Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives

References

• Davi G, Patrono C. Platelet activation and atherothrombosis. N. Engl. J. Med.357, 2482–2494 (2007).
   PubMed Web of Science ®Google Scholar
• Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler. Thromb. Vasc. Biol.28, 403–412 (2008).
   PubMed Web of Science ®Google Scholar
• Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb. Haemost.102, 248–257 (2009).
   PubMed Web of Science ®Google Scholar
• Patrono C, Andreotti F, Arnesen H et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Eur. Heart J.32, 2922–2932 (2011).
   PubMed Web of Science ®Google Scholar
• Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat. Rev. Drug. Discov.9, 154–169 (2011).
   Google Scholar
• Papathanasiou A, Goudevenos J, Tselepis AD. Resistance to aspirin and clopidogrel: possible mechanisms, laboratory investigation, and clinical significance. Hellenic J. Cardiol.48, 352–363 (2007).
   PubMedGoogle Scholar
• Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ324, 71–86 (2002).
   PubMed Web of Science ®Google Scholar
• Krasopoulos G, Brister S, Beattie WS, Buchanan MR. Aspirin ‘resistance’ and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ336, 195–198 (2008).
   PubMed Web of Science ®Google Scholar
• Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch. Intern. Med.167, 1593–1159 (2007).
   PubMed Web of Science ®Google Scholar
• Loureiro-Silva MR, Kouyoumdjian M, Borges DR. Plasma kallikrein and thrombin are cleared through unrelated hepatic pathways. Blood Coagul. Fibrinolysis4, 551–554 (1993).
   PubMedGoogle Scholar
• Undas A, Siudak R, Topór-Mądry R et al. Simvastatin administration reduces thromboxane production in subjects taking aspirin: links between aspirin resistance and thrombin generation. Int. J. Cardiol.154, 59–64 (2012).
   PubMedGoogle Scholar
• Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J. Am. Coll. Cardiol.46, 1705–1709 (2005).
   PubMed Web of Science ®Google Scholar
• Di Minno G. Aspirin resistance and platelet turnover: a 25-year old issue. Nutr. Metab. Cardiovasc. Dis.21, 542–545 (2011).
   PubMed Web of Science ®Google Scholar
• Feher G, Feher A, Pusch G et al. The genetics of antiplatelet drug resistance. Clin. Genet.75, 1–18 (2009).
   PubMed Web of Science ®Google Scholar
• Anninos H, Andrikopoulos G, Pastromas S, Sakellariou D, Theodorakis G, Vardas P. Triflusal: an old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic J. Cardiol.50, 199–207 (2009).
   PubMed Web of Science ®Google Scholar
• Valle M, Barbanoj M, Donner A et al. Access of HTB, main metabolite of triflusal, to celebrospinal fluid in healthy volunteers. Eur. J. Clin. Pharmacol.61, 103–111 (2005).
   PubMedGoogle Scholar
• Antonijoan RM, Gish I, Azaro A et al. Gastrointestinal safety of triflusal solution in healthy volunteers: a proof of concept endoscopic study. Eur. J. Clin. Pharmacol.67, 663–669 (2011).
   PubMedGoogle Scholar
• Matias-Guiu J, Ferro J, Álvarez-Sabin J et al. Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP study: a randomized, double-blind, multicenter trial. Stroke34, 840–848 (2003).
   PubMed Web of Science ®Google Scholar
• Mega JL, Close S, Wiviott SD et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation119, 2553–2560 (2009).
   PubMed Web of Science ®Google Scholar
• Bonello L, Camoin-Jau L, Armero S et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am. J. Cardiol.103, 5–10 (2009).
   PubMed Web of Science ®Google Scholar
• Wallentin L. P2Y12 inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur. Heart J.30, 1964–1977 (2009).
   PubMed Web of Science ®Google Scholar
• Aleil B, Jacquemin L, De Poli F et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc. Interv.1, 631–638 (2008).
   PubMedGoogle Scholar
• Bhatt DL, Bertrand ME, Berger PB et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J. Am. Coll. Cardiol.39, 9–14 (2002).
   PubMed Web of Science ®Google Scholar
• Tselepis AD, Tsoumani M, Kalantzi K et al. Influence of HDL and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy. J. Thromb. Haemost.9(12), 2371–2378 (2011).
