Combination Pharmacotherapy

The goal of improving coronary arterial patency, microcirculatory blood flow, and myocardial perfusion represents the essence of fibrinolytic–adjunctive therapy combinations. Because fibrinolytic resistance, patency without perfusion, and reocclusion are platelet-mediated phenomena, considerable emphasis has been placed on the development of platelet antagonists. Coronary arterial thrombi consist of platelets and fibrin bound in a tightly packed meshwork. Platelets modify the intrinsic properties of the fibrin network, causing changes in permeability and vasoelasticity, which decrease fibrinolysis rates. The addition of aspirin and the glycoprotein (GP) IIb/IIIa receptor antagonist abciximab modulates the interaction of platelets and fibrin, improving both accessibility to fibrinolytics and the overall rates of fibrinolysis (Collet et al., 2001). The Thrombolysis in Myocardial Infarction (TIMI) 14 trial (Antman et al., 1999) randomized 888 patients with ST-segment elevation myocardial infarction (MI) to receive (1) accelerated tissue plasminogen activator (tPA; ≤100 mg) plus standard dose of unfractionated heparin (UFH); (2) tPA (920 mg bolus) plus abciximab (0.25 mg/kg bolus, 7 μg/min); (3) streptokinase (800,000 to 1.5 million units) and low-dose UFH; or (4) abciximab plus low-dose UFH. TIMI 3 flow rates 90 minutes from treatment initiation were 52%, 53%, 42%, and 32%, respectively. In subsequent dose/strategy studies, a combination of tPA (35 mg) plus abciximab and tPA (15 mg bolus, 31 mg over 60 minutes) plus abciximab revealed 63% and 73% TIMI 3 flow rates, respectively. Rates of major hemorrhage were similar in all tPA treatment groups. The Strategies for Patency Enhancement in the Emergency Department (SPEED) trial (SPEED Group, 2000) included two phases. Phase A (n = 241) randomized patients to receive either abciximab (bolus plus infusion) alone or combined with 5 U, 7.5 U, 10 U, 5 U + 2.5 U, or 5U + 5 U of reteplase. Phase B tested the best strategy from phase A (abciximab plus 5 U + 5 U of reteplase) against 10 U + 10 U of reteplase. In phase A, 62% of the abciximab–reteplase 5 U + 5 U patient group had TIMI 3 flow rates at 60 to 90 minutes vs. 27% of those given abciximab alone (p = .001).