NOVEL ANTITHROMBOTIC APPROACHES TO CORONARY-ARTERY DISEASE

Current prevention or treatment of coronary thrombosis relies on antiplatelet agents (aspirin), antithrombin agents (heparin), and plasminogen activators (t-PA). The purpose of this review is to describe novel antithrombotic agents in each of these classes and to discuss recent and future clinical trials with the new agents. Whereas aspirin is a cyclo-oxygenase inhibitor, the most promising new antiplatelets are directed at an integrin cell surface receptor-glycoprotein (GP) IIb/IIIa - which represents the final common pathway for platelet aggregation. The monoclonal F(ab) antibody c7E3, a chimeric murine-human immunoglobulin G (IgG) fragment, is the most Intensively studied to date. c7E3 was assessed by the Evaluation of Platelet Monoclonal Antibody to Prevent Ischemic Complications (EPIC) trial in which 2,099 high-risk angioplasty patients were randomized to bolus (placebo) plus infusion (placebo), bolus (c7E3, 0.25 mg/kg) plus infusion (placebo), and bolus (c7E3, 0.25 mg/kg) plus infusion (c7E3, 10 mu g/min; 12 hours). The overall event rate at 30 days was significantly decreased from 12.8% (placebo) to 8.3% (c7E3), a 36% relative reduction (p = 0.009). Integrelin is a cyclic heptapeptide with marked specificity for GP IIb/ IIIa integrin. It was studied during the Integrelin to Manage Platelet aggregation to Prevent Coronary Thrombosis (IMPACT) trial, which enrolled 150 routine coronary intervention patients. At endpoint, overall event rate was reduced from 11.9% (placebo) to 5.6% (integrelin). The much larger (4,010 patients) IMPACT-II trial has just completed enrollment to confirm and extend these encouraging results. Hirudin is the prototype of the direct antithrombins; it binds to the active catalytic site and the substrate recognition she (exosite) of thrombin. Hirulog is a dodecapeptide fashioned after hirudin, and binds to the active site via a Phe-Pro-Arg linker molecule; argatroban and efegatran are active-site inhibitors of thrombin. All these direct thrombin Inhibitors have a potential mechanistic advantage over heparin in that they Inactivate clot-bound thrombin and are not inactivated by platelet factor 4 or heparinase. Large trials of hirudin versus heparin are under way. Two recently evaluated PAs are recombinant PA and prourokinase. Results of clinical trials are encouraging for equivalent or improved infarct vessel patency compared with currently available thrombolytics. Another novel PA is from the vampire bat; it is resistant to PA inhibitor and is highly fibrin selective; clinical trials are imminent.