Development of glycoprotein IIb–IIIa antagonists: translation of pharmacodynamic effects into clinical benefit

References

• Thaulow E, Erikssen J, Sandvik L, Stromorken H, Cohn PE Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 84, 613–617 (1991).
   PubMed Web of Science ®Google Scholar
• ••Increased reactivity of platelets is associatedwith an increased risk of cardiovascular death in healthy subjects.
   Google Scholar
• Trip MD, Cats VM, van Capelle FJ et al. Platelet hyper-reactivity and prognosis in survival of myocardial infarction. N Engl. J Med. 322, 1549–1554 (1990).
   PubMed Web of Science ®Google Scholar
• ••Increased reactivity of platelets is associatedwith an increased risk of cardiovascular death in patients with coronary artery disease.
   Google Scholar
• Kabbani SS, Watkins MW Ashikaga T et al. Platelet reactivity characterized prospectively. A determinant of outcome 90 days after percutaneous coronary intervention. Chrulation 104, 181–186 (2001).
   PubMed Web of Science ®Google Scholar
• ••Prospective determination of plateletreactivity identifies patients at high and low risk of cardiac events after coronary intervention.
   Google Scholar
• Kabbani SS, Watkins MW Ashikaga T, Terrien EF, Sobel BE, Schneider DJ. Usefulness of platelet reactivity before percutaneous coronary intervention in determining cardiac risk 1 year later. Am. J. Cardiol. 91, 876–878 (2003).
   PubMed Web of Science ®Google Scholar
• •Increased platelet reactivity before coronary intervention identifies subjects at high risk of cardiac events 3 to 6 months after the intervention.
   Google Scholar
• Ault KA, Cannon CF, Mitchell J et al. Platelet activation in patients after an acute coronary syndrome. J. Arn. Coll. Cardiol. 33, 634–639 (1999).
   PubMed Web of Science ®Google Scholar
• Van Belle E, Lablanche JM, Bauters C et al. Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction. Circulation 97, 26–33 (1998).
   PubMedGoogle Scholar
• •Thrombosis persists in most patients up to 1 month after myocardial infarction.
   Google Scholar
• Chakhtoura EY, Shamoon FE, Haft JI, Obiedzinski GR, Cohen AJ, Watson RM. Comparison of platelet activation in unstable and stable angina pectoris and correlation with coronary angiographic findings. Am. J. Cardiol. 86, 835–839 (2000).
   PubMed Web of Science ®Google Scholar
• Gasperetti CM, Gonias SL, Gimple LW Powers ER. Platelet activation during coronary angioplasty in humans. Chrulation 88, 2728–2734 (1993).
   PubMed Web of Science ®Google Scholar
• Inoue T, Sohma R, Miyazaki T, Iwasaki Y, Yaguchi I, Morooka S. Comparison of activation process of platelets and neutrophils after coronary stent implantation versus balloon angioplasty for stable angina pectoris. Am. J. Cardiol. 86, 1057–1062 (2000).
   PubMed Web of Science ®Google Scholar
• Nurden AT, Caen JP. An abnormal platelet glycoprotein pattern in three cases of Glanzmann thrombasthenia. Br. Haematol. 28, 253–260 (1974).
   PubMed Web of Science ®Google Scholar
• •Identified the absence of glycoprotein IIb—IIIa in patients with Glanzmann thrombasthenia.
   Google Scholar
• Phillips DR, Jenkins CSP, Luscher EF, Larrieu MJ. Molecular differences of exposed surface proteins on thrombasthenic platelet plasma membranes. Nature 257, 599–600 (1975).
   PubMed Web of Science ®Google Scholar
• Kunicki TJ, Pidard D, Rosa JP, Nurden AT. The formation of calcium-dependent complexes of platelet membrane glycoproteins lib and IIIa in solution as determined by crossed immunoelectrophoresis. Blood 58, 268–278 (1981).
   PubMed Web of Science ®Google Scholar
• Caller BS. Interaction of normal, thrombasthenic, and Bernard—Soulier platelets with immobilized fibrinogen: defective platelet—fibrinogen interaction in thrombasthenia. Blood 55, 169–178 (1980).
