ASSENT-3 was a randomized but unblinded trial of 6095 patients with STE-AMI who were enrolled within 6 h of AMI onset and assigned to one of three regimens: (i) TNK-tPA and unfractionated heparin (both weight adjusted); (ii) TNK-tPA with the LMWH enoxaparin; or (iii) half-dose TNK-tPA with heparin and full-dose abciximab (146). Enoxaparin was given as a 30 mg iv bolus and 1 mg/kg sc repeated every 12 h until hospital discharge or for 7 d. The first two SC doses could not exceed 100 mg. Unfractionated heparin was dosed according to American College of Cardiology/American Heart Association (ACC/AHA) guidelines (9): 60 U/kg bolus (maximum, 4000 U) and 12 U/kg/h initial infusion (maximum, 1000 U/h), adjusted after 3 h to an aPTT of 50-70 s. With abciximab co-therapy, the heparin dose was further reduced to a 40 mg/kg bolus (maximum 3000 U) followed by a 7 U/kg per h initial infusion (maximum, 800 U/h).
The primary efficacy endpoint of ASSENT-3 was the composite of 30-d mortality and in-hospital reinfarction or refractory ischemia. The primary efficacy plus safety endpoint was the efficacy endpoint plus in-hospital ICH or other major bleeding. The efficacy endpoint was significantly lower in both the enoxaparin (11.4%, p = 0.0002) and the abciximab co-therapy groups (11.1%, p < 0.0001) than the TNK-tPA/heparin group (15.4%) (146). The efficacy plus safety endpoint also was significantly lower with adjunctive enoxaparin (13.7%, p < 0.004) and conjunctive abciximab (14.2%, p = 0.014) than with unfractionated heparin (17.0%) (Fig. 7), although the advantage of combination therapy was not seen in the elderly. A lesser need for urgent coronary interventions was observed with the two experimental therapies.
Fig. 6. Percent risk of death or ICH for full dose rPA or half-dose rPA plus abciximab (rPA + Abx) in the GUSTO-V trial. Data from ref. 145.
Despite the positive composite efficacy result with combination abciximab, there was no mortality benefit (6.6 vs 6.0% for TNK-tPA/heparin control). Moreover, significant adverse interactions of treatment with age (RR = 1.30 for >75 yr vs 0.74 for ^75, p = 0.001) and diabetes (RR = 1.35 with vs 0.74 without diabetes, p = 0.0007) were observed for the efficacy plus safety end point (Fig. 8). More major bleeding complications, transfusions, and thrombocytopenia occurred in the abciximab group (all p < 0.001), and the rates were three times higher in those older than 75 yr.
In contrast, enoxaparin increased bleeding rates only slightly, and no treatment interactions were seen. Taking into account efficacy and safety, TNK-tPA with adjunctive enoxaparin emerged as the best overall therapy. Ease of administration and lack of need for monitoring advantaged enoxaparin over heparin, and greater safety in the elderly and diabetics distinguished it from the abciximab combination.
ENTIRE: a Test of Three-Way Combinations
A combination of half-dose thrombolytic, GP Ilb/IIIa inhibition and enoxaparin was studied in ENTIRE-TIMI 23 (Enoxaparin and TNK-tPA with or without GP IIb/IIIa Inhibitor as Reperfusion strategy in STE MI). Preliminary results were presented at the 2001 European Society of Cardiology meetings. A total of 461 patients were enrolled. Patients tended to have higher rates of ST-segment resolution with enoxaparin vs heparin and with combination therapy vs TNK-tPA alone. Rates of major hemorrhage were higher with TNK-tPA combinations. However, bleeding rates trended lower if enoxaparin was used instead of heparin (5.6 vs 7.8%). Although the study was not powered to detect efficacy, the 30-d rates of MI or death were reduced in the enoxaparin groups (14.9% with TNK-tPA/heparin vs 4.4% with TNK-tPA/enoxaparin and 6.2% with half-dose TNK-tPA/abciximab/heparin vs 4.8% with half-dose TNK-tPA/abciximab/ enoxaparin).
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