   PubMed Web of Science ®Google Scholar
• Bouman HJ, Schömig E, van Werkum JW et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat. Med.1, 110–116 (2011).
   Google Scholar
• Sibbing D, Koch W, Massberg S et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur. Heart J.32, 1605–1613 (2011).
   PubMed Web of Science ®Google Scholar
• Kalantzi KI, Dimitriou A, Goudevenos JA et al. The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within one month of treatment. Platelets23(2), 121–131 (2011).
   PubMedGoogle Scholar
• Tsoumani ME, Kalantzi K, Goudevenos I et al. Platelet-mediated inflammation in cardiovascular disease. Potential role of platelet-endothelium interactions. Curr. Vascul. Pharmacol. (2012) (In Press).
   PubMedGoogle Scholar
• von Beckerath N, Kastrati A, Wieczorek A et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur. Heart. J.28, 1814–1819 (2007).
   PubMed Web of Science ®Google Scholar
• Palmerini T, Barozzi C, Tomasi L et al. A randomised study comparing the antiplatelet and antinflammatory effect of clopidogrel 150 mg/day versus 75 mg/day in patients with ST-segment elevation acute myocardial infarction and poor responsiveness to clopidogrel: results from the DOUBLE study. Thromb. Res.125, 309–314 (2007).
   Google Scholar
• Mega JL, Close S, Wiviott SD et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N. Engl. J. Med.360, 354–362 (2009).
   PubMed Web of Science ®Google Scholar
• Mega JL, Simon T, Collet JP et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA304, 1821–1830 (2010).
   PubMed Web of Science ®Google Scholar
• Serebruany V, Cherala G, Williams C et al. Association of platelet responsiveness with clopidogrel metabolism: role of compliance in the assessment of ‘resistance’. Am. Heart. J.158, 925–932 (2009).
   PubMed Web of Science ®Google Scholar
• Qureshi Z, Hobson A. Clopidogrel ‘resistance’: where are we now? Cardiovasc. Ther. doi:10.1111/j.1755-5922.2011.00296.x (2011) (Epub ahead of print).
   PubMedGoogle Scholar
• Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N. Engl. J. Med.352, 1179–1189 (2005).
   PubMed Web of Science ®Google Scholar
• Steinhubl SR, Berger PB, Mann JT 3rd et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA288, 2411–2420 (2002).
   PubMed Web of Science ®Google Scholar
• Kalantzi KI, Dimitriou A, Milionis HJ, Goudevenos IA, Tselepis AD. Clopidogrel differentially affects platelet-mediated thrombosis and inflammatory response in patients with acute coronary syndromes. J. Thromb. Haemost.4, 875–878 (2011).
   Google Scholar
• Mega JL, Hochholzer W, Frelinger AL et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA306, 2221–2228 (2011).
   PubMed Web of Science ®Google Scholar
• Bonello L, Camoin-Jau L, Arques S et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J. Am. Coll. Cardiol.51, 1404–1411 (2008).
   PubMed Web of Science ®Google Scholar
• Price MJ, Berger P, Teirstein PS et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA305, 1097–1105 (2011).
   PubMed Web of Science ®Google Scholar
• Valgimigli M, Campo G, de Cesare N et al.; Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R) Investigators. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel study. Circulation119, 3215–3222 (2009).
   PubMed Web of Science ®Google Scholar
• Angiolillo DJ, Gibson CM, Cheng S et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin. Pharmacol. Ther.89, 65–74 (2011).
   PubMed Web of Science ®Google Scholar
• Fernando H, Dart A, Peter K, Shaw JA. Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy. Thromb. Haemost.105, 933–944 (2011).
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Cryer BL, Contant CF et al. Clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med.363, 1909–1917 (2010).
   PubMed Web of Science ®Google Scholar
• Abraham NS, Hlatky MA, Antman EM et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on expert consensus documents. Circulation122, 2619–2633 (2010).
   PubMed Web of Science ®Google Scholar
• Neubauer H, Gunesdogan B, Hanefeld C, Spiecker M, Mugge A. Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function – a flow cytometry study. Eur. Heart J.24, 1744–1749 (2003).
   PubMed Web of Science ®Google Scholar
• Lau WC, Waskell LA, Watkins PB et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug–drug interaction. Circulation107, 32–37 (2003).
   PubMed Web of Science ®Google Scholar
• Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, Tselepis AD. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation109, 1335–1338 (2004).
   PubMed Web of Science ®Google Scholar
• Bates ER, Lau WC, Angiolillo DJ. Clopidogrel–drug interactions. J. Am. Coll. Cardiol.57, 1251–1263 (2011).
   PubMed Web of Science ®Google Scholar
• Smith SM, Judge HM, Peters G, Storey RF. Multiple antiplatelet effects of clopidogrel are not modulated by statin type in patients undergoing percutaneous coronary intervention. Platelets15, 465–474 (2004).
   PubMed Web of Science ®Google Scholar
• Saw J, Brennan DM, Steinhubl SR et al. Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial. J. Am. Coll. Cardiol.50, 291–295 (2007).
   PubMed Web of Science ®Google Scholar
• Kim SD, Kang W, Lee HW et al. Bioequivalence and tolerability of two clopidogrel salt preparations, besylate and bisulfate: a randomized, open-label, crossover study in healthy Korean male subjects. Clin. Ther.31, 793–803 (2009).
   PubMed Web of Science ®Google Scholar
• Park JY, Kim KA, Ryu JH, Lee GH, Jeon SH, Kim JS. Pharmacokinetics and the antiplatelet effect of a new clopidogrel formulation, clopidogrel besylate, in healthy subjects. Int. J. Clin. Pharmacol. Ther.48, 259–269 (2010).
   PubMedGoogle Scholar
• Tsoumani ME, Kalantzi K, Dimitriou AA, Ntalas IV, Goudevenos IA, Tselepis AD. Antiplatelet efficacy of long-term treatment with clopidogrel besylate in patients with a history of acute coronary syndrome: comparison with clopidogrel hydrogen sulfate. Angiology doi:10.1177/0003319711427697 (2011) (Epub ahead of print).
   PubMedGoogle Scholar
• Tsoumani ME, Kalantzi K, Dimitriou AA, Ntalas IV, Goudevenos IA, Tselepis AD. Effect of clopidogrel besylate on platelet reactivity in patients with acute coronary syndromes. Comparison with clopidogrel hydrogen sulfate. Exp. Opin. Pharmacother.13, 149–158 (2012).
   PubMed Web of Science ®Google Scholar
• Wiviott S, Trenk D, Frelinger AL et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-thrombolysis in myocardial infarction 44 trial. Circulation116, 2923–2932 (2007).
   PubMed Web of Science ®Google Scholar
• Mega JL, Close S, Wiviott SD et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON–TIMI 38 trial: a pharmacogenetic analysis. Lancet376, 1312–1319 (2010).
   PubMed Web of Science ®Google Scholar
• Alexopoulos D, Dimitropoulos G, Davlouros P et al. Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150 mg) clopidogrel. The importance of CYP2C19*2 genotyping. J. Am. Coll. Cardiol.4, 403–410 (2011).
   Google Scholar
• Bonello L, Tantry U, Marcucci R et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J. Am. Coll. Cardiol.56, 919–933 (2010).
   PubMed Web of Science ®Google Scholar
• Springthorpe B, Bailey A, Barton P et al. From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorgan. Med. Chem. Lett.17, 6013–6018 (2007).
   PubMed Web of Science ®Google Scholar
• Storey RF. Pharmacology and clinical trials of reversibly-binding P2Y12 inhibitors. Thromb. Haemost.105, S75–S81 (2011).
   PubMed Web of Science ®Google Scholar
• Gurbel PA, Bliden K, Butler K et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation120, 2577–2585 (2009).
   PubMed Web of Science ®Google Scholar
• James S, Budaj A, Aylward P et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the platelet inhibition and patient outcomes (PLATO) trial. Circulation122, 1056–1067 (2010).
   PubMed Web of Science ®Google Scholar
• Wallentin L, James S, Storey RF et al. PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet376, 1320e8 (2010).
   Google Scholar
• Angiolillo DJ, Bhatt D, Gurbel PA, Jennings LK. Advances in antiplatelet therapy: agents in clinical development. Am. J. Cardiol.103(Suppl.), 40A–51A (2009).
