Abstract
Although the hypothesis of benefit from prolonged oral IIb/IIIa inhibition was appealing, the large Phase III trials have uniformly shown there was no improvement in outcome. In addition, there was an increased mortality seen in patients treated with the oral IIb/IIIa inhibitor. This latter finding is not adequately explained, but is likely a multifactorial problem of this strategy of platelet inhibition. The trials found that, even with no improvement in efficacy, there was increased bleeding, meaning that for chronic therapy with IIb/IIIa inhibition there does not appear to be a therapeutic window. Accordingly, chronic oral IIb/IIIa inhibition appears to have been well tested but has not worked. Fortunately, there are several other oral antiplatelet agents available that have shown beneficial results, including clopidogrel. In addition, other newer classes of antiplatelet agents are in earlier stages of development. Thus, agents targeted more “upstream” in platelet activation pathways may offer a more tolerable and efficacious approach to long‐term antiplatelet therapy.
Keywords: platelets, acute coronary syndromes, myocardial infarction, unstable angina, antiplatelet therapy, prognosis, angioplasty
Full Text
The Full Text of this article is available as a PDF (73.9 KB).
References
- 1. Boersma E, Harrington RA, Moliterno DJ, White H, Théroux P, Van de Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML: Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta‐analysis of all major randomised clinical trials. Lancet 2002; 359: 189–198 [DOI] [PubMed] [Google Scholar]
- 2. Newby LK, Califf RM, White HD, Harrington RA, Van de Werf F, Granger CB, Simes RJ, Hasselblad V, Armstrong PW: The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events. Am J Med 2002; 112: 647–658 [DOI] [PubMed] [Google Scholar]
- 3. Cannon CP, McCabe CH, Wilcox RG, Langer A, Caspi A, Bernink P, Lopez‐Sendon J, Toman J, Charlesworth A, Anders RJ, Alexander JC, Skene A, Braunwald E, for the OPUS‐TIMI 16 Investigators : Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS‐TIMI 16) trial. Circulation 2000; 102: 149–156 [DOI] [PubMed] [Google Scholar]
- 4. O'Neill WW, Serruys P, Knudtson M, van Es GA, Timmis GC, van der Zwaan C, Kleiman J, Gong J, Roecker EB, Dreiling R, Alexander J, Anders R, for the EXCITE Trial Investigators : Long‐term treatment with a platelet glycoprotein‐receptor antagonist after percutaneous coronary revascularization. N Engl J Med 2000; 342: 1316–1324 [DOI] [PubMed] [Google Scholar]
- 5. The SYMPHONY Investigators : Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: A randomised trial. Lancet 2000; 355: 337–345 [PubMed] [Google Scholar]
- 6. Second Symphony Investigators : Randomized trial of aspirin, sibrafiban, or both for secondary prevention after acute coronary syndromes. Circulation 2001; 103: 1727–1733 [DOI] [PubMed] [Google Scholar]
- 7. Mousa SA, Khurana S, Forsythe MS: Comparative in vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists on platelet‐mediated clot strength induced by tissue factor with use of thromboelastography: Differentiation among glycoprotein IIb/IIIa antagonists. Arterioscler Thromb Vasc Biol 2000; 20: 1162–1167 [DOI] [PubMed] [Google Scholar]
- 8. 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. Am J Cardiol 2000; 85: 491–493 [DOI] [PubMed] [Google Scholar]
- 9. Casey M, Fornari C, Bozovich G, Iglesias Varela ML, Mautner B, Cannon CP: Increased expression of platelet P‐selectin in patients treated with oral orbofiban in the OPUS TIMI 16 study. Circulation 1999; 100 (suppl. I):I–681 [Google Scholar]
- 10. Peter K, Schwarz M, Ylanne J, Kohler B, Moser M, Nordt T, Salbach P, Kubler W, Bode C: Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (αIIbB3) inhibitors. Blood 1998; 92: 3240–3249 [PubMed] [Google Scholar]
- 11. O'Neill WW, Serruys P, Knudtson M, van Es GA, Timmis GC, van der Zwaan C, Kleiman J, Gong J, Roecker EB, Dreiling R, Alexander J, Anders R: 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 2000; 342: 1316–1324 [DOI] [PubMed] [Google Scholar]
- 12. Cannon CP, McCabe CH, Borzak S, Henry TD, Tischler MD, Mueller HS, Feldman R, Palmeri ST, Ault K, Hamilton SA, Rothman JM, Novotny WF, Braunwald E: Randomized trial of an oral platelet glycoprotein IIb/IIIa antagonist, sibrafiban, in patients after an acute coronary syndrome: Results of the TIMI 12 trial. Thrombolysis in Myocardial Infarction (see comments). Circulation 1998; 97: 340–349 [DOI] [PubMed] [Google Scholar]
- 13. Hughes S: BRAVO trial stopped: Lotrafiban increases mortality. In the‐heart.org (“Heartwire>News”) Conceptis Technologies, 2000.
- 14. Mousa SA, Kapil R, Mu DX: Intravenous and oral antithrombotic efficacy of the novel platelet GPIIb/IIIa antagonist roxifiban (DMP754) and its free acid form, XV459. Arterioscler Thromb Vasc Biol 1999; 19: 2535–2541 [DOI] [PubMed] [Google Scholar]
- 15. Mousa SA, Forsythe M, Bozarth J, Youssef A, Wityak J, Olson R, Sielecki T: XV454, a novel nonpeptide small‐molecule platelet GIIb/IIIa antagonist with comparable platelet alpha(IIb)beta3‐binding kinetics to c7E3. J Cardiovasc Pharmacol 1998; 32: 736–744 [DOI] [PubMed] [Google Scholar]
- 16. Mousa SA, Bozarth JM, Lorelli W, Forsythe MS, Thoolen MJ, Slee AM, Reilly TM, Friedman PA: Antiplatelet efficacy of XV459, a novel nonpeptide platelet GPIIb/IIIa antagonist: Comparative platelet binding profiles with c7E3. J Pharmacol Exp Ther 1998; 286: 1277–1284 [PubMed] [Google Scholar]
- 17. Mousa SA, Bozarth J, Youssef A, Levine B: Oral antiplatelet efficacy of the platelet GPIIb/IIIa antagonist, DMP754 in non‐human primates. Thromb Res 1998; 89: 217–225 [DOI] [PubMed] [Google Scholar]
- 18. Langer A, Goodman SG, Reilly TM, Mousa SA, Racanelli AL, O'Connor C, O'Neill WW, Kleiman NS, Gurbel P, Daly RN: Second generation oral IIb/IIIa receptor blockade: Phase II experience with roxifiban. J Am Coll Cardiol 2000; 35 (suppl. A): 308A 10676674 [Google Scholar]
- 19. Hiatt WR, Dormandy JA, Norgran L, Hirsch A, Creager M, Califf R, Murray G: Roxifiban in the prevention of ischemic events in peripheral arterial disease. Circulation 2002; 106 (suppl. II):II–474 [Google Scholar]
- 20. Giugliano RP, McCabe CH, Sequeira RF, Frey MJ, Henry TD, Piana RN, Tamby J‐F, Jensen BK, Nicholas SB, Jennings LK, Wise RJ, Braunwald E, for the TIMI 15 A and 15B Investigators : First report of an intravenous and oral GP IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: Results of the TIMI 15Aand 15B trials. Am Heart J 2000; 140: 81–93 [DOI] [PubMed] [Google Scholar]
- 21. Muller TH, Weisenberger H, Brickl R, Narjes H, Himmelsbach F, Krause J: Profound and sustained inhibition of platelet aggregation by fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active pro‐drug, lefradafiban, in men. Circulation 1997; 96: 1130–1138 [DOI] [PubMed] [Google Scholar]
- 22. Akkerhuis KM, Neuhaus KL, Wilcox RG, Vahanian A, Boland JL, Hoffmann J, Baardman T, Nehmiz G, Roth U, Klootwijk AP, Deckers JW, Simoons ML: Safety and preliminary efficacy of one month glycoprotein IIb/IIIa inhibition with lefradafiban in patients with acute coronary syndromes without ST‐elevation: A phase II study. Eur Heart J 2000; 21: 2042–2055 [DOI] [PubMed] [Google Scholar]
- 23. Hamm CW, Heeschen C, Goldmann B, Vahanian A, Adgey J, Miguel CM, Rutsch W, Berger J, Kootstra J, Simoons ML, for the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators : Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med 1999; 340: 1623–1629 [DOI] [PubMed] [Google Scholar]
- 24. Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD, for the PRISM Study Investigators : Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 1999; 354: 1757–1762 [DOI] [PubMed] [Google Scholar]
- 25. Chew DP, Bhatt DL, Sapp S, Topol EJ: Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists : A meta‐analysis of phase III multicenter randomized trials. Circulation 2001; 103: 201–206 [DOI] [PubMed] [Google Scholar]
- 26. Quinn MJ, Plow EF, Topol EJ: Platelet glycoprotein IIb/IIIa inhibitors: Recognition of a two‐edged sword? Circulation 2002; 106: 379–385 [DOI] [PubMed] [Google Scholar]
- 27. Cannon CP, McCabe CH, Borzak S, Henry TD, Tischler MD, Mueller HS, Feldman R, Palmeri ST, Ault K, Hamilton SA, Rothman JM, Novotny WF, Braunwald E, for the TIMI 12 Investigators : A randomized trial of an oral platelet glycoprotein IIb/IIIa antagonist, sibrafiban, in patients after an acute coronary syndrome: Results of the TIMI 12 trial. Circulation 1998; 97: 340–349 [DOI] [PubMed] [Google Scholar]
- 28. Kereiakes DJ, Runyon JP, Kleiman NS, Higby NA, Anderson LC, Hantsbarger G, McDonald S, Anders RJ: Differential dose‐response to oral xemilofiban after antecedant intravenous abciximab. Administration for complex coronary intervention. Circulation 1996; 94: 906–910 [DOI] [PubMed] [Google Scholar]
- 29. Nicholson NS, Abood NA, Panzer‐Knodle SG, Frederick LG, Page JD, Salyers AK, Suleymanov OD, Szalony JA, Taite BB, Anders RJ: Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonist. Med Res Rev 2001; 21: 211–226 [DOI] [PubMed] [Google Scholar]
- 30. Harrington RA, Armstrong PW, Graffagnino C, Van De Werf F, Kereiakes DJ, Sigmon KN, Card T, Joseph DM, Samuels R, Granett J, Chan R, Califf RM, Topol EJ: Dose‐finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease. Circulation 2000; 102: 728–735 [DOI] [PubMed] [Google Scholar]
- 31. Serrano CV, Venturinelli M, Ramires JAF, Cannon CP, Nicolau JC: Role of oral blockade of platelet glycoprotein IIb/IIIa on neutrophil‐platelet interactions in patients with acute coronary syndromes. J Am Coll Cardiol 2000; 35 (suppl A): 343A [Google Scholar]
- 32. Adderley SR, Fitzgerald DJ: Glycoprotein IIb/IIIa antagonists induce apoptosis in rat cardiomyocytes by caspase‐3 activation. J Biol Chem 2000; 275: 5760–5766 [DOI] [PubMed] [Google Scholar]