   PubMed Web of Science ®Google Scholar
• •• Determined that fibrinogen binds to glycoprotein IIb—IIIa mediating aggregation.
   Google Scholar
• Bennett JS, Vilaire G. Exposure ofplatelet fibrinogen receptors by ADP and epinephrine. J. Clin. Invest. 64, 1393–1401 (1979).
   PubMed Web of Science ®Google Scholar
• Peerschke El. The platelet fibrinogen receptor. Semin. Hematol. 22, 241–259 (1985).
   PubMed Web of Science ®Google Scholar
• Hynes RO. Integrins: a family of cell surface receptors. Cell 48, 549–554 (1987).
   PubMed Web of Science ®Google Scholar
• Ginsberg MH, Xiaoping D, O'Toole TE, Loftus JC, Plow ER Platelet integrins. Thromb. Haemost. 70, 87–93 (1993).
   PubMed Web of Science ®Google Scholar
• Plow EF, D'Souza SE, Ginsberg MH. Ligand binding to GP lib—IIIa: a status report. Semin. Thromb. Hemost. 18, 324–332 (1992).
   PubMed Web of Science ®Google Scholar
• Gogstad GO, Brosstad F, Krutnes MB, Hagen I, Solum NO. Fibrinogen-binding properties of the human platelet glycoprotein lib—IIIa complex: a study using crossed radioimmunoelectrophoresis. Blood 60, 663–671 (1982).
   PubMed Web of Science ®Google Scholar
• Parise LV, Phillips DR. Reconstitution of the purified platelet fibrinogen receptor: fibrinogen-binding properties of the glycoprotein lib—IIIa complex. J. Biol. Chem. 260, 10698–10707 (1985).
   PubMed Web of Science ®Google Scholar
• Plow EF, McEver RP, Caller BS, Woods VL Jr, Marguerie GA, Ginsberg MH. Related binding mechanisms for fibrinogen, fibronectin, von Willebrand factor, and thrombospondin on thrombin-stimulated human platelets. Blood 66, 724–727 (1985).
   PubMed Web of Science ®Google Scholar
• Plow EF, Srouji Aft Meyer D, Marguerie G, Ginsberg MH. Evidence that three adhesive proteins interact with a common recognition site on activated platelets. J Biol. Chem. 259, 5388–5391 (1984).
   PubMed Web of Science ®Google Scholar
• •Identification of the site of binding of fibrinogen.
   Google Scholar
• Pierschbacher MD, Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309, 30–33 (1984).
   PubMed Web of Science ®Google Scholar
• Plow EF, Marguerie G, Ginsberg M. Fibrinogen, fibrinogen receptors, and the peptides that inhibit these interactions. Biochem. Pharmacol. 36, 4035–4040 (1987).
   PubMed Web of Science ®Google Scholar
• Kloczewiak M, Timmons S, Hawiger J. Recognition site for the platelet receptor is present on the 15-residue carboxy-terminal fragment of the 7-chain of human fibrinogen and is not involved in the fibrin polymerization reaction. Thromb. Res. 29, 249–255
   PubMedGoogle Scholar
• Weisel JW, Nagaswami C, Vilaire G,Bennett JS. Examination of the platelet membrane glycoprotein lib—IIIa complex and its interaction with fibrinogen and other ligands by electron microscopy. J Biol. Chem. 267, 16637–16643 (1992).
   PubMed Web of Science ®Google Scholar
• Gralnick HR, Williams SB, Caller BS. Fibrinogen competes with von Willebrand factor for binding to the glycoprotein Hb/IIIa complex when platelets are stimulated with thrombin. Blood 64, 797–800 (1984).
   PubMed Web of Science ®Google Scholar
• Weiss HJ, Hawiger J, Ruggeri ZM, TurrittoVT, Thiagarajan P, Hoffman T. Fibrinogen-independent platelet adhesion and thrombus formation on subendothelium mediated by glycoprotein lib—IIIa complex at high shear rate. J. Clin. Invert. 83, 288–297 (1989).
   PubMed Web of Science ®Google Scholar
• •Identification of the influence of shear stress on platelet aggregation. High shear stress is associated with aggregation mediated by the preferential binding of von Willebrand factor over fibrinogen.
   Google Scholar
• Bennett JS, Hoxie JA, Leitman SF, Vilaire G, Cines DB. Inhibition of fibrinogen binding to stimulated human platelets by a monoclonal antibody. Proc. Natl Acad. Sci. USA 80,2417–2421 (1983).
   PubMed Web of Science ®Google Scholar
• Caller BS, Peerschke El, Scudder LE, Sullivan CA. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin. Invest. 72,325–338 (1983).
   Google Scholar
• •Identification of 7E3, which was subsequently developed for clinical use as abciximab.
   Google Scholar
• Caller BS. Blockade of platelet GP IIb/IIIa receptors as an antithrombotic strategy. Circulation 92,2373–2380 (1995).
   PubMed Web of Science ®Google Scholar
• Caller BS, Scudder LE. Inhibition of dog platelet function by in vivo infusion of F(ab')2 fragments of a monoclonal antibody. Blood 66, 1456–1459 (1985).
   PubMed Web of Science ®Google Scholar
• Tcheng JE, Ellis SG, George BS et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 90,1757–1764 (1994).
   PubMed Web of Science ®Google Scholar
• •Characterization of the pharmacodynamic effects of abciximab.
   Google Scholar
• Suzuki K, Sakai Y, Hisamichi N et al. Comparison of the antiplatelet effect of YM 337 and abciximab in rhesus monkeys. Eur. PharmacoL 336,169–176 (1997).
   PubMed Web of Science ®Google Scholar
• Kleiman NS, Raizner AE, Jordan R et al. Differential inhibition of platelet aggregation induced by adenosine triphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GP IIb/IIIa inhibitors. J Am. Coll. CardioL 26,1665–1671 (1995).
   PubMed Web of Science ®Google Scholar
• •Demonstration that an internal pool of glycoprotein IIb—IIIa could be recruited with platelet activation. This study provides a pharmacodynamic rationale for the bolus plus infusion regimen of abciximab.
   Google Scholar
• Jordan RE, Wagner CL, Mascelli MA et al. Preclinical development of c7E3, a mouse/human chimeric monoclonal antibody fragment that inhibits platelet function by blockade of GP IIb/IIIa receptors with observations on the immunogenicity of c7E3 in humans. In: Adhesion Receptors as Therapeutic Targets. Horton MA (Ed.). CRC Press, Fl, USA, 281–305 (1996).
   Google Scholar
• Mascelli MA, Lance ET, Damaraju L, Wagner CL, Weisman HF, Jordan RE. Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation 97,1680–1688 (1998).
   PubMed Web of Science ®Google Scholar
• Kastrati A, Mehilli J, Schuhlen H et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl. Med. 350,232–238 (2004).
   PubMed Web of Science ®Google Scholar
• Tam SH, Sassoli PM, Jordan RE, Nakada MT. Abciximab (Reopro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and av133 integrins. Circulation 98, 1085–1091 (1998).
   PubMed Web of Science ®Google Scholar
• Simon DI, Xu H, Ortlepp S, Rogers C, Rao NK. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa crossreacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler. Thromb. Vasc. Biol. 17,528–535 (1997).
   PubMed Web of Science ®Google Scholar
• Stouffer GA, Hu Z, Sajid M et al. 1-3 integrins are upregulated after vascular injury and modulate thrombospondin- and thrombin-induced proliferation of cultured smooth muscle cells. Circulation 97, 907–915 (1998).
   PubMed Web of Science ®Google Scholar
• Phillip DR, Charo IF, Scarborough RM. GP IIb/IIIa; the responsive integrin. Ce1165, 359–362 (1991).
   Google Scholar
• Tcheng JE, Harrington RA, Kottke- Marchant K et al Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blacker integrelin in elective coronary intervention. Clirulation 91,2151–2157 (1995).
   PubMed Web of Science ®Google Scholar
• Kereiakes DJ, Kleiman NS, Ambrose J et al. Randomized, double-blind study of tirofiban (MK-383) platelet IIb—IIIa blockade in high-risk patients undergoing coronary angioplasty. J. Am. Coll. CardioL 27, 536–542 (1996).
