The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events.
OBJECTIVE
Despite the success of intravenous glycoprotein IIb/IIIa antagonists, oral formulations have failed to show benefit and have been associated with increased mortality. To understand these findings, we performed a meta-analysis of results from four phase 3 trials.


METHODS
Trials were identified by MEDLINE search; review of abstracts from American College of Cardiology, European Society of Cardiology, and American Heart Association scientific sessions; or querying investigators in the field. Published, phase 3, randomized, placebo-controlled trials involving more than 1000 patients with coronary artery disease that compared an oral glycoprotein IIb/IIIa antagonist with or without background aspirin versus aspirin, and that had a planned follow-up of > or =30 days, were included. Four trials met these criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were generated from results, and combined using an empirical Bayes random-effects model.


RESULTS
Among 33,326 patients, oral glycoprotein IIb/IIIa agents were associated with 31% increased mortality (OR = 1.31; 95% CI: 1.12 to 1.53; P= 0.0001). Results were similar whether the agent was added to (OR = 1.38; 95% CI: 1.15 to 1.67) or substituted for (OR = 1.37; 95% CI: 1.00 to 1.86) aspirin. Ischemic events or sudden death (OR = 1.22; 95% CI: 0.91 to 1.63) were also more common. Among patients with acute coronary syndromes, the incidence of myocardial infarction was increased (OR = 1.16; 95% CI: 1.03 to 1.29).


CONCLUSIONS
Oral glycoprotein IIb/IIIa inhibitor therapy is associated with increased mortality and myocardial infarction. No single explanation for these findings is satisfactory; the problem is likely to be multifactorial.
Newby
L Kristin
LK
Duke Clinical Research Institute, Durham, North Carolina 27707, USA.
Califf
Robert M
RM
White
Harvey D
HD
Harrington
Robert A
RA
Van de Werf
Frans
F
Granger
Christopher B
CB
Simes
R John
RJ
Hasselblad
Vic
V
Armstrong
Paul W
PW
D000284:Administration, Oral; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use*; D003327:Coronary Disease / Q000150:complications / Q000401:mortality / Q000517:prevention & control*; D016757:Death, Sudden, Cardiac; D006801:Humans; D009203:Myocardial Infarction / Q000209:etiology; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic; D017211:Treatment Failure
D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001241:Aspirin