8 5.6 0.68 0.37 0.37 1.00 x 48 hr MI, RA 30 day 15.9 17.1 (0.48–0.93) (0.32–3.09) 0.93 (0.80–1.09) PRISM-PLUS Tirofiban 1915 Death, 7 day 12.9 17.9 0.72 4.0 3.0 1.33 (18) x Ͼ48 hr MI, RA 30 day (0.57–0.91) (0.79–2.25) 0.83 (0.68–1.01) PURSUIT Eptifibatide 10,948 Death, 30 day 14.2 15.7 0.91 9.0 10.5 1.16 (19) x Ͻ72 hr MI (0.83–1.00) (1.03–1.32) PARAGON Lamifiban 2282 Death, 30 day 10.6 11.7 0.90 3.0 3.0 1.00 A (20) low dose MI 12.0 (0.68–1.20) 6.0 (0.57–1.77) x 3–5 day 1.02 1.97 Lamifiban (0.78–1.34) (1.21–3.22) high dose x 3–5 day PARAGON Lamifiban 5225 Death, 30 day 11.8 12.8 0.92 1.3 0.9 1.46 B (21) x Ͻ72 hr MI, RA (0.80–1.07) 14.0 a 11.7 a (0.86–2.47) 1.20 (1.04–1.39) a GUSTO Abciximab 7800 Death, 30 day 9.1 8.0 1.02 0.6 0.3 2.29 IV-ACS (22) 24 hr MI 8.2 (0.85–1.22) 1.0 (0.94–5.56) Abciximab 1.13 3.69 48 hr (0.95–1.35) (1.61–8.50) a Coronary artery bypass graft-related bleeding. Abbreviations : GP, glycoprotein; MI, myocardial infarction; PEP, primary end-point; RA, refractory angina. Table 3 Randomized clinical trials of platelet glycoprotein IIb/IIIa inhibitors in medical management of unstable angina and NSTEMI The GUSTO IV-ACS trial demonstrated no clinical benefit with abciximab (Table 3). Paradoxically, a statistically significant increase in mortality was observed at the end of 48 hours abciximab infusion (0.9% vs. 0.3% placebo; P ϭ 0.006) (22). No subgroup benefited from abciximab; in fact, those with body weight Ͻ75 kg, low baseline troponin, or elevated baseline C-reactive protein (CRP) had excess mortality at one year with abciximab (23). The precise reasons for the nega- tive findings in GUSTO IV-ACS are not clear but may be related to: (i) enrollment of low-risk patients (only 30% patients had ST depression and troponin elevation), (ii) lack of power (due to low event rate of 8% instead of projected 11%); (iii) dosing and the degree of platelet inhibition (main- tenance dose based on 12-hour infusion derived from PCI studies may have been insufficient); (iv) lack of intervention— less than 2% underwent early revascularization; or (v) simply due to play of chance. Major bleeding was significantly increased in PURSUIT [it reported coronary artery bypass graft (CABG)-related bleeding], both PARAGON trials, and in the 48-hour-infusion arm of GUSTO-IV ACS trial. A meta-analysis from Boersma et al. (24) showed an over- all modest 1% ARD treatment effect of GPIIb/IIIa inhibitors on death and MI (Table 4). The treatment was particularly robust in 19% of patients undergoing intervention (PCI or CABG) within five days (3% ARD, RRR 0.79; 95% confi- dence interval: 0.68–0.91) and those with troponin elevations [risk reduction of 0.84 (0.70–1.30) vs. 1.17 (0.94–1.44) in troponin-negative patients]. However, the interaction of GPIIb/IIIa inhibitors with troponin elevation or revascularization was not tested in a randomized fashion (except in GUSTO-IV ACS), thereby weakening the clinical implication of these findings. 1180 Chap03 3/14/07 11:22 AM Page 45 [...]... 25 990) (Plavix® Sanofi-Aventis) is the hydrogen sulfate salt of the S enanthiomer of methyl 2- ( 2chlorophenyl ) -2 -[ 4,5,6,7-tetrahydrothieno(3,4-c)pyridine5-yl] acetate Its molecular formula is C16H16CINO2S, H2SO4 (molecular weight of 419.9) (Fig 2) 3 Prasugrel (CS-747, LY 640315)(Eli Lilly) is a thienopyridine under development that antagonizes the P2Y 12 1180 Chap04 3/14/07 60 11 :23 AM Page 60 Adenosine... ϭ 20 ,137 0.65 (0.59–0. 72) NNT ϭ 28 (22 –36) NA 0.69 (0.53–0.90) NNT ϭ 322 (175 20 00) 0.63 (0.56–0.70) NNT ϭ 43 (34–60) NA 1 .26 (1.09–1.46) NNH ϭ 76 (54– 127 ) ACS (24 ); N ϭ 6 trials, N ϭ 31,4 02 0.98 (0.93–1. 02) NNT ϭ 65 (38 23 3) 0.91 (0.85–0.99) NNT ϭ 99 (58–341) 0.91 (0.81–1.03) NNT ϭ 396 (14 9- ) 0.90 (0.83–0.98) NNT ϭ 133 (74–658) 0.99 (0.94–1.03) NNT ϭ70 (40 28 9) 1. 62 (1.36–1.97) NNH ϭ 87 (68– 122 )... to 24 hours after abciximab treatment), as well as the subgroup of 3/14/07 11 :22 AM Page 47 Clinical evaluation of glycoprotein IIb/IIIa inhibitors (A) 10 n = 2, 754 p = 0.001 n = 12, 296 p = 0.001 8 6 n = 2, 736 p = 0.474 8% Rx benefit 3.1% PCI Hazard 3.7% Placebo IIb/IIIa blocker 4.9% 4 4.3% 2 2.9% 1.6% 1.3% 0 1 2 3 1 2 7 14 21 Days PCI (B) EPISTENT ESPRIT 20 % 20 % Death or MI 15% 10% 10 .2% 4.7% 4 .2% ... 11:180–198 Seyfarth HJ, Koksch M, Roethig G, et al Effect of 30 0- and 450-mg clopidogrel loading doses on membrane and soluble 1180 Chap04 3/14/07 11 :23 AM Page 67 References 14 15 16 17 18 19 20 21 22 23 24 25 26 27 P-selectin in patients undergoing coronary stent implantation Am Heart J 20 02; 143:118– 123 Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schomig A Loading with 600 mg... Lupker J, Herbert JM , , P2y( 12) , a new platelet ADP receptor, target of clopidogrel Biochem Biophys Res Commun 20 01; 28 3:379–383 Caplain H, Donat F, Gaud C, Necciari J Pharmacokinetics of clopidogrel Semin Thromb Hemost 1999; 25 (suppl 2) : 25 28 Lins R, Broekhuysen J, Necciari J, Deroubaix X Pharmacokinetic profile of 14C-labeled clopidogrel Semin Thromb Hemost 1999; 25 (suppl 2) :29 –33 Gachet C, Cazenave... 1180 Chap03 3/14/07 56 24 25 26 27 28 29 30 31 32 33 34 35 36 11 :22 AM Page 56 Glycoprotein IIb/IIIa inhibitors unstable angina One-year survival in the GUSTO-IV ACS Trial Circulation 20 03; 107:437 Boersma E, Harrington R, Moliterno D, et al Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials Lancet 20 02; 359:189–198 Chew DP... intervention: results of the Joint Utilization of Medications to Block Platelets Optimally ( JUMBO)-TIMI 26 trial Circulation 20 05; 111:3366–3373 28 29 30 31 32 33 34 35 36 37 38 39 40 41 67 Sabatine MS, McCabe CH, Gibson CM, Cannon CP Design and rationale of Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITYTIMI) 28 trial Am Heart J 20 05; 149 :22 7 23 3 Sabatine MS,... JAMA 20 04; 29 2:55–64 SYNERGY Trial Investigators Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the synergy randomized trial JAMA 20 04; 29 2:45–54 Steinhubl SR, Talley JD, Braden GA, et al Point -of- care measured platelet inhibition correlates with a reduced risk of an... Structure of adenosine diphosphate receptor inhibitors There are several drugs, but only the first two in the following list are available on the market 1 Ticlopidine (Ticlid® Sanofi-Aventis) which is the Chloro -2 Benzyl-5 Tetrahydro-4,5,6,7 Thieno[3 , 2- C]Pyridine Chlorhydrate Ticlopidine differs from clopidogrel by the presence of a radical H instead of CO2CH3 in the molecule 2 Clopidogrel (SR 25 990)... of eptifibatide on complications of percutaneous coronary intervention: the IMPACT-II Lancet 1997; 349:1 422 –1 428 The EPISTENT Investigators Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade Lancet 1998; 3 52: 87– 92 The ESPRIT Investigators Novel dosing regimen of eptifibatide in planned coronary . product of the lipoxyge- nase pathway, 5-oxo-6,8,11,14-eicosatetraenoic acid (5-Oxo-ETE), induces leukocyte chemotaxis and inflamma- tion. 5-Oxo-ETE is formed by the oxidation of 5S-hydroxy-ETE (5-HETE). arterial thrombi by a beta 3 integrin-dependent mechanism. Nat Med 20 02; 8 :24 7 25 2. 13 Freedman J. Molecular regulation of platelet dependent throm- bosis. Circulation 20 05; 1 12: 2 725 27 34. 14 Brass LF. Thrombin. monophosphate; COX-1, cyclooxygenase-1; COX -2 , cyclooxygenase -2 ; GP, glycoprotein; PAR, protease activated receptor; PGG 2 , prostaglandin G 2 ; PGH 2 , prostaglandin H 2 ; PGI 2 , prostacyclin; TXA2, thromboxane