Antman E M, Giugliano R P, Gibson C M, McCabe C H, Coussement P, Kleiman N S, Vahanian A, Adgey A A, Menown I, Rupprecht H J, Van der Wieken R, Ducas J, Scherer J, Anderson K, Van de Werf F, Braunwald E
Brigham and Women's Hospital, Boston, MA, USA.
Circulation. 1999 Jun 1;99(21):2720-32. doi: 10.1161/01.cir.99.21.2720.
The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI.
Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 microg. kg-1. min-1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U. kg-1. h-1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U. kg-1. h-1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion (P<0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U. kg-1. h-1) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%; P=0.0009) and 90 minutes (77% versus 62%; P=0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70).
Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.
心肌梗死溶栓治疗（TIMI）14试验检验了如下假设：阿昔单抗（一种针对血小板糖蛋白（GP）IIb/IIIa受体的单克隆抗体的Fab片段）可有效且安全地添加至降低剂量的溶栓方案中，用于治疗ST段抬高型心肌梗死。
症状发作后12小时内就诊的ST段抬高型心肌梗死患者（n = 888）服用阿司匹林，并随机分为两组，一组接受100mg加速剂量的阿替普酶（对照组），另一组单独使用阿昔单抗（静脉推注0.25mg/kg，随后12小时静脉输注0.125μg·kg-1·min-1），或与降低剂量的阿替普酶（20至65mg）或链激酶（500000U至1500000U）联合使用。对照组患者接受标准体重调整剂量的肝素（静脉推注70U/kg；静脉输注15U·kg-1·h-1），而接受含阿昔单抗方案治疗的患者接受低剂量肝素（静脉推注60U/kg；静脉输注7U·kg-1·h-1）。单独接受加速阿替普酶治疗的患者90分钟时TIMI 3级血流率为57%，单独使用阿昔单抗的患者为32%，阿昔单抗联合500000U至1250000U链激酶治疗的患者为34%至46%。随着阿替普酶给药时间延长，从单纯静脉推注到静脉推注后30分钟或60分钟输注，60分钟和90分钟时TIMI 3级血流率均更高（P<0.02）。最有前景的方案是50mg阿替普酶（静脉推注15mg；60分钟内静脉输注35mg），该方案90分钟时TIMI 3级血流率为76%，随后与低剂量或极低剂量（静脉推注30U/kg；静脉输注4U·kg-1·h-1）肝素联合进行了测试。50mg阿替普酶加阿昔单抗组60分钟（72%对43%；P = 0.0009）和90分钟（77%对62%；P = 0.02）时TIMI 3级血流率显著高于单纯阿替普酶组。单独接受阿替普酶治疗的患者（n = 235）大出血发生率为6%，单独使用阿昔单抗的患者为3%（n = 32），链激酶加阿昔单抗的患者为10%（n = 143），50mg阿替普酶加阿昔单抗和低剂量肝素的患者为7%（n = 103），50mg阿替普酶加阿昔单抗和极低剂量肝素的患者为1%（n = 70）。
阿昔单抗可促进溶栓速度和程度，与通常剂量一半的阿替普酶联合使用时可使TIMI 3级血流率早期显著增加。阿替普酶再灌注改善的同时并未增加大出血风险。大幅降低肝素剂量可能进一步降低出血风险。阿昔单抗与链激酶联合使用时TIMI 3级血流率有适度改善，但出血风险增加。
