The term “thrombolytic” therapy is somewhat of a misnomer, as these agents act principally to cleave the fibrin molecule and, in doing so, expose substantial amount of thrombin, one of the most potent prothrombotic moieties known. So, while these agents are fibrinolytic, acting to cleave the culprit fibrin clot, they may be creating a prothrombotic milieu, theoretically resulting in reocclusion of an IRA that had transiently been rendered patent.

The recent impressive success of the platelet GP IIb/IIIa inhibitors in the treatment of ACS and as adjuvant therapy in the setting of PTCA and intracoronary stenting has led to their consideration as potential agents to enhance the efficacy of fibrinolytic therapy. The fact that the thrombin exposed during fibrinolysis is one of the most potent activators of platelet aggregation further supports the utilization of these potent platelet inhibitors in the development of new pharmacologic treatment strategies aimed at increasing IRA patency rates without significantly increased risk of complications.

To date, several dose finding studies and treatment trials are complete or underway. TIMI 14, one of the earliest of these studies, investigated the combination of abciximab and reduced dose tPA or SK with IV heparin and consisted of both dose finding and dose confirmation phases [1]. The study included a control arm which consisted of treatment with accelerated dose (100mg) tPA. Reduced doses of tPA from 20 to 65mg in combination with a bolus (0.25mg/kg) plus 12hr infusion (0.125mcg/kg/min) of abciximab. All patients underwent angiography at 90 minutes.

Preliminary analyses reveal that abciximab alone resulted in a 32% TIMI-III flow rate at 90 min (similar to that of full dose SK alone as seen in the early lytic trials). SK + abciximab resulted in 39-47% 90min TIMI-III flow (dose dependent). The SK arm was subsequently abandoned due to excess bleeding complications. All of the tested doses of tPA plus abciximab demonstrated a significant enhancement in the time to TIMI-III flow and the 50mg dose given as a 15mg bolus plus 35mg infusion over 60min resulted in 79% TIMI-III flow at 90min. No increase in major bleeding or intracranial hemmorhage over the control arm was noted. This preliminary trial strongly suggested that the addition of abciximab to the reduced dose tPA regimen led to more prompt restoration of TIMI-III flow in a greater number of cases without a significant increase in major bleeding complications.

A second phase of TIMI-14 is studying the combination of abciximab and reduced dose rPA. The control arm is a double bolus (10u + 10u) of rPA. Preliminary results suggest that the combination of abciximab and either the longer acting reteplase (rPA) given as a double bolus or reduced dose Alteplase (tPA) given as a bolus and 60min infusion resulted in similar improvement in patency of the IRA.

Similarly, GUSTO-IV is investigating the combination of rPA and abciximab in the treatment of patients with unstable angina and non-ST-elevation MI. The dose finding study suggests that the rate of patency is related to the rPA dose and that the combination therapy compares favorably to tPA alone (from meta analysis data). SPEED, the GUSTO-IV pilot study, was similiar in design to TIMI-14, but enrolled patients within 6hrs of symptom onset rather than 12hrs as in TIMI-14. Also, patients were taken to angiography at 60min in SPEED and 90min in TIMI-14. The dose escalation phase was followed by a dose confirmation phase where split dose (5u+5u) of rPA in combination with full dose abciximab and low dose heparin resulted in 63% TIMI-III flow in the IRA at 60min. Abciximab alone yielded 29% TIMI-III flow at 60min.

The large scale GUSTO-IV study will study the combination of low dose rPA, abciximab and low dose heparin in 17,000 patients. The primary endpoint is 30day mortality and the hypothesis is that the combination therapy will either reduce mortality, complications, or both as compared to full dose fibrinolytic therapy.

Concurrently, the INTRO-AMI trial is studying the combination of eptifibatide, reduced dose tPA and heparin in AMI in a prospective randomized fashion. The study plans to enroll 400 patients to assess whether patency is improved at 60 and 90min.

Finally, the IMPACT-AMI and PARADIGM trials in unstable angina and non-Qwave MI, combining eptifibatide and Lamifiban respectively with full dose tPA or full dose tPA or SK respectively have both suggested benefit in AMI and ACS. Unfortunately, the IMPACT-MI data is somewhat difficult to interpret as the dose of eptifibatide was likely too low as an assay artifact resulted in a dose 50% of necessary to yield an 80% inhibition of platelet aggregation [2].

Nonetheless, certain dose combinations yielded an 80% TIMI-III flow rate and no excess of bleeding complications was noted in the combined group. Sample sizes were too small to make any definitive statements regarding dosing or superiority of the combined regimens. The PARADIGM data is interesting in that while there was no short term benefit over lytic therapy alone, the 6 month analysis suggested a 40% decrease in recurrent events in the low dose Laimfiban combination treatment group [3].

Clearly, these data are still preliminary and not substantiated adequately to make definitive statements regarding these combination therapies for AMI. However, given the pathophysiology of the syndrome and the promise of these preliminary and pilot studies, it seems very likely that future pharmacologic treatment of AMI will include not only a fibrinolytic agent but a potent anti-platelet agent as well.

1. Antman EM, Guigliano RP, Gibson CM, et al. Abciximab Facilitates the Rate and Extent of the Thrombolysis: Results of the Thrombolysis in Myocardial Infarction (TIMI) 14 Trial. Circulation 1999: 99: 2720-2732.

2. Ohman EM, Kleiman NS, Gacioch G, et al. Combined accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein Iib/IIIa Integrin Receptor Blockade With Integrelin in Acute Myocardial Infarction. Circulation 1997; 95: 846-854.

3. The PARADIGM Investigators. J Am Coll Cardiol 1998; 32: 2003-2010.


Last modified: October 14, 1999 (PL)





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