Overcoming heparin limitations in high-risk percutaneous coronary intervention: The alternative strategy - Replacing heparin with bivalirudin

Multiple factors predict the risk of ischemic complications following percutaneous coronary intervention (PCI). Many of these high-risk characteristics are related to intracoronary thrombus formation. The indirect thrombin inhibitor heparin does not inhibit fibrin-bound thrombin due to stereochemical constraints. Consequently, heparin is relatively ineffective in the presence of intracoronary thrombus. Patients with acute coronary syndrome (ACS) may also experience heparin resistance due to the drug's inhibition by platelet factor-IV, or non-specific heparin binding to other acute phase reactants. The effectiveness of heparin may also be reduced among specific patient groups (elderly, females, extreme body mass) and disease states (diabetes, chronic kidney disease), which are associated with hypercoagulability and arterial dysfunction - also linked to an increased incidence of intracoronary thrombosis. In recent years, the pharmacological and clinical limitations of heparin have been addressed by adding potent antiplatelet inhibitors [thienopyridines and glycoprotein (GP) IIb/IIIa inhibitors] to heparin and aspirin. This increases the risk of bleeding and results in the need to reduce the dose of heparin, potentially compounding its relative lack of effectiveness in highrisk PCI. An alternative strategy to overcome heparin resistance is to replace heparin with more effective and safer antithrombin agents. Direct thrombin inhibitors are superior to heparin for the prevention of death or myocardial infarction (MI) in patients with ACS. In a recent meta-analysis of 35,970 patients, direct thrombin inhibitors were associated with a lower risk of death or MI (4.3% versus 5.1%; odds ratio, 0.85; 95% CI, 0.77-0.94; p = 0.001). Subgroup analyses suggested a benefit of direct thrombin inhibitors in trials of both ACS and PCI, but the benefit was restricted to bivalent inhibitors. Among the agents that were more effective than heparin, only bivalirudin also demonstrated a reduced risk of bleeding. Three direct thrombin inhibitors have been studied in PCI trials: argatroban, desirudin (Revasc) and bivalirudin (Angiomax). Argatroban is available for use in patients with heparin-induced thrombocytopenia, but has not shown improvements in clinical outcome compared to heparin in randomized trials. Lepirudin is also available for HITS patients, but with no available data in PCI and evidence of increased bleeding risk compared to heparin. Desirudin has shown improved effectiveness compared to heparin in high-risk patients undergoing PCI, but with no reduction in the risk of bleeding. Desirudin is not currently available for clinical use in the United States. Bivalirudin is a reversible direct thrombin inhibitor that has been tested in a series of randomized PCI trials. Data from these trials demonstrate substantial improvements in therapeutic ratio compared to heparin. In particular, analysis of high-risk subgroups, including patients who are elderly, female, abnormally heavy or light in weight, diabetic, renally impaired or ACS including post-infarction and refractory unstable angina, demonstrates an improved therapeutic ratio with both reduced ischemic complications and reduced bleeding complications of PCI. Bivalirudin appears to be an excellent agent to improve the antithrombotic foundation in these high-risk patients.