   PubMed Web of Science ®Google Scholar
• Phillips DR, Scarborough RM. Clinical pharmacology of eptifibatide. Am. J. CardioL 80, B11—B20 (1997).
   Web of Science ®Google Scholar
• Moussa SA, Bennet JS. Platelets in health and disease: platelet GP IIb/IIIa structure and function: recent advances in antiplatelet therapy. Drugs Future 21,1141–1154 (1996).
   Google Scholar
• Caller BS. Monitoring platelet GP IIb/IIIa antagonist therapy. Circulation 97,5–9 (1998).
   PubMed Web of Science ®Google Scholar
• Bernadi MM, Califf RM, Kleiman N, Ellis SG, Topol EJ. Lack of usefulness of prolonged bleeding times in predicting hemorrhagic events in patients receiving the 7E3 glycoprotein IIb/IIIa antibody. Am. J. CardioL 72,1121–1125 (1993).
   PubMed Web of Science ®Google Scholar
• Born GV. Platelets in thrombogenesis: mechanism and inhibition of platelet aggregation. Ann. R. Coll. Surg. Engl. 36, 200–206 (1965).
   PubMedGoogle Scholar
• White MM, Jennings LK (Eds). Laboratory evaluation of platelet function. In: Platelet Protocols. Academic Press, CA, USA, 28–66 (1999).
   Google Scholar
• Kleiman NS. Pharmacology of the intravenous platelet receptor glycoprotein IIb—IIIa antagonists. Coron. Artery Dis. 9, 603–616 (1998).
   PubMed Web of Science ®Google Scholar
• Schneider DJ, Tracy PB, Mann KG, Sobel BE. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 96,2877-2883 (1997). •In vitro study demonstrating that chelation of calcium alters platelet function.
   Google Scholar
• Rebello SS, Huang J, Faul JD, Lucchesi BR. Role of extracellular ionized calcium in the in vitro assessment of GP IIb/IIIa receptor antagonists. J. Thromb. Thrombolysis 9,23–28 (2000).
   PubMed Web of Science ®Google Scholar
• ••Demonstrated that the use of calcium chelating agents alters the inhibitory effects of each glycoprotein IIb—IIIa antagonist.
   Google Scholar
• Kereiakes DJ, Lorenz T, Young JJ et al. Differential effects of citrate versus PPACK anticoagulation on measured platelet inhibition by abciximab, eptifibatide and tirofiban. I Thromb. Thrombolysis 12, 123–127 (2001).
   PubMed Web of Science ®Google Scholar
• Phillips DR, Teng W, Arfsten A et al. Effect of Ca2+ on GP IIb—IIIa interactions with integrelin: enhanced GP IIb—IIIa binding and inhibition of platelet aggregation by reductions in concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 96,1488–1494 (1997).
   PubMed Web of Science ®Google Scholar
• ••Provides a pharmacodynamic rationale forthe lack of efficacy of eptifibatide in the Integrilin to Minimize Platelet Aggregation and prevent Coronary Thrombosis (IMPACT) study. Antiplatelet effects were over-estimated because they were determined in blood anticoagulated with calcium chelators.
   Google Scholar
• Kabbani SS, Aggarwal A, Terrien ET, DiBattiste PM, Sobel BE, Schneider DJ. Suboptimal early inhibition of platelets by treatment with tirofiban and implications for coronary interventions. Am. J. CardioL 8,647–650 (2002).
   Google Scholar
• ••Provides a rationale for the greater efficacyof abciximab compared with tirofiban in the do Tirofiban And ReoPro Give similar Efficacy outcome Trial (TARGET). Antiplatelet effects of abciximab were greater than those of tirofiban from 15 to 60 min after onset of therapy.
   Google Scholar
• Herrmann HC, Swierkosz TA, Kapoor S et al. Comparison of degree of platelet inhibition by abciximab versus tirofiban in patients with unstable angina and non-q-wave myocardial infarction undergoing percutaneous coronary intervention. Am. J. CardioL 89, 1293–1296 (2002).