   PubMed Web of Science ®Google Scholar
• Steinhubl SR, Oh J, Oestreich JH et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb. Res.121, 527–534 (2008).
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Lincoff AM, Gibson CM et al. Intravenous platelet blockade with cangrelor during PCI. N. Engl. J. Med.361, 2330–2341 (2009).
   PubMed Web of Science ®Google Scholar
• Harrington RA, Stone GW, McNulty S et al. Platelet inhibition with cangrelor in patients undergoing PCI. N. Engl. J. Med.361, 2318–2329 (2009).
   PubMed Web of Science ®Google Scholar
• Berger JS, Roe MT, Gibson CM et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the early rapid reversal of platelet thrombosis with intravenous elinogrel before PCI to optimize reperfusion in acute myocardial infarction (ERASE MI) pilot trial. Am. Heart J.158, 998–1004.E1 (2009).
   PubMed Web of Science ®Google Scholar
• Leonardi S, Rao S, Harrington RA et al. Rationale and design of the randomized, double-blind trial testing intravenous and oral administration of elinogrel, a selective and reversible P2Y(12)- receptor inhibitor, versus clopidogrel to valuate tolerability and efficacy in nonurgent percutaneous coronary interventions patients (INNOVATE-PCI). Am. Heart J.160, 65–72 (2010).
   PubMed Web of Science ®Google Scholar
• Gurbel PA, Bliden KP, Antonino MJ et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP 2C19*2 genotype: first experience in patients. J. Thromb. Haemost.8, 43–53 (2010).
   PubMedGoogle Scholar
• Phillips DR, Charro I, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein IIb–IIIa complex. Blood71, 831–843 (1988).
   PubMed Web of Science ®Google Scholar
• Wagner CL, Maselli M, Neblock DS, Weisman HF, Coller BS, Jordan RE. Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood88, 907–914 (1996).
   PubMed Web of Science ®Google Scholar
• Mitsios JV, Tambaki A, Abatzis M et al. Effect of synthetic peptides corresponding to residues 313–332 of the aIIb subunit on platelet activation and fibrinogen binding to aIIbb3. Eur. J. Biochem.271, 855–862 (2004).
   PubMedGoogle Scholar
• Kloczewiak M, Timmons S, Hawiger J. Localization of a site interacting with human platelet receptor on carboxy-terminal segment of human fibrinogen γ chain. Biochem. Biophys. Res. Commun.107, 181–187 (1982).
   PubMed Web of Science ®Google Scholar
• Vergara-Jimenez J, Tricoci P. Safety and efficacy of abciximab as an adjunct to percutaneous coronary intervention. Vasc. Health. Risk. Manag.6, 39–45 (2010).
   PubMedGoogle Scholar
• Lippi G, Montagnana M, Danese E, Favaloro EJ, Franchini M. Glycoprotein IIb/IIIa inhibitors: an update on the mechanism of action and use of functional testing methods to assess anti-platelet efficacy. Biomark. Med.5, 63–70 (2011).
   PubMedGoogle Scholar
• Goudevenos JA, Tselepis A. Basic and clinical aspects of platelet integrin αIIbβ3 receptor antagonists in acute coronary syndromes. Curr. Opin. Investig. Drugs2, 244–249 (2001).
   PubMedGoogle Scholar
• Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev.75, 725–748 (1995).
   PubMed Web of Science ®Google Scholar
• Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol. Rev.58, 488–520 (2006).
   PubMed Web of Science ®Google Scholar
• Ji X, Hou M. Novel agents for anti-platelet therapy. J. Hematol. Oncol.4, 44 (2011).
   PubMedGoogle Scholar
• Born G, Patrono C. Antiplatelet drugs. Br. J. Pharmacol.147(Suppl. 1), S241–S251 (2006).
   PubMedGoogle Scholar
• Weyrich AS, Denis MM, Kuhlmann-Eyre JR et al. Dipyridamole selectively inhibits inflammatory gene expression in platelet–monocyte aggregates. Circulation111, 633–642 (2005).
   PubMed Web of Science ®Google Scholar
• Muller TH, Su CA, Weisenberger H, Brickl R, Nehmiz G, Eisert WG. Dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo. Br. J. Clin. Pharmacol.30, 179–186 (1990).
