C-2. Clinical trial updates: Direct thrombin inhibitors Major actions of antithrombotic agents Content Points: Aspirin: Mechanism of action involves irreversible inactivation of cyclooxygenase-1, the enzyme that catalyzes the rate-limiting step in thromboxane A2 synthesis.1 Since platelets cannot synthesize additional cyclooxygenase-1 in response, aspirin inhibits thromboxane A2-mediated effects for the lifetime of the platelets (~7-10 days) despite a plasma half-life of only 20 min for aspirin. Thienopyridines (ticlopidine, clopidogrel): inhibit ADP-dependent platelet aggregation.1 They also inhibit platelet responses to a number of other stimuli (eg, platelet-activating factor, collagen, shear stress) and inhibit formation of platelet-monocyte aggregates. Direct thrombin inhibitors: polypeptides that inactivate free thrombin and fibrin-bound thrombin.1 They do not require a cofactor such as antithrombin. Some are specific for the thrombin active site (argatroban, efegatran, inogatran); others also target the fibrinogen-binding site on thrombin (bivalirudin, hirudin). GP IIb/IIIa-receptor inhibitors: Because all platelet activators increase expression of the GP IIb/IIIa receptor, antagonism of this receptor produces potent inhibition of platelet aggregation.1 LMWH: Major actions include potentiation of antithrombin effects, release of tissue-factor-pathway inhibitor (TFPI), and reduction in vWF and factor VIIa levels.1,2 Other effects of LMWH that may contribute to antithrombotic efficacy include interaction with heparin cofactor II, inhibition of the procoagulant effects of leukocytes, promotion of fibrinolysis, reduction of endothelial cell activation, and inhibition of endothelial cell activation 1 Selwyn AP. Prothrombotic and antithrombotic pathways in acute coronary syndromes. Am J Cardiol. 2003. In press. 2 Gerotziafas GT, Zafiropoulos A, Van Dreden P, Karavaggeli E, Goutzoumas N, Nikolaidis P, et al. Inhibition of factor VIIa generation and prothrombin activation by treatment with enoxaparin in patients with unstable angina. Br J Haematol. 2003;120:611-617.

Clinical and bleeding outcomes are summarized in the next slide. Direct thrombin inhibitors in PCI: Peak-activated clotting time by dose (CACHET) Content Points: To assess the role of bivalirudin in contemporary interventional strategies, CACHET (Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial) enrolled 268 patients scheduled for PCI with planned or provisional administration of abciximab.1 Patients were randomized to three sequential phases: Unfractionated heparin ([UFH] with planned abciximab) or bivalirudin (1-mg/kg bolus followed by 4-h infusion at 2.5 mg/kg/h); n = 60 UFH (with provisional abciximab) or bivalirudin (0.5-mg/kg bolus followed by 1.75-mg/kg/h infusion until the end of procedure); n = 129 UFH (with provisional abciximab) or bivalirudin (0.75-mg/kg bolus followed by 1.75-mg/kg/h infusion until the end of procedure); n = 80 The boxes on the slide span the 25th to 75th quartiles of activated clotting time (ACT); vertical lines indicate 10th to 90th quartiles; the line within each box indicates the median value; and the triangle indicates the mean value. In patients who received high-dose bivalirudin plus abciximab, peak ACT levels were an average 150 seconds longer than in patients who received UFH plus abciximab. In patients who received the two lower bivalirudin doses, ACT values were ~40 seconds longer. Clinical and bleeding outcomes are summarized in the next slide. 1 Lincoff AM, Kleiman NS, Kottke-Marchant K, Maierson ES, Maresh K, Wolski KE, Topol EJ. Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: Results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). Am Heart J. 2002;143:847-853.

REPLACE-2: Death, MI, urgent revascularization, major bleeding Content Points: The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial compared two antithrombotic regimens in patients undergoing urgent or elective PCI1: UFH (65-IU/kg bolus) plus either abciximab (0.25-mg/kg bolus, then 0.125-mg/kg/min infusion for 12 h) or eptifibatide (2 X 180-mg/kg boluses, then 2.0-mg/kg/min infusion for 18 h) Bivalirudin (0.75-mg/kg bolus, then 1.75-mg/kg/h infusion for duration of PCI) All patients received aspirin prior to procedure. Pretreatment with clopidogrel was strongly encouraged. The study's objective was to determine if bivalirudin with provisional GP IIb/IIIa inhibition was not inferior to the current standard combination UFH plus GP IIb/IIIa inhibitor with regard to primary outcome: a quadruple composite of death, MI, urgent revascularization, and major bleeding (defined as intracranial, intraocular, or retroperitoneal hemorrhage, clinically overt blood loss resulting in a >3 g/dL decrease in hemoglobin, any decrease in hemoglobin >4 g/dL, or transfusion of >2 units of blood). This outcome occurred in 10.0% and 9.2% of the UFH plus GP IIb/IIIa inhibitor and the bivalirudin groups, respectively, a nonsignificant difference (P = 0.324) Considered separately, rates of death, MI, and urgent revascularization also did not differ significantly between groups Major bleeding occurred in 4.1% and 2.4% of the UFH plus GP IIb/IIIa inhibitor and the bivalirudin groups, respectively (P < 0.001) The REPLACE-2 investigators concluded that bivalirudin with provisional GP IIb/IIIa inhibition is not inferior to UFH plus GP IIb/IIIa inhibitor with regard to suppression of acute ischemic events and is associated with less bleeding. 1 Lincoff AM, Bittl JA, Harrington RA, Feit F, Keilman NS, Jackman JD, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853-863.