(Circulation. 1996;94:866-868.)
© 1996 American Heart Association, Inc.
Articles |
Inhibitors of Platelet Glycoprotein IIb/IIIa Receptors
Will They Be Useful When Given Chronically?
St Luke's Episcopal Hospital/Texas Heart Institute, Houston.
Correspondence to James T. Willerson, MD, St Luke's Episcopal Hospital/Texas Heart Institute, 6720 Bertner Ave, Room B524 (MC1-267), Houston, TX 77030-2697.
Key Words: Editorials • glycoproteins • receptors • platelets
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Introduction |
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 Top Introduction References |
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Inhibitors of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptors prevent platelet aggregation in response to a wide variety of agonists of platelet aggregation, reducing the likelihood of thrombus development at sites of vascular injury.1 2 3 4 A monoclonal antibody (7E3, Coller antibody, or ReoPro) given to high-risk patients undergoing coronary artery angioplasty, including those with unstable angina, recent myocardial infarction, and complicated coronary artery stenoses, reduced the risk of myocardial infarction and the need for a second interventional procedure in the initial 30 days after the procedure and reduced the need for a second interventional procedure in the following 6 months.5 6 This same antibody also reduced the risk of development of myocardial infarction and continuing rest angina in patients with unstable angina.4 Synthetic peptide inhibitors of GP IIb/IIIa receptors have been modestly protective to date,7 and it is not clear whether their less marked protective effect than ReoPro has been the result of less-than-optimal dosing or because ReoPro blocks fibronectin receptors in addition to its GP IIb/IIIa receptor inhibition. In this issue of Circulation, Theroux et al8 demonstrate that a nonpeptide inhibitor of GP IIb/IIIa receptors reduces the risk of continuing unstable angina, death, and nonfatal myocardial infarction and the need for interventional procedures in patients with unstable angina, and Kereiakes et al9 describe an altered dose-effectiveness of an oral GP IIb/IIIa inhibitor when given after ReoPro.
Protection by inhibition of GP IIb/IIIa receptors should be anticipated from a knowledge of the pathophysiology of conversion from stable to unstable angina and myocardial infarction.10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Constantinides,21 Falk et al,22 and Davies and Thomas23 have shown that atherosclerotic plaque fissuring and ulceration in the "culprit artery" are found in patients with unstable angina and acute myocardial infarction. Plaque fissuring and ulceration may be a consequence of release of metalloproteinases from inflammatory cells present in plaques with thin fibrous caps and adjacent lipid pools.22 24 Our group and others have shown that the conversion from stable to unstable angina is associated with platelet aggregation at sites of vascular injury and constriction and the release of mediators promoting further platelet aggregation and vasoconstriction, including thromboxane A2, serotonin, ADP, and platelet-activating factor (Figure
).10 11 12 13 14 15 16 17 18 19 20 Thrombin, oxygen-derived free radicals, endothelin, and tissue factor also accumulate at the same sites25 (K. Fujise, L. Stacy, P. Beck, E. Yeh, A. Chuang, T. Brock, J.T. Willerson, unpublished observations, 1996) and together with the relative depletion of normally present endothelial inhibitors of thrombus development and vasoconstriction, including tissue plasminogen activator, NO, and prostacyclin, create a potent prothrombotic environment. Most of the platelet-aggregating mediators that accumulate at sites of atherosclerotic plaque fissuring/ulceration are also vasoconstrictors and mitogens. Increases in platelet-derived mediators and of thrombin and oxygen-derived free radicals promote the expression of other growth factors, including platelet-derived and fibroblast growth factors. By antagonizing most of the prothrombotic effects of the agonists and attenuating platelet aggregation and substantial mediator accumulation, an inhibitor of the platelet GP IIb/IIIa receptors should provide considerable protection against the development of myocardial infarction and its consequences. One would predict that an effective and safe orally available inhibitor of GP IIb/IIIa receptors should provide substantial protection at the time of atherosclerotic plaque fissuring/ulceration or other injury that predisposes to thrombosis. One might also predict that such an inhibitor would be superior to any antagonist that inhibits only one mediator, including aspirin. Additional controlled clinical trials will be necessary to determine whether the oral inhibitor of platelet GP IIb/IIIa receptors described in the reports by Theroux et al8 and Kereiakes et al9 will prove to be effective.
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However, since the protection provided against thrombosis and myocardial infarction/death has not been complete, one needs to ask additional questions about this class of inhibitors. The answers to these questions will help determine and shape future clinical strategies designed to prevent unstable angina/myocardial infarction/cerebrovascular accidents and their consequences. These questions are listed below.
1. Is the vasoconstrictor effect of mediators that are not platelet-derived, ie, thrombin and endothelin, important in the pathophysiology of progression from stable to unstable angina with atherosclerotic plaque fissuring/ulceration and with other types of endothelial injury or dysfunction?
2. Is the platelet-aggregating effect of thrombin effectively neutralized in vivo by the GP IIb/IIIa receptor inhibitors? If the in vivo effects of thrombin and/or endothelin remain a factor with the administration of GP IIb/IIIa inhibitors, a thrombin and/or endothelin inhibitor may also be needed.
3. How many platelet GP IIb/IIIa receptor sites need to be occupied to provide protection against thrombosis but minimize the risk of bleeding?
4. Does chronic dosing with a GP IIb/IIIa receptor antagonist change its efficacy, possibly by upregulating the number of receptors or some other mechanism?
5. Does the protective effect of ReoPro, in both the short and the longer term, relate in part to its antagonism of fibronectin receptors?
6. Does aspirin add to the protective effect of a GP IIb/IIIa receptor antagonist, possibly by inhibiting platelet–white blood cell interaction or by diminishing subsequent inflammation at sites of vascular injury?
7. Is additional protection against vascular thrombosis and its complications provided by lipid lowering and a GP IIb/IIIa receptor antagonist?
8. Is there an additional protective role for inhibitors of platelet adhesion that antagonize platelet glycoprotein Ib receptors with a relatively low risk of bleeding?
The earlier EPIC study, the evaluation of ReoPro and integrelin in patients with unstable angina, earlier experimental work, and now the studies by Theroux et al and Kereiakes et al with a nonpeptide inhibitor of GP IIb/IIIa receptors provide optimism for the potential utility of GP IIb/IIIa receptor antagonists in protecting patients with acute coronary syndromes against vascular thrombosis. The answers to the questions posed above may help in developing this class of agents to their greatest protective capability.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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