   PubMed Web of Science ®Google Scholar
• Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J. Neurol. Sci.143, 1–13 (1996).
   PubMed Web of Science ®Google Scholar
• Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet367, 1665–1673 (2006).
   PubMed Web of Science ®Google Scholar
• Verro P, Gorelick PB, Nguyen D. Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis. Stroke39, 1358–1363 (2008).
   PubMed Web of Science ®Google Scholar
• Sacco RL, Diener HC, Yusuf S et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N. Engl. J. Med.359, 1238–1251 (2008).
   PubMed Web of Science ®Google Scholar
• Uchiyama S, Demaerschalk BM, Goto S et al. Stroke prevention by cilostazol in patients with atherothrombosis: meta-analysis of placebo-controlled randomized trials. J. Stroke Cerebrovasc. Dis.18, 482–490 (2009).
   PubMedGoogle Scholar
• Schror K. The pharmacology of cilostazol. Diabetes Obes. Metab.4(Suppl. 2), S1–S19 (2002).
   PubMedGoogle Scholar
• Jeong YH, Hwang JY, Kim IS et al. Adding cilostazol to dual antiplatelet therapy achieves greater platelet inhibition than high maintenance dose clopidogrel in patients with acute myocardial infarction: results of the Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With AMI (ACCEL-AMI) study. Circ. Cardiovasc. Interv.3, 17–26 (2010).
   PubMed Web of Science ®Google Scholar
• Jeong YH, Lee SW, Choi BR et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J. Am. Coll. Cardiol.53, 1101–1109 (2009).
   PubMed Web of Science ®Google Scholar
• Kumbhani DJ, Bhatt DL. Secondary prevention of stroke: can we do better than aspirin? Lancet Neurol.9, 942–943 (2010).
   PubMedGoogle Scholar
• Tamhane U, Meier P, Chetcuti S et al. Efficacy of cilostazol in reducing restenosis in patients undergoing contemporary stent based PCI: a meta-analysis of randomised controlled trials. EuroIntervention5, 384–393 (2009).
   PubMed Web of Science ®Google Scholar
• Suh JW, Lee SP, Park KW et al. Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (Influence of Cilostazol-Based Triple Antiplatelet Therapy on Ischemic Complication After Drug-Eluting Stent Implantation) trial. J. Am. Coll. Cardiol.57, 280–289 (2011).
   PubMed Web of Science ®Google Scholar
• Brummel KE, Paradis SG, Butenas S, Mann KG. Thrombin functions during tissue factor-induced blood coagulation. Blood100, 148–152 (2002).
   PubMed Web of Science ®Google Scholar
• Chackalamannil S. Thrombin receptor antagonists as novel therapeutic targets. Curr. Opin. Drug. Discov. Devel.4(4), 417–427 (2001).
   PubMedGoogle Scholar
• Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol. Rev.84, 579–621 (2004).
   PubMed Web of Science ®Google Scholar
• Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost.3, 1800–1814 (2005).
   PubMed Web of Science ®Google Scholar
• Doller D, Chackalamannil S, Czarniecki M, McQuade R, Ruperto V. Design, synthesis, and structure–activity relationship studies of himbacine derived muscarinic receptor antagonists. Bioorg. Med. Chem. Lett.9, 901–906 (1999).
   PubMed Web of Science ®Google Scholar
• Oestreich J. SCH-530348, a thrombin receptor (PAR-1) antagonist for the prevention and treatment of atherothrombosis. Curr. Opin. Investig. Drugs10, 988–996 (2009).
   PubMed Web of Science ®Google Scholar
• Becker RC, Moliterno DJ, Jennings LK et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled Phase II study. Lancet373, 919–928 (2009).
   PubMed Web of Science ®Google Scholar
• Morrow DA, Scirica BM, Fox KA et al. Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the thrombin-receptor antagonist in secondary prevention of atherothrombotic ischemic events (TRA 2 degrees P)-TIMI 50 trial. Am. Heart J.158, 335–341.E3 (2009).
   PubMed Web of Science ®Google Scholar
• Ueno M, Ferreiro JL, Angiolillo DJ. Mechanism of action and clinical development of platelet thrombin receptor antagonists. Expert Rev. Cardiovasc. Ther.8(8), 1191–1200 (2010).
