The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists.
Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
Shields
D C
DC
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland. dshields@rcsi.ie
Fitzgerald
A P
AP
O'Neill
P A
PA
Muckian
C
C
Kenny
D
D
Moran
B
B
Cannon
C P
CP
Byrne
C E
CE
Fitzgerald
D J
DJ
D000409:Alanine / Q000009:adverse effects* / Q000627:therapeutic use*; D003327:Coronary Disease / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics; D006470:Hemorrhage / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D009203:Myocardial Infarction / Q000097:blood / Q000517:prevention & control; D009204:Myocardial Revascularization; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011110:Polymorphism, Genetic / Q000235:genetics; D011759:Pyrrolidines / Q000009:adverse effects* / Q000627:therapeutic use*; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D013927:Thrombosis / Q000139:chemically induced* / Q000235:genetics*; D016896:Treatment Outcome
D006023:Glycoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011759:Pyrrolidines; C120234:orbofiban; D000409:Alanine