Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis

Abstract

Background: We evaluated the effects of a novel platelet fibrinogen receptor antagonist, Integrelin, and a direct thrombin inhibitor, recombinant hirudin, given together with recombinant tissue plasminogen activator (rTPA) in a canine experimental model of intracoronary thrombosis. We tested the hypothesis that combination of both agents at low doses would have an additive antithrombotic effect, resulting in a significant improvement in the efficacy of rTPA. Methods and Results: Thirty-two dogs with an electrically induced coronary thrombus were treated with rTPA (1 mg/kg over 20 minutes) together with one of the following adjunctive treatments in a random fashion. Eight dogs received saline for 90 minutes; Integrelin (5 μg · kg-1 · min-1 for 90 minutes) was given to 8 dogs; 8 dogs received recombinant hirudin (20 μg · kg-1 · min-1 for 90 minutes); and 8 dogs were treated with a low-dose combination of Integrelin (2.5 μg · kg-1 · min-1) plus recombinant hirudin (10 μg · kg-1 · min-1) for 90 minutes. Integrelin or recombinant hirudin, when given as single adjunct to rTPA, enhanced the lysis of the occlusive thrombus, causing full restoration of coronary blood flow (100% of its baseline value) for 29±16 and 26±5 minutes, respectively, whereas coronary blood flow was fully restored for only 5±1 minutes in dogs receiving rTPA plus saline (both P