   PubMedGoogle Scholar
• Chintala M, Shimizu K, Ogawa M, Yamaguchi H, Doi M, Jensen P. Basic and translational research on proteinase-activated receptors: antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease. J. Pharmacol. Sci.108, 433–438 (2008).
   PubMed Web of Science ®Google Scholar
• White HD. Oral antiplatelet therapy for atherothrombotic disease: current evidence and new directions. Am. Heart J.161, 450–461 (2011).
   PubMed Web of Science ®Google Scholar
• Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P. Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome. J. Atheroscler. Thromb.17, 156–164 (2010).
   PubMed Web of Science ®Google Scholar
• TRA*CER Executive and Steering Committees. The thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA*CER) trial: study design and rationale. Am. Heart J.158, 327–334.e4 (2009).
   PubMed Web of Science ®Google Scholar
• Tricoci P, Huang Z, Held C et al.; TRACER investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N. Engl. J. Med.366, 20–33 (2012).
   PubMed Web of Science ®Google Scholar
• Martorell L, Martinez-Gonzalez J, Rodriguez C, Gentile M, Calvayrac O, Badimon L. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb. Haemost.99, 305–315 (2008).
   PubMed Web of Science ®Google Scholar
• Kai Y, Hirano K, Maeda Y, Nishimura J, Sasaki T, Kanaide H. Prevention of the hypercontractile response to thrombin by proteinase-activated receptor-1 antagonist in subarachnoid hemorrhage. Stroke38, 3259–3265 (2007).
   PubMed Web of Science ®Google Scholar
• Tello-Montoliu A, Tomasello SD, Ueno M, Angiolillo DJ. Antiplatelet therapy: thrombin receptor antagonists. Br. J. Clin. Pharmacol.72, 658–671 (2011).
   PubMed Web of Science ®Google Scholar
• Wiviott SD, Flather MD, O’Donoghue ML et al. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of thrombin-coronary artery disease trial. Circulation123, 1854–1863 (2011).
   PubMed Web of Science ®Google Scholar
• Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur. Heart J.31, 2601–2613 (2010).
   PubMed Web of Science ®Google Scholar
• O’Donoghue ML, Bhatt DL, Wiviott SD et al. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: the lessons from antagonizing the cellular effects of thrombin-acute coronary syndromes trial. Circulation123, 1843–1853 (2011).
   PubMed Web of Science ®Google Scholar
• Giannarelli C, Zafar M, Badimon JJ. Prostanoid and TP-receptors in atherothrombosis: is there a role for their antagonism? Thromb. Haemost.104, 949–954 (2010).
   PubMed Web of Science ®Google Scholar
• Chamorro A. TP receptor antagonism: a new concept in atherothrombosis and stroke prevention. Cerebrovasc. Dis.27(Suppl. 3), 20–27 (2009).
   PubMedGoogle Scholar
• Smith EM. Thromboxane and the thromboxane receptor in cardiovascular disease. Clin. Lipidol.5, 209–219 (2010).
   PubMedGoogle Scholar
• Hong TT, Huang J, Driscoll E, Lucchesi BR. Preclinical evaluation of S18886 in an experimental model of coronary arterial thrombosis. J. Cardiovasc. Pharmacol.48, 239–248 (2006).
   PubMed Web of Science ®Google Scholar
• Vilahur G, Casani L, Badimon L. A thromboxane A2/prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis. Thromb. Haemost.98, 662–669 (2007).
   PubMed Web of Science ®Google Scholar
• Gaussem P, Reny JL, Thalamas C et al. The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies. J. Thromb. Haemost.3, 1437–1345 (2005).
   PubMed Web of Science ®Google Scholar
• Bousser MG, Amarenco P, Chamorro A et al. Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study. Cerebrovasc. Dis.27, 509–518 (2009).
   PubMed Web of Science ®Google Scholar
• Spiel AO, Gilbert JC, Jilma B. Von Willebrandt factor in cardiovascular disease: focus on acute coronary syndromes. Circulation117(11), 1449–1459 (2008).
   PubMed Web of Science ®Google Scholar
• Sarratt KL, Chen H, Zutter MM, Santoro SA, Hammer DA, Kahn ML. GPVI and α2β1 play independent critical roles during platelet adhesion and aggregate formation to collagen under flow. Blood106, 1268–1277 (2005).
