title: Continued thromboxane A2 formation despite administration of a platelet glycoprotein IIb/IIIa antagonist in patients undergoing coronary angioplasty.
abstract: Experimental data suggest that formation of thromboxane A2 may be suppressed during administration of a glycoprotein IIb/IIIa antagonist. We determined the dose of one such compound, fradafiban, required to provide > 80% occupancy of the platelet glycoprotein IIb/IIIa and examined its effects on thromboxane A2 formation in patients undergoing PTCA. The dose response to fradafiban and additional effects of aspirin were explored initially in patients with stable coronary artery disease. Fradafiban induced a dose-dependent inhibition of platelet aggregation that correlated with fibrinogen receptor occupancy and plasma drug concentration. Addition of aspirin 300 mg had no effect on these parameters. At the highest dose, mean fibrinogen receptor occupancy was 89.7 +/- 1.2% (n = 3) at 4 hours and platelet aggregation had decreased by 93.4 +/- 2.7%. Eighteen patients undergoing coronary angioplasty were randomized to receive either aspirin 330 mg or that dose of fradafiban producing > 80% fibrinogen receptor occupancy. Platelet aggregation was suppressed throughout the infusion of fradafiban to a greater extent than with aspirin. However, there was a marked increase in urinary excretion of 11-dehydrothromboxane B2 in patients treated with fradafiban: from 1973 +/- 889 to a peak of 9760 +/- 3509 pg/mg creatinine (P = .0046). Despite this evidence of continued platelet activation in vivo, there were no cases of coronary thrombosis. In conclusion, fradafiban suppresses platelet aggregation and may be a useful alternative to aspirin in the prevention of thrombotic events in patients undergoing PTCA. However, there is continued formation of thromboxane A2, which may continue to exert its effects as a potent vasoconstrictor and vascular smooth muscle mitogen.
authors.affiliation: Centre for Cardiovascular Science, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Byrne
authors.forename: N
authors.initials: N
authors.lastname: Moran
authors.forename: M
authors.initials: M
authors.lastname: Maher
authors.forename: N
authors.initials: N
authors.lastname: Walsh
authors.forename: P
authors.initials: P
authors.lastname: Crean
authors.forename: D J
authors.initials: DJ
authors.lastname: Fitzgerald
mesh_terms: D000284:Administration, Oral; D015906:Angioplasty, Balloon, Coronary; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001760:Bleeding Time; D002455:Cell Division; D003327:Coronary Disease / Q000150:complications / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D019007:P-Selectin / Q000096:biosynthesis; D010865:Pilot Projects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000097:blood; D014661:Vasoconstriction
chemical_list: D000925:Anticoagulants; D001713:Biphenyl Compounds; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011759:Pyrrolidines; D013929:Thromboxane B2; D013928:Thromboxane A2; D005340:Fibrinogen; D006493:Heparin; C107917:fradafiban; D001241:Aspirin