Skip Navigation

European Heart Journal 2000 21(24):2042-2055; doi:10.1053/euhj.2000.2309
Copyright © 2000 by the European Society of Cardiology.
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (17)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Akkerhuis, K. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Akkerhuis, K. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

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

K. M. Akkerhuisa,b,f1, K.-L. Neuhausc,f3, R. G. Wilcoxd, A. Vahaniane, J.-L. Bolandf, J. Hoffmanng, T. Baardmanh, G. Nehmizg, U. Rothg, A. P. J. Klootwijka, J. W. Deckersa,b and M. L. Simoonsa Fibrinogen Receptor Occupancy STudy (FROST) Investigatorsf2

a Thoraxcenter, Erasmus University and University Hospital Rotterdam, The Netherlands
c Städtische Kliniken Kassel, Germany
d Queen's Medical Centre, University Hospital Nottingham, United Kingdom
e Hopital Tenon, Paris, France
f Hopital de la Citadelle, Liege, Belgium
g Boehringer Ingelheim Pharma KG, Germany
h Boehringer Ingelheim BV, The Netherlands
b Cardialysis BV, Clinical Research Management and Core Laboratories, Rotterdam, The Netherlands

revised June 26, 2000; accepted June 28, 2000

Abstract

Aims Oral glycoprotein IIb/IIIa inhibitors might enhance the early benefit of an intravenous agent and prevent subsequent cardiac events in patients with acute coronary syndromes. We assessed the safety and preliminary efficacy of 1 month treatment with three dose levels of the oral GP IIb/IIIa blocker lefradafiban in patients with unstable angina or myocardial infarction without persistent ST elevation.

Methods The Fibrinogen Receptor Occupancy STudy (FROST) was designed as a dose-escalation trial with 20, 30 and 45mg lefradafiban t.i.d. or placebo. Five hundred and thirty-one patients were randomized in a 3:1 ratio to lefradafiban or placebo in a double-blind manner. Efficacy was assessed by the incidence of death, myocardial infarction, coronary revascularization and recurrent angina. Safety was evaluated by the occurrence of bleeding classified according to the TIMI criteria and by measuring clinical laboratory parameters.

Results There was a trend towards a reduction in cardiac events with lefradafiban 30mg when compared with placebo and lefradafiban 20mg. The benefit was particularly apparent in patients with a positive (≥0·1ng.ml–1) troponin I test at baseline and less so in those with a negative test result. In patients receiving lefradafiban, the cardiac event rate decreased with increasing minimal levels of fibrinogen receptor occupancy. There was a dose-dependent increase in the incidence of bleeding: the composite of major or minor bleeding occurred in 1% of placebo patients, 5% of patients receiving lefradafiban 20mg and in 7% of patients receiving 30mg, with an excessive risk (15%) in the 45mg group which resulted in early discontinuation of this dose level. Gingival and arterial or venous puncture site bleedings were most common and accounted for more than 60% of all haemorrhagic events. There was an increased incidence of neutropenia (neutrophils <1·5x109/l) in the lefradafiban groups (5·2% vs 1·5% in the placebo group), which did not result from bone marrow depression but rather from a reversible redistribution of neutrophils by margination or clustering.

Conclusion One month's treatment with the oral glycoprotein IIb/IIIa inhibitor lefradafiban in patients with unstable angina and myocardial infarction without persistent ST elevation resulted in a decrease in cardiac events with lefradafiban 30mg and a dose-dependent increase in haemorrhagic events. The observed favourable trend towards a reduction in cardiac events in patients with elevated troponin levels requires confirmation in a large clinical trial.

Key Words: Unstable angina, myocardial infarction, lefradafiban, glycoprotein IIb/IIIa blockers, platelet aggregation inhibitors

f1 Correspondence: K. Martijn Akkerhuis, MD, Cardialysis BV, P.O. Box 2125, 3000 CC Rotterdam, The Netherlands.

f3 Professor Neuhaus has died since the acceptance of this paper.

f2 Investigators and study organization of the Fibrinogen Receptor Occupancy STudy are listed in the Appendix. {dagger}Professor Neuhaus has died since the acceptance of this paper.

References

  1. Davies MJ, Thomas AC. Plaque fissuring—the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985;53:363–373[Free Full Text]
  2. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250[Web of Science][Medline]
  3. Ambrose JA, Weinrauch M. Thrombosis in ischemic heart disease. Arch Intern Med. 1996;156:1382–1394[Abstract/Free Full Text]
  4. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med. 1995;332:1553–1559[Free Full Text]
  5. N Engl J Med. 1994;330:956–961[Abstract/Free Full Text]
  6. Lancet. 1997;349:1429–1435[CrossRef][Web of Science][Medline]
  7. N Engl J Med. 1997;336:1689–1696[Abstract/Free Full Text]
  8. Lancet. 1997;349:1422–1428[CrossRef][Web of Science][Medline]
  9. Circulation. 1997;96:1445–1453[Abstract/Free Full Text]
  10. Lancet. 1998;352:87–92[Web of Science][Medline]
  11. N Engl J Med. 1998;338:1498–1505[Abstract/Free Full Text]
  12. N Engl J Med. 1998;338:1488–1497[Abstract/Free Full Text]
  13. N Engl J Med. 1998;339:436–443[Abstract/Free Full Text]
  14. Tanguay J-F. Do differences in pharmacology of platelet glycoprotein IIb/IIIa inhibitors affect clinical outcomes. Eur Heart J Supplements. 1999;1:E27–35
  15. Ronner E, Dykun Y, Van den Brand MJBM, Van der Wieken LR, Simoons ML. Platelet glycoprotein IIb/IIIa receptor antagonists. An asset for treatment of unstable coronary syndromes and coronary intervention. Eur Heart J. 1998;19:1608–1616[Free Full Text]
  16. Lancet. 1996;347:561–568[CrossRef][Web of Science][Medline]
  17. Circulation. 1994;89:1545–1556[Abstract/Free Full Text]
  18. Merlini PA, Bauer KA, Oltrona L. Persistent activation of the coagulation system in unstable angina and myocardial infarction. Circulation. 1994;90:61–68[Abstract/Free Full Text]
  19. Ault KA, Cannon CP, Mitchell J. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1999;33:634–639[Abstract/Free Full Text]
  20. Müller 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 prodrug, lefradafiban, in men. Circulation. 1997;96:1130–1138[Abstract/Free Full Text]
  21. Van den Brand MJBM, Baardman T, Suryapranata H. Initial experience with BIBU 104XX; a new, oral glycoprotein IIb/IIIa receptor blocker. Eur Heart J. 1997;18:244
  22. Klootwijk P, Meij S, van Es Ga. Comparison of usefulness of computer assisted continuous 48-h 3-lead with 12-lead ECG ischaemia monitoring for detection and quantitation of ischaemia in patients with unstable angina. Eur Heart J. 1997;18:931–940[Abstract/Free Full Text]
  23. Klootwijk P, Meij S, Melkert R, Lenderink T, Simoons ML. Reduction of recurrent ischemia with abciximab during continuous ECG-ischemia monitoring in patients with unstable angina refractory to standard treatment (CAPTURE). Circulation. 1998;98:1358–1364[Abstract/Free Full Text]
  24. Rao AK, Pratt C, Berke A. Thrombolysis in Myocardial Infarction (TIMI) Trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11:1–11[Abstract]
  25. Landefeld CS, McGuire E, Rosenblatt MW. A bleeding risk index for estimating the probability of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med. 1990;89:569–578[CrossRef][Web of Science][Medline]
  26. Cannon CP, McCabe CH, Borzak S. 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[Abstract/Free Full Text]
  27. Kereiakes DJ, Kleiman NS, Ferguson JJ. Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial. Circulation. 1998;98:1268–1278[Abstract/Free Full Text]
  28. O'Neill WW, Serruys P, Knudtson M. Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. N Engl J Med. 2000;342:1316–1324[Abstract/Free Full Text]
  29. Cannon CP, McCabe CH, Wilcox RG. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation. 2000;102:149–156[Abstract/Free Full Text]
  30. Lancet. 2000;355:337–345[CrossRef][Web of Science][Medline]
  31. George JN, Caen JP, Nurden AT. Glansmann's thrombasthenia: the spectrum of clinical disease. Blood. 1990;75:1383–1395[Free Full Text]
  32. Lincoff AM, Tcheng JE, Califf RM. Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3 Fab) during percutaneous coronary revascularization. Am J Cardiol. 1997;79:286–291[CrossRef][Web of Science][Medline]
  33. Coller BS. Monitoring platelet GP IIb/IIIa antagonist therapy. Circulation. 1998;97:5–9[Free Full Text]
  34. Smith JW, Steinhubl SR, Lincoff AM. Rapid platelet-function assay: an automated and quantitative cartridge-based method. Circulation. 1999;99:620–625[Abstract/Free Full Text]
  35. Yeh SP, Hsueh EJ, Wu H, Wang YC. Ticlopidine-associated aplastic anemia. A case report and review of literature. Ann Hematol. 1998;76:87–90[CrossRef][Web of Science][Medline]
  36. Lancet. 1999;354:701–707[CrossRef][Web of Science][Medline]
  37. Lancet. 1999;354:708–715[CrossRef][Web of Science][Medline]
  38. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. FRISC study group. J Am Coll Cardiol. 1997;29:43–48[Abstract]
  39. Ohman EM, Armstrong PW, Christenson RH. Cardiac Troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med. 1996;335:1333–1341[Abstract/Free Full Text]
  40. Antman EM, Tanasijevic MJ, Thompson B. Cardiac-specific Troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;335:1342–1349[Abstract/Free Full Text]
  41. Hamm CW, Meinertz T, Berger J, Kreymann G, Heeschen C, Goldmann BU. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med. 1997;337:1648–1653[Abstract/Free Full Text]
  42. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death: autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation. 1985;71:699–708[Abstract/Free Full Text]
  43. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation. 1986;73:418–427[Abstract/Free Full Text]
  44. Heeschen C, Van den Brand MJ, Hamm CW, Simoons ML. Angiographic findings in patients with refractory unstable angina according to troponin T status. Circulation. 1999;100:
  45. Hamm CW, Heeschen C, Goldmann B. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med. 1999;340:1623–1629[Abstract/Free Full Text]
  46. Hamm CW, Heeschen C, Goldmann BU, White HD. Benefit of tirofiban in high-risk patients with unstable angina identified by troponins in the PRISM trial. Circulation. 1999;18:4092
  47. Peter K, Straub A, Kohler B. Platelet activation as a potential mechanism of GP IIb/IIIa inhibitor-induced thrombocytopenia. Am J Cardiol. 1999;84:519–524[CrossRef][Web of Science][Medline]
  48. Peter K, Schwarz M, Ylanne J. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa ({alpha}IIBß3) inhibitors. Blood. 1998;92:3240–3249[Abstract/Free Full Text]
  49. Vorchheimer DA, Fuster V. Oral platelet glycoprotein IIb/IIIa receptor antagonists: the present challenge is safety. Circulation. 1998;97:312–314[Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Crit Care NurseHome page
K. E. Sandau and M. Smith
Continuous ST-Segment Monitoring: 3 Case Studies in Progressive Care
Crit. Care Nurse, October 1, 2009; 29(5): 18 - 27.
[Full Text] [PDF]

Home page
 JAMAHome page
Additional Information
JAMA, March 15, 2006; 295(11): E1 - E6.
[Full Text] [PDF]

Home page
 Eur Heart JHome page
F.W.G. Leebeek, E. Boersma, C.P. Cannon, F.J.J. van de Werf, and M.L. Simoons
Oral glycoprotein IIb/IIIa receptor inhibitors in patients with cardiovascular disease: why were the results so unfavourable
Eur. Heart J., March 2, 2002; 23(6): 444 - 457.
[Full Text] [PDF]

Home page
 Eur Heart JHome page
K.M. Akkerhuis, P.A.J. Klootwijk, W. Lindeboom, V.A.W.M. Umans, S. Meij, P.-P. Kint, and M.L. Simoons
Recurrent ischaemia during continuous multilead ST-segment monitoring identifies patients with acute coronary syndromes at high risk of adverse cardiac events; meta-analysis of three studies involving 995 patients
Eur. Heart J., November 1, 2001; 22(21): 1997 - 2006.
[Abstract] [PDF]

Home page
 Eur Heart JHome page
R. Curtin and D.J. Fitzgerald
A cold start for oral glycoprotein IIb/IIIa antagonists
Eur. Heart J., December 2, 2000; 21(24): 1992 - 1994.
[PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (17)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Akkerhuis, K. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Akkerhuis, K. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?