   PubMed Web of Science ®Google Scholar
• Kageyama S, Yamamoto H, Nakazawa H et al. Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys. Arterioscler. Thromb.22, 187–192 (2002).
   PubMed Web of Science ®Google Scholar
• Vanhoorelbeke K, Depraetere H, Romijn RA, Huizinga EG, De Maeyer M, Deckmyn H. A consensus tetrapeptide selected by phage display adopts the conformation of a dominant discontinuous epitope of a monoclonal anti-vWF antibody that inhibits the von Willebrand factor-collagen interaction. J. Biol. Chem.278, 37815–37821 (2002).
   Google Scholar
• Ulrichts H, Schoolmeester A, Hoefman S et al. Anti-thrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with current marketed antiplatelet drugs. J. Thromb. Haemost. Suppl.118(3), 757–765 (2009).
   Google Scholar
• Abd-Elaziz K, Kamphuisen P, Lyssesns C et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of anti-vWF nanobody ALX-0681 after single and multiple subcutaneous administrations to healthy volunteers. Presented at: 51st ASH Annual Meeting and Exposition. New Orleans, LA, USA, 5–8 December 2009.
   Google Scholar
• Gilbert JC, DeFeo-Fraulini T, Hutabarat RM et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation116, 2678–2686 (2007).
   PubMed Web of Science ®Google Scholar
• Bouchard PR, Hutabarat R, Thompson KM. Discovery and development of therapeutic aptamers. Annu. Rev. Pharmacol. Toxicol.50, 237–257 (2010).
   PubMed Web of Science ®Google Scholar
• Diener JL, Daniel Lagasse H, Duerschmied D et al. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J. Thromb. Haemost.7, 1155–1162 (2009).
   PubMed Web of Science ®Google Scholar
• Cauwenberghs N, Vanhoorelbeke K, Vauterin S et al. Epitope mapping of inhibitory antibodies against platelet glycoprotein Iba reveals interaction between the leucine-rich repeat N-terminal and C-terminal flanking domains of glycoprotein Iba. Blood98, 652–660 (2001).
   PubMed Web of Science ®Google Scholar
• Hennan JK, Swillo R, Morgan GA et al. Pharmacologic inhibition of platelet vWF–GPIb a interaction prevents coronary artery thrombosis. Thromb. Haemost.95, 469–475 (2006).
   PubMed Web of Science ®Google Scholar
• Yang J, Ji S, Dong N, Zhao Y, Ruan C. Engineering and characterization of a chimeric anti-platelet glycoprotein Iba monoclonal antibody and preparation of its Fab fragment. Hybridoma (Larchmt)29, 125–132 (2010).
   PubMedGoogle Scholar
• Best D, Senis YA, Jarvis GE et al. GPVI levels in platelets: relationship to platelet function at high shear. Blood102, 2811–2818 (2003).
   PubMed Web of Science ®Google Scholar
• Li H, Lockyer S, Concepcion A et al. The Fab fragment of a novel anti-GPVI monoclonal antibody, OM4, reduces in vivo thrombosis without bleeding risk in rats. Arterioscler. Thromb. Vasc. Biol.27, 1199–1205 (2007).
   PubMed Web of Science ®Google Scholar
• Qian MD, Villeval JL, Xiong X et al. Anti GPVI human antibodies neutralizing collagen-induced platelet aggregation isolated from a combinatorial phage display library. Hum. Antibodies11, 97–105 (2002).
   PubMedGoogle Scholar
• Smethurst PA, Joutsi-Korhonen L, O’Connor MN et al. Identification of the primary collagen-binding surface on human glycoprotein VI by site-directed mutagenesis and by a blocking phage antibody. Blood103, 903–911 (2004).
   PubMed Web of Science ®Google Scholar
• Gruner S, Prostredna M, Aktas B et al. Anti-glycoprotein VI treatment severely compromises hemostasis in mice with reduced α2β1 levels or concomitant aspirin therapy. Circulation110, 2946–2951 (2004).
   PubMed Web of Science ®Google Scholar
• Morrow DA, Braunwald E, Bonaca MP et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med.366(15), 1404–1413 (2012).
   PubMed Web of Science ®Google Scholar