   PubMed Web of Science ®Google Scholar
• Lakkis N, Lakiss N, Bobek J, Farmer J. Platelet inhibition with tirofiban early during PCI: dosing revisited. Catheter Cardiovasc. Interv. 56, 474–477 (2002).
   PubMed Web of Science ®Google Scholar
• Schneider DJ, Herrmann HC, Lakkis N et al. Enhanced early inhibition of platelet aggregation with an increased bolus of tirofiban. Am. J. CardioL 90, 1421–1423 (2002).
   PubMed Web of Science ®Google Scholar
• •Pharmacodynamic assessment of greater bolus doses of tirofiban designed to overcome the limited inhibition during the first hour of treatment.
   Google Scholar
• Schneider DJ, Herrmann HC, Lakkis N et al. Increased concentrations of tirofiban in blood and their correlation with inhibition of platelet aggregation after greater bolus doses of tirofiban. Am. J. CardioL 91, 334–336 (2003).
   PubMed Web of Science ®Google Scholar
• Lincoff AM, Calif RM, Topol EJ. Platelet glycoprotein Hb/IIIa receptor blockade in coronary artery disease. J. Am. Coll. CardioL 35, 1103–1115 (2000).
   PubMed Web of Science ®Google Scholar
• Boersma E, Akkerhuis KM, Theroux P, Calif RM, Topol EJ, Simoons ML. Platelet glycoprotein Hb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation 100, 2045–2048 (1999).
   PubMed Web of Science ®Google Scholar
• EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein Hb/IIIa receptor in high-risk coronary angioplasty. N Engl. J. Med. 330, 956–961 (1994).
   PubMed Web of Science ®Google Scholar
• Muller I, Seyfarth M, Rudiger S et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 85, 92–93 (2001).
   PubMed Web of Science ®Google Scholar
• •A pharmacodynamic study demonstrating that a greater loading dose of clopidogrel (600 mg) is associated with earlier maximal inhibition (after 2 h).
   Google Scholar
• EPILOG Investigators. Platelet glycoproteinblockade withabciximab with low-dose heparin during percutaneous coronary revascularization. N Engl. J Med. 336, 1689–1696 (1997).
   PubMed Web of Science ®Google Scholar
• EPISTENT Investigators. Randomized placebo-controlled and balloon-angioplasty controlled trial to assess safety of coronary stenting with use of platelet glycoprotein Hb/IIIa blockade. Lancet 352, 87–92 (1998).
   PubMed Web of Science ®Google Scholar
• Simoons ML, GUSTO IV-ACS Investigators. Effect of glycoprotein receptor blacker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularization: the GUSTO IV-ACS randomized trial. Lancet357, 1915-1924 (2001).
   Google Scholar
• Topol EJ, GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein inhibition: the GUSTO V randomized trial. Lancet357, 1905-1914 (2001).
   Google Scholar
• Lincoff AM, Calif RM, Van de Werf F et al Mortality at 1 year with combination platelet glycoprotein Hb/IIIa inhibition and reduced-dose fibrinolytic therapy vs. conventional fibrinolytic therapy for acute myocardial infarction: GUSTO V randomized trial. J Am. Med. Assoc. 288, 2130–2135 (2002).
   PubMed Web of Science ®Google Scholar
• Montalescot G, Barragan P, Wittenberg 0 et al. Platelet glycoprotein inhibition with coronary stenting for acute myocardial infarction. N Engl. J. Med. 344, 1895–1903 (2001).
   PubMed Web of Science ®Google Scholar
• Stone GW, Grines CL, Cox DA et al.Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl. J. Med. 346, 957–966 (2002).
   PubMed Web of Science ®Google Scholar
• IMPACT II investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention. IMPACT II. Lancet349, 1422–1428 (1997).
   Google Scholar
• Gilchrist IC, O'Shea JC, Kosoglou T et al. Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention. Circulation 104, 406–411 (2001).
   PubMed Web of Science ®Google Scholar
• •Pharmacodynamic effect of a higher double bolus regimen of eptifibatide.
   Google Scholar
• The ESPRIT investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial. Lancet 356, 2037–2044 (2000).
   PubMed Web of Science ®Google Scholar
• The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein with eptifibatide in patients with acute coronary syndromes. N Engl. J. Med. 339, 436–443 (1998).
   PubMed Web of Science ®Google Scholar
• Kleiman NS, Lincoff AM, Raker GC et al. Early percutaneous coronary intervention, platelet inhibition with eptifibatide, and clinical outcomes in patients with acute coronary syndromes. Circulation 101, 751–757 (2000).
   PubMed Web of Science ®Google Scholar
• The RESTORE Investigators. Effects of platelet glycoproteinblockade withtirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 96, 1445–1453 (1997).
   PubMed Web of Science ®Google Scholar
• The PRISM-PLUS Investigators. Inhibition of the platelet glycoproteinreceptorwith tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl. Med. 338, 1488–1497 (1998).
   PubMed Web of Science ®Google Scholar
• Cannon CP, Weintraub WS, Demopoulos LA et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoproteininhibitor tirofiban.N Engl. J Med. 344, 1879–1887 (2001).
   PubMed Web of Science ®Google Scholar
• Topol EJ, Moliterno DJ, Herrmann HC et al. Comparison of two platelet glycoprotein Hb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl. Med. 344, 1888–1894 (2001).
   PubMed Web of Science ®Google Scholar
• O'Neil WW Serruys P, Knudtson M et al Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization: EXCITE Trial Investigators: Evaluation of oral Xemilofiban In controlling Thrombotic Events. N Engl. J Med. 342, 1316–1324 (2000).
   PubMed Web of Science ®Google Scholar
• Cannon CP, McCabe CH, Wilcox RG et al.Oral glycoproteininhibition withorofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 102, 149–156 (2000).
   PubMed Web of Science ®Google Scholar
• SYMPHONY Investigators. Comparison ofsibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomized trial: Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart Events Post-Acute Coronary Syndromes. Lancet 355, 337–345 (2000).
   PubMed Web of Science ®Google Scholar
• Second SYMPHONY Investigators.Randomized trial of aspirin, sibrafiban, or both for secondary prevention after acute coronary syndromes. Circulation 103, 1727–1733 (2001).
   PubMed Web of Science ®Google Scholar
• Topol EJ, Easton JD, Amarenco P et al.Design of the blockade of the glycoprotein receptor to avoid vascular occlusion (BRAVO) trial. Am. Heart J. 139, 927–933 (2000).
   PubMed Web of Science ®Google Scholar
• Chew DP, Bhatt DL. A meta-analysis of Phase III multicenter randomized trials. Circulation 103,201–206 (2001).
   PubMed Web of Science ®Google Scholar
• •• Meta-analysis demonstrating that treatment with an oral glycoprotein Jib—IIIa antagonist is associated with an increased risk of death.
   Google Scholar
• Holmes MB, Sobel BE, Cannon CP, Schneider DJ. Increased platelet reactivity in patients given orbofiban after an acute coronary syndrome: an OPUS-TIMI 16 substudy. Orbofiban in Patients with Unstable coronary Syndromes. Thrombolysis In Myocardial Infarction. Am. J. Cardiol. 85,491–493 (2000).
   PubMedGoogle Scholar
• ••Pharmacodynamic assessment of plateletfunction in patients treated with orbofiban suggesting a rationale for the increased incidence of mortality in patients treated with an oral glycoprotein Jib—IIIa antagonist. Patients treated with orbofiban had increased platelet reactivity.
   Google Scholar
• Cox D, Smith R, Quinn M, Theroux P, Crean P, Fitzgerald DJ. Evidence of platelet activation during treatment with a GP IIb/IIIa antagonist in patients presenting with acute coronary syndromes. I Am. Coll. Cardiol. 36, 1514–1519 (2000).
   PubMed Web of Science ®Google Scholar
• •Pharmacodynamic assessment of platelet function in patients treated with orbofiban demonstrating increased platelet reactivity in patients treated with orbofiban.
   Google Scholar
• Serrano CV Jr, Nicolau JC, Venturinelli M et al. Role of oral blockade of platelet glycoproteinon neutrophilactivation in patients with acute coronary syndromes. Cardiovasc. Drugs Ther. 17, 129–132 (2003).
   PubMed Web of Science ®Google Scholar