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.