Building a Stronger Foundation: Improved Antithrombin Therapy with Bivalirudin in Percutaneous Coronary Intervention


William Knopf, MD

Heparin has served an important role in percutaneous coronary interventions (PCI) as the standard antithrombin agent since the procedure was first introduced. Modifications in heparin therapy and technological advancements have improved procedure-related outcomes considerably. Weight-adjustment and lowering of the heparin dose or duration of therapy has resulted in reduced bleeding complications, and some of the therapeutic limitations of heparin have been overcome by adding thienopyridines and glycoprotein (GP) IIb/IIIa receptor inhibitors to reduce ischemic complications associated with PCI by inhibiting platelet function.

Nevertheless, ischemic and bleeding complications remain a substantial clinical and economic problem among the PCI population. This is particularly true among high-risk patients, for whom heparin is far from an ideal antithrombin agent. These high-risk patients include: 1) patients with ongoing thrombosis or acute coronary syndromes (ACS) where heparin is unable to inhibit clot-bound thrombin and may actually increase platelet aggregation; 2) patients with demographic risk factors that predispose them to high risk of bleeding; 3) patients with renal impairment who may experience both relatively high ischemic and bleeding rates; 4) patients at risk of iatrogenic thrombocytopenia; and 5) situations where heparin is used with aspirin and thienopyridines, but no GP II/IIIa inhibitor is used.

Bivalirudin, a reversible direct thrombin inhibitor that demonstrates potent but reversible suppression of thrombin’s protease actions as well as its direct cellular platelet activation, is the most promising replacement for heparin among the novel anticoagulants. In this supplement, Jeff Weitz reviews the pivotal importance of thrombin on both coagulation and platelet aggregation, outlines the mechanisms responsible for heparin limitations and how direct thrombin inhibitors overcome these limitations. Jonathan Marmur reviews the evidence for use of heparins (indirect thrombin inhibitors) and direct thrombin inhibitors during PCI, comparing the pharmacokinetic and pharmacodynamic properties of each agent as well as clinical outcomes of direct versus indirect thrombin inhibitors. Domenic Sica discusses the important implications of renal impairment in patients undergoing PCI, the pathophysiological changes associated with renal impairment, and the evidence supporting each of the current therapeutic options available to the interventional cardiologist. Timothy Henry reviews the characteristics related to intracoronary thrombus formation among patients with ACS undergoing PCI and demonstrates a need to replace heparin as the foundation anticoagulant in these high-risk patients. Procedure-related bleeding complications and their inherent relationship to the underlying risk profile of various patient populations undergoing PCI is reviewed by Frank Aguirre as he considers the potential role of bivalirudin in reducing procedure-related hemorrhagic events in selected patient populations. The review by Bruce Lewis focuses on drug-induced platelet abnormalities, the incidence, risks and contributors to thrombocytopenia, and strategies to lessen this risk. Finally, the frequency and cost of PCI complications in clinical trials and actual practice and potential improvements in patient management and anticoagulation therapy that might impact total costs of PCI is examined by Mauro Moscucci.

Improved thrombin inhibition — dealing with all thrombin’s functions including platelet activation — remains a key pharmacological goal if we are to further reduce procedure-related complications of PCI. To date, most pharmacotherapeutic improvement strategies have been “add-on”; e.g., augmenting and overcoming heparin’s limitations by adding thienopyridines and GP IIb//IIIa receptor inhibitors. There is increasing evidence that these add-on strategies build excellent antiplatelet therapy on a rather shaky foundation of inadequate antithrombin inhibition. Worse still, heparin may be compounding the problem by promoting platelet activation. Particularly among patients with high-risk characteristics, our heparin foundations may fail. Replacement of heparin with an improved antithrombin such as bivalirudin provides a more secure anticoagulation foundation, including inhibition of thrombin-mediated platelet aggregation.

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