Oral glycoprotein IIb/IIIa inhibitors: why don't they work?
Despite their promise as orally active potent inhibitors of platelet aggregation, the oral platelet glycoprotein IIb/IIIa inhibitors have failed to provide a reduction in late ischemic events. In fact, with five large-scale randomized trials now complete, including over 42 000 patients, these agents have been associated with a surprising, yet consistent, excess in mortality. Peculiarly, this fatality risk has occurred in the absence of a commensurate increase in other ischemic end-points. While these findings have curtailed the further clinical development of this class of potent platelet inhibitors, the obvious dissociation between platelet suppression and adverse outcome requires further clarification. Multiple putative explanations for this excess in ischemic events with oral glycoprotein IIb/IIIa inhibitors have been proposed, but definitive data implicating a specific mechanism are currently not available. While the lack of concurrent aspirin may account for some of this effect, it is unlikely to fully explain the mortality excess. Potential mechanisms include partial agonist activity leading to increased expression of platelet-leukocyte adhesion molecules, sub-optimal inhibition of platelet aggregation, genetic polymorphisms, especially phospholipase A(2) polymorphism, and promotion of cardiac myocyte apoptosis via activation of caspase 3. Definitive elucidation of these adverse mechanisms will be required if further clinical development of the oral platelet glycoprotein IIb/IIIa inhibitors is to be pursued.
Chew
D P
DP
Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Bhatt
D L
DL
Topol
E J
EJ
D000284:Administration, Oral; D017209:Apoptosis / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017202:Myocardial Ischemia / Q000517:prevention & control; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000235:genetics; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic
D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex