PubMed2002
The best conventional fibrinolytic regimens succeed in restoring unimpeded coronary flow (i.e., TIMI grade 3 reperfusion) in only about 50% of lytic-eligible patients. In experienced hands, percutaneous coronary intervention (angioplasty + stent implantation) can restore TIMI 3 flow in more than 80% of patients; however, it is not universally available, and usually cannot be performed as promptly as fibrinolytic therapy. Researchers now recognize that one key reason fibrinolytic therapy fails is that it does not adequately address the role of platelets in both the initial formation and posttreatment recurrence of coronary thrombus activated, aggregating platelets at the site of plaque fissure or rupture form the core ("white" clot) of an intracoronary thrombus. The platelets contribute to the further development of a meshwork of fibrin, thrombin, and entrapped blood cells ("red" clot), which usually makes up the bulk of an occlusive coronary thrombus. Plasminogen activators, such as alteplase and reteplase, lyse fibrin in the red thrombus but leave the platelet-rich core intact. The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban, and eptifibatide bind to GP IIb/IIIa receptors on the surfaces of activated platelets. By preventing the receptors from binding to fibrinogen (and, hence, to each other) GP IIb/IIIa inhibitors block the "final common pathway" to platelet aggregation. Combining fibrinolysis with GP IIb/IIIa blockade to treat acute myocardial infarction could, theoretically, yield a number of benefits. It would attack both red and white components of the occlusive thrombus, help suppress the thrombotic rebound effect of fibrinolytics by preventing platelet activation in response to newly exposed thrombin, improve reperfusion and microvascular flow, reduce the incidence of postfibrinolytic hemorrhagic stroke (currently approximately 1%) if combination therapy permits use of lower dosages of fibrinolytic agents. Two phase II trials of fibrinolytic therapy plus GP IIb/IIIa blockade have recently been reported. In TIMI 14, the reduced-dose combinations of alteplase plus abciximab produced TIMI 3 rates higher than the control group. In the TIMI 14 reteplase substudy, TIMI 3 flow rates with reteplase at 90 min was 70% for standard dose reteplase alone, 70% for reteplase 5 IU + 5 IU plus abciximab, and 77% for reteplase 10 IU + 5 IU plus abciximab. In the SPEED pilot study the highest TIMI 3 rates was seen with the regimen of 5 IU + 5 IU double-bolus reteplase plus abciximab (54 vs 47%). The findings of both the SPEED and TIMI 14 trials were incorporated into the design of the large (approximately 17,000 patients) GUSTO V mortality trial, which compared standard reteplase therapy with abciximab plus low-dose reteplase. Unfortunately, the results did not confirm the favorable angiographic findings of the phase II trials reported above, because the two strategies showed the same mortality rate at 30-day follow-up. The present review will try to shed light on the "dark side of the moon" of the association between IIb/IIIa inhibitors and fibrinolytic drugs in order to understand the unexpected GUSTO V results, now matched by the ASSENT-3 disappointing results with tenecteplase plus abciximab.