Integrating antithrombin and antiplatelet therapies with early invasive management for non-ST-segment elevation acute coronary syndromes.
ABSTRACT Non-ST-segment elevation acute coronary syndromes are a dramatic manifestation of coronary artery disease. Multiple clinical trials have shown that early cardiac catheterization improves clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes. Many antithrombotic agents effectively manage unstable coronary syndromes and serve as adjuncts to percutaneous coronary intervention. Yet, the growing number of pharmacologic agents makes early management of non-ST-segment elevation acute coronary syndromes increasingly complex. We review the current evidence regarding the optimal integration of early antithrombotic and antiplatelet therapies with early coronary angiography and subsequent revascularization.
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ABSTRACT: Background: Drugs that block platelet–platelet and platelet–fibrin interactions via the IIbβ3 (glycoprotein IIb/IIIa) receptor are used daily in patients undergoing percutaneous coronary interventions. Along with expected increases in spontaneous bleeding, clinical trials have revealed a surprising increase in thrombosis when these drugs are used without other anticoagulants. A better understanding of their mechanisms can minimize these risks. Objectives: This study tested the hypothesis that interventions designed to block fibrinogen binding inevitably leave the IIbβ3 receptor in an activated state. It compared the effects on platelet function and IIbβ3 conformation of the orally active compounds orbofiban and roxifiban, the i.v. agents eptifibatide and tirofiban, and echistatin, an arginine-glycine-aspartate (RGD) disintegrin. Methods: The integrin antagonist concentrations required to saturate platelets and to block platelet–platelet and platelet–fibrin interactions were determined by flow cytometery, aggregometry, and clot-based adhesion assays, respectively. Analytical ultracentrifugation measured each antagonist's effects on the solution structure of IIbβ3. Fluorescence anisotropy provided equilibrium and kinetic data for integrin:antagonist interactions. Results: Both orally active drugs bound more tightly and inhibited platelet aggregation and adhesion to fibrin more effectively than echistatin. Analytical ultracentrifugation yielded this order for perturbing IIbβ3 conformation (priming) and promoting oligomerization (clustering): echistatin > eptifibatide > orbofiban > tirofiban > roxifiban. Roxifiban was also most effective at disrupting the rapidly forming/slowly dissociating IIbβ3:echistatin complex. Conclusions: Our results suggest that the same molecular mechanisms that enable glycoprotein IIb/IIIa inhibitors to bind tightly to the IIbβ3 receptor and block fibrinogen binding contribute to their ability to perturb the resting integrin's conformation, thus limiting the safety and efficacy of both oral and i.v. integrin antagonists.Journal of Thrombosis and Haemostasis 02/2007; 5(3):542 - 550. · 6.08 Impact Factor
- Medicine - Programa de Formación Médica Continuada Acreditado. 11/2004; 9(22).