Intravenous glycoprotein IIb/IIIa inhibition in non-ST segment elevation acute coronary syndromes

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Abstract

Over recent years, substantial clinical trial evidence regarding glycoprotein IIb/IIIa inhibition for the medical management of non-ST segment elevation acute coronary syndromes has been compiled. Despite being recently advocated for the management of coronary instability within widely accepted guidelines, its use among patients presenting with acute coronary syndromes remains somewhat contentious. Within randomized placebo-controlled trials, uniform efficacy with the glycoprotein IIb/IIIa inhibitors has not been shown, whereas a disturbing excess in adverse events is evident within some trials. Currently, the basis for this heterogeneity of clinical evidence has not been adequately explained. However, evolving insights from clinical trials and basic research have further refined our understanding of glycoprotein IIb/IIIa antagonist therapy and the potential effects beyond the inhibition of the fibrinogen receptor. Likewise, appreciation of the pharmacokinetic characteristics of these agents provides putative explanations for the diverse findings of the randomized trials. Reexamination of the clinical trial data in light of this recent evidence provides a basis for interpreting the marginal results of glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Consideration of these factors may facilitate the optimal clinical application of this class of agents to the management of coronary instability. Copyright Ā© 2001 by W.B. Saunders Company

Progress in Cardiovascular Diseases, Vol. 44, No. 3, (November/December) 2001: pp 195-206

Section snippets

Summary of platelet biology

Before considering the clinical trials, a discussion of the platelet physiology and the glycoprotein IIb/IIIa antagonist pharmacology may provide a biologic basis for interpreting the varied results. Beyond adhesion and aggregation, platelets secrete prothrombotic and proinflammatory cytokines, express adhesion/signaling molecules involved in the inflammatory process, and provide the essential phospholipid membrane that facilitates thrombin generation.[8], [9], [10] As the principle molecule

The glycoprotein IIb/IIIa inhibitor pharmacology

Currently, 3 intravenous glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban) have been approved for clinical use. Owing to the lack of overall efficacy within 2 phase III ACS trials, the development of a fourth agent, lamifiban, has ceased. Similarly, the development of orally active platelet glycoprotein IIb/IIIa inhibitors for chronic platelet inhibition has stalled because of a consistent increase in mortality observed within 5 large-scale randomized clinical trials.18

Clinical trials

Collectively, the clinical experience of the glycoprotein IIb/IIIa inhibitors for the management of non-ST segment elevation myocardial infarction (MI) ACS spans 7 randomized placebo-controlled trials, including over 30,000 patients.[1], [2], [3], [4], [6], [38] These data show an overall benefit associated with the use of glycoprotein IIb/IIIa inhibition in addition to aspirin and unfractionated heparin among high-risk patients presenting with coronary instability.[39], [40] Nevertheless, a

Gender

In comparison with men, an excess rate of adverse outcome often has been observed among women presenting with ACS. Most of this excess risk is attributable to older age and the greater prevalence of cardiac risk factors among women. Nevertheless, gender-related differences in platelet physiology and thrombotic potential have been noted, although the clinical relevance of these differences remains speculative.[46], [47] Approximately 30% of the patients enrolled within the ACS trials have been

Conclusion

Given the diverse spectrum of risk associated with the diagnosis of non-ST segment elevation ACS and the wide array of treatment strategies, the moderate overall benefit observed within the clinical trials of the glycoprotein IIb/IIIa inhibitors is not altogether unexpected. Although some trials show results that remain statistically significant, inclusion of low-risk patients and low rates of PCI in several studies contribute to an overall impression of marginal benefit associated with the use

Acknowledgments

The authors thank Ms. Donna Bressan for her expert editorial assistance in the preparation of this